Donald W. Weaver

Colloid (mucinous noncystic) carcinoma of the pancreas

In the past, colloid (mucinous noncystic) carcinoma (CC) of the pancreas had been included under the category of ordinary ductal adenocarcinoma, a tumor with a dismal prognosis, or was frequently misdiagnosed as mucinous cystadenocarcinoma. The clinicopathologic features of CC have not yet been well characterized, because most cases on record have been parts of studies on either mucinous cystic neoplasms (MCN) or intraductal papillary mucinous neoplasms (IPMN), with which colloid carcinomas are frequently associated. To determine the clinicopathologic characteristics of CC, 17 pancreatic tumors composed predominantly (>80%) of CC (defined as nodular extracellular mucin lakes with scanty malignant epithelial cells) and in which the invasive carcinoma measured larger than 1 cm were studied. Ten of these were originally classified as mucinous ductal adenocarcinoma and four as mucinous cystadenocarcinoma. The mean age of the patients was 61 years; 9 were men and 8 were women. The mean size of the CC was 5.3 cm (range, 1.2–16 cm). In more than half of the patients, CC represented the invasive component of an IPMN (in nine cases) or MCN (in one case). The tumors were composed of well-defined pools of mucin with sparse malignant cells in various patterns of distribution. Signet-ring cells floating in the mucin (but not as individual cells infiltrating stroma, a characteristic finding of signet-ring cell adenocarcinomas) were commonly identified and were prominent in five cases. Perineurial invasion was noted in six cases and regional lymph node metastases in eight. Mutation in codon 12 of the k-ras gene was detected in only 4 of 12 cases studied and p53 mutation in 2 of 9. Immunohistochemical and histochemical mucin stains suggested luminalization of the basal aspects of the cells. Five-year survival was 57%. At an overall mean follow up of 57 months, 10 patients were alive with no evidence of disease (median, 79 mos), including four with lymph node metastasis, three others with perineurial invasion, and another with vascular invasion. Four patients died of disease (18, 18, 25, and 26 mos), and three died of thromboembolism (with persistent disease) at 2, 5, 10 months. All seven patients who died with or of tumor had undergone incisional biopsy of the tumor either before the operation or intraoperatively, whereas none of the patients who were alive had incisional biopsy. When compared with 82 cases of resectable ordinary ductal adenocarcinoma on whom follow-up and staging information was complete, it was found that the patients with CC present with larger tumors (p = 0.03) but lower stage (p = 0.01). The prognosis of CC is significantly better: 2-year and 5-year survival are 70% versus 28% and 57% versus 12%, respectively (p = 0.001). In conclusion, pancreatic CC may occur with or without an identifiable IPMN and MCN component, and should be distinguished from mucinous cystadenocarcinoma, ordinary ductal adenocarcinoma, and signet-ring cell adenocarcinoma. CC of the pancreas is associated with a significantly better prognosis than ordinary ductal adenocarcinoma. In addition to its distinctive morphologic and clinical characteristics, CC of the pancreas also appears to have a low incidence of mutation in codon 12 of the k-ras gene. In cases with a clinical suspicion of colloid carcinoma, the possibility that an incisional biopsy may contribute to thromboembolic complications or even dissemination of the tumor may need to be considered. The luminalization of the basal aspects of the tumor cells may be the cause of stromal mucin accumulation that characterizes colloid carcinoma and may act as a containing factor.

Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma

Pancreatic carcinoma is considered among the most chemoresistant of human malignancies. The most commonly used cytotoxic single agents, 5‐fluorouracil and 2′‐deoxy‐2′,2′‐difluorocytidine (gemcitabine), have objective response rates of less than 10% in large studies. Hypothesizing noncross resistance and a synergistic interaction between gemcitabine and cisplatin, early clinical studies have demonstrated significant activity with this combination in patients with several types of malignant disease. A Phase II study was undertaken to determine the efficacy of gemcitabine in combination with cisplatin in patients with locally advanced and metastatic pancreatic carcinoma based on these considerations.

Impaired Pulmonary Function after Albumin Resuscitation from Shock

The effects of albumin supplementation on pulmonary function were studied in 94 injured patients of whom 46 received albumin. The 94 patients received an average of 14.5 transfusions, 9.2 L crystalloid, and 0.9 L plasma in the emergency room and operating room; 46 patients received an average of 31 gm albumin during operation and 150 gm/day for 5 days. Blood pressure (BP), pulse, CVP, wedge pressure (PWP), red cell (RBCV), and plasma volumes (PV), total serum proteins (TSP), serum albumin (SA), cardiac output (CO), the per cent inspired oxygen/arterial O2 tension (FIO2/pO2), and the per cent of physiologic shunting in the lungs (p shunt) were noted serially following operation; only the first study on each patient was used for statistical correlations between the two groups. Albumin supplementation significantly (p =

Ritonavir blocks AKT signaling, activates apoptosis and inhibits migration and invasion in ovarian cancer cells

BackgroundOvarian cancer is the leading cause of mortality from gynecological malignancies, often undetectable in early stages. The difficulty of detecting the disease in its early stages and the propensity of ovarian cancer cells to develop resistance to known chemotherapeutic treatments dramatically decreases the 5-year survival rate. Chemotherapy with paclitaxel after surgery increases median survival only by 2 to 3 years in stage IV disease highlights the need for more effective drugs. The human immunodeficiency virus (HIV) infection is characterized by increased risk of several solid tumors due to its inherent nature of weakening of immune system. Recent observations point to a lower incidence of some cancers in patients treated with protease inhibitor (PI) cocktail treatment known as HAART (Highly Active Anti-Retroviral Therapy).ResultsHere we show that ritonavir, a HIV protease inhibitor effectively induced cell cycle arrest and apoptosis in ovarian cell lines MDH-2774 and SKOV-3 in a dose dependent manner. Over a 3 day period with 20 μM ritonavir resulted in the cell death of over 60% for MDAH-2774 compared with 55% in case of SKOV-3 cell line. Ritonavir caused G1 cell cycle arrest of the ovarian cancer cells, mediated by down modulating levels of RB phosphorylation and depleting the G1 cyclins, cyclin-dependent kinase and increasing their inhibitors as determined by gene profile analysis. Interestingly, the treatment of ritonavir decreased the amount of phosphorylated AKT in a dose-dependent manner. Furthermore, inhibition of AKT by specific siRNA synergistically increased the efficacy of the ritonavir-induced apoptosis. These results indicate that the addition of the AKT inhibitor may increase the therapeutic efficacy of ritonavir.ConclusionOur results demonstrate a potential use of ritonavir for ovarian cancer with additive effects in conjunction with conventional chemotherapeutic regimens. Since ritonavir is clinically approved for human use for HIV, drug repositioning for ovarian cancer could accelerate the process of traditional drug development. This would reduce risks, limit the costs and decrease the time needed to bring the drug from bench to bedside.

Sulforaphane induces cell cycle arrest by protecting RB-E2F-1 complex in epithelial ovarian cancer cells

BackgroundSulforaphane (SFN), an isothiocyanate phytochemical present predominantly in cruciferous vegetables such as brussels sprout and broccoli, is considered a promising chemo-preventive agent against cancer. In-vitro exposure to SFN appears to result in the induction of apoptosis and cell-cycle arrest in a variety of tumor types. However, the molecular mechanisms leading to the inhibition of cell cycle progression by SFN are poorly understood in epithelial ovarian cancer cells (EOC). The aim of this study is to understand the signaling mechanisms through which SFN influences the cell growth and proliferation in EOC.ResultsSFN at concentrations of 5 - 20 μM induced a dose-dependent suppression of growth in cell lines MDAH 2774 and SkOV-3 with an IC50 of ~8 μM after a 3 day exposure. Combination treatment with chemotherapeutic agent, paclitaxel, resulted in additive growth suppression. SFN at ~8 μM decreased growth by 40% and 20% on day 1 in MDAH 2774 and SkOV-3, respectively. Cells treated with cytotoxic concentrations of SFN have reduced cell migration and increased apoptotic cell death via an increase in Bak/Bcl-2 ratio and cleavage of procaspase-9 and poly (ADP-ribose)-polymerase (PARP). Gene expression profile analysis of cell cycle regulated proteins demonstrated increased levels of tumor suppressor retinoblastoma protein (RB) and decreased levels of E2F-1 transcription factor. SFN treatment resulted in G1 cell cycle arrest through down modulation of RB phosphorylation and by protecting the RB-E2F-1 complex.ConclusionsSFN induces growth arrest and apoptosis in EOC cells. Inhibition of retinoblastoma (RB) phosphorylation and reduction in levels of free E2F-1 appear to play an important role in EOC growth arrest.

MicroRNA-101 Inhibits Growth of Epithelial Ovarian Cancer by Relieving Chromatin-Mediated Transcriptional Repression of p21 waf1/cip1

ABSTRACTPurposeMicroRNA-101 (miR-101) expression is negatively associated with tumor growth and proliferation in several solid epithelial cancers. Enhancer of zeste homolog 2 (EzH2) appears to be a functional target of miR-101. We explore the role of miR-101 and its interaction with EzH2 in epithelial ovarian carcinoma (EOC).MethodsIn situ hybridization (ISH) for miR-101 was performed on EOC patient tissues and normal controls. EOC cell lines were transfected with miR-101 and subjected to growth analysis and clonogenic assays. Cell motility was assessed by Boyden chamber and wound-healing assays. P21waf1/cip1 and EzH2 interaction was assessed by Chromatin Immunoprecipitation (ChIP) assay in MDAH-2774 cells. SCID mice were assessed for tumor burden after injection with miR-101 or control vector-treated MDAH-2774 cells.ResultsISH analysis revealed a decrease in miR-101 expression in EOC compared with normal tissue. MiR-101 re-expression in EOC cell lines resulted in increased apoptosis, decreased cellular proliferation, invasiveness, and reduced growth of tumor xenografts. CHIP assays revealed that re-expression of miR-101 inhibited the interaction of EzH2 with p21waf1/cip1 promoter.ConclusionsMiR-101 re-expression appears to have antitumor effects, providing a better understanding of the role of miR-101 in EOC.

Analysis of hyperamylasemia in patients with severe head injury

To evaluate the influence of severe head injury (SHI) on amylase activity, we studied the amylase profile of 60 patients with SHIs and Glasgow Coma Scores 2 SD above the normal mean were considered elevated. All SHI patients were comatose; 14 died. In the SHI group, TA increased in 23 patients, PA increased in 40, and NPA increased in 14. The source of hyperamylasemia was PA in 14, NPA in one, and mixed in 8 patients. While PA increases occurred throughout the study, NPA elevations occurred early. These increases did not correlate with shock (BP < 80 mm Hg; 17 patients), facial trauma (24 patients), or associated injury (29 patients). On Day 7 postinjury, the mean TA (215 du%) and the mean PA (203.8 du%) were significantly elevated in the SHI patients compared to controls (122.1 du%, P < 0.05, Wilcoxons rank sum test). These data indicate that serum amylase is not a reliable index of pancreatic injury in patients with SHI. Severe head injury and multiple trauma activate pathways that increase amylase levels in the blood, suggesting a central nervous system regulation of serum amylase levels.

The number of lymph nodes identified in a simple pancreatoduodenectomy specimen: comparison of conventional vs orange-peeling approach in pathologic assessment

Lymph node status is one of the most important predictors of survival in resectable pancreatic ductal adenocarcinoma; therefore, thorough lymph node evaluation is a critical assessment in pancreatoduodenectomy specimens. There is considerable variability in pancreatoduodenectomy specimens processed histologically. This study compares two approaches of lymph node dissection and evaluation (standard vs orange peeling) of pancreatoduodenectomy specimens. A different approach to dissection of pancreatoduodenectomy specimens was designed to optimize lymph node harvesting: All peripancreatic soft tissues were removed in an orange-peeling manner before further dissection of the pancreatic head. This approach was applied to 52 consecutive pancreatoduodenectomy specimens performed for ductal adenocarcinoma at two institutions. Specimen dissection was otherwise performed routinely. Overall number of lymph nodes harvested, number of positive lymph nodes, and their anatomic distribution were analyzed and compared with cases that had been dissected by the conventional approach. The mean number of lymph nodes identified by the orange-peeling approach was 14.1 (by institution, 13.8 and 14.4), as opposed to 6.1 (by institution, 7 and 5.3) in cases processed by conventional approach (P=0.0001). The number of lymph node-positive cases also increased substantially from 50% (by institution, 54 and 46%) in the conventional method to 73% (by institution, 88 and 58%) in the orange-peeling method (P=0.02). The orange-peeling method of lymph node harvest in pancreatoduodenectomy specimens for ductal adenocarcinoma enhances overall and positive lymph node yield and optimizes ductal adenocarcinoma staging. Therefore, lymph node harvest by the orange-peeling method should be performed routinely before specimen sectioning in assessment of pancreatoduodenectomy for ductal adenocarcinoma.

Serum amylase and its isoenzymes: A clarification of their implications in trauma

Previous reports on the use of the serum amylase level to assess pancreatic injury in patients with blunt abdominal trauma have been disappointing. The availability of methods to measure the serum isoamylases (P & NP) might be expected to improve the accuracy with which the serum amylase level is used. Sixty-one patients treated for a variety of blunt trauma injuries were studied. All categories of injury were included. Isoamylase levels were determined from admission sera and were compared to injuries found at laparotomy. Three patients had major pancreatic injury but only two of these patients showed a rise in the pancreatic isoamylase. Sixteen additional patients had a rise in the pancreatic isoamylase without evidence of pancreatic injury. Eight of these patients had no component of abdominal injury whatsoever. Two patients with isolated head injury had substantial elevations of pancreatic isoamylase. The regulation of serum amylase is multifactorial and variable. The measurement of serum isoamylase levels does not offer great improvement over the serum amylase in evaluating patients with blunt abdominal trauma.

High 2-deoxy-2-[18F]fluoro-D-glucose accumulation in a case of retroperitoneal fibrosis following resection of carcinoid tumor.

Positron emission tomography (PET) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) has been shown to be a highly sensitive diagnostic tool to stage, restage, and monitor the progress of various neoplasms. A number of physiological and non-neoplastic conditions, however, also may be associated with focal accumulation of FDG and can cause false-positive results. This work reports a 52-year-old man who had marked FDG accumulation in carcinoid tumor of the distal ileum. The tumor was resected. A follow-up FDG-PET scan one and a half years later revealed intense FDG accumulation in the abdominal periaortic region, suggesting recurrent malignancy. Computerized tomography (CT) of the abdomen showed soft tissue mass surrounding the aorta. Fine-needle aspiration biopsy of the periaortic soft tissue confirmed benign retroperitoneal fibrosis. This case shows that retroperitoneal fibrosis can cause intense FDG accumulation giving false impression of malignancy. In interpretation of whole-body FDG-PET, various physiological and benign causes of FDG accumulation must be considered in order to avoid pitfalls. The authors have reviewed the literature and discussed association of carcinoid tumor and retroperitoneal fibrosis.