Aram N. Demirjian

Predominant Bcl-XL Knockdown Disables Antiapoptotic Mechanisms: Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Based Triple Chemotherapy Overcomes Chemoresistance in Pancreatic Cancer Cells In vitro

Pancreatic cancer is lethal because of its invasiveness, rapid progression, and profound resistance to chemotherapy and radiation therapy. To identify the molecular mechanisms underlying this, we have examined the expression and potency of three major death receptors: tumor necrosis factor receptor (TNF-R), TNF-related apoptosis-inducing ligand receptor (TRAIL-R), and Fas in mediating cytotoxicity in four invasive pancreatic cancer cell lines. We have analyzed the expression of major antiapoptotic factors, cell cycle regulators and death receptor decoys (DcR) in comparison with normal pancreas tissues and five other human malignant tumor cell lines. We have found that different pancreatic cancer cell lines coexpress high-level TRAIL-R, Fas, and TNF-R1 but are strongly resistant to apoptosis triggered by the death receptors. DcR2 and DcR3 overexpression may partly contribute to the resistance of pancreatic cancer cells to TRAIL-R- and Fas-mediated cytotoxicity. Bcl-XL and Bcl-2 are predominantly overexpressed in pancreatic cancer cell lines, respectively. Bcl-XL is also predominantly overexpressed in prostate, colorectal, and intestinal cancer cells. The knockdown of the predominant Bcl-XL overexpression significantly reduces the viability of pancreatic cancer cells to TNFalpha- and TRAIL-mediated apoptosis by sublethal-dose single and combined antitumor drugs, including geldanamycin, PS-341, Trichostatin A, and doxorubicine. Geldanamyin and PS-341 synergistically block NFkappaB activation, suppress Akt/PKB pathway, and down-regulate Bcl-XL, Bcl-2, cIAP-1, and cyclin D1 expression. This combined regimen dramatically enhances TRAIL cytotoxic effects and breaks through chemoresistance. Bcl-XL plays a vital role in pancreatic cancer chemoresistance. Geldanamycin, PS-341, and TRAIL triple combination may be a novel therapeutic strategy for pancreatic cancer.

Epidemiology of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancer, accounting for between 85% and 90% of these malignancies. The overall prognosis of patients with liver cancer is poor, and an understanding of this disease and its risk factors is crucial for screening at-risk individuals, early recognition, and timely diagnosis. Most HCCs arise in the background of chronic liver disease caused by hepatitis B virus, hepatitis C virus, and chronic excessive alcohol intake. These underlying causes are characterized by marked variations in geography, gender, and other well-documented risk factors, some of which are potentially preventable.

Surgery for gallstone ileus: a nationwide comparison of trends and outcomes.

Introduction:Gallstone ileus is a mechanical bowel obstruction caused by a biliary calculus originating from a bilioenteric fistula. Because of the limited number of reported cases, the optimal surgical method of treatment has been the subject of ongoing debate. Methods:A retrospective review of the Nationwide Inpatient Sample from 2004 to 2009 was performed for gallstone ileus cases treated surgically by enterotomy with stone extraction alone (ES), enterotomy and cholecystectomy with fistula closure (EF), bowel resection alone (BR), and bowel resection with fistula closure (BF). Patient demographics, hospital factors, comorbidities, and postoperative outcomes were reported. Multivariate analysis was performed comparing mortality, morbidity, length of stay, and total cost for the different procedure types. Results:Of the estimated 3,452,536 cases of mechanical bowel obstruction from 2004 to 2009, 3268 (0.095%) were due to gallstone ileus—an incidence lower than previously reported. The majority of patients were elderly women (>70%). ES was the most commonly performed procedure (62% of patients) followed by EF (19% of cases). In 19%, a bowel resection was required. The most common complication was acute renal failure (30.44% of cases). In-hospital mortality was 6.67%. On multivariate analysis, EF and BR were independently associated with higher mortality than ES [(odds ratio [OR] = 2.86; confidence interval [CI]: 1.16–7.07) and (OR = 2.96; CI: 1.26–6.96) respectively]. BR was also associated with a higher complication rate, OR = 1.98 (CI: 1.13–3.46). Conclusions:Gallstone ileus is a rare surgical disease affecting mainly the elderly female population. Mortality rates appear to be lower than previously reported in the literature. Enterotomy with stone extraction alone appears to be associated with better outcomes than more invasive techniques.

Infiltrating Hepatocellular Carcinoma: Seeing the Tree through the Forest

IntroductionHepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. It is traditionally difficult to cure, especially when discovered at later stages, making early diagnosis and intervention of paramount importance. HCC typically arises in the background of chronic liver disease and can have various morphologic appearances. One of the most difficult of these to recognize on early surveillance imaging is the infiltrative subtype, which can account for up to 13% of all HCC cases, and may be more closely associated with background hepatitis B infection.DiscussionCertain imaging characteristics can provide vital clues, including differing signal intensity on the T1 and T2 sequences of magnetic resonance imaging (MRI) and the presence/appearance of portal vein thrombus. Owing to the diffuse and infiltrating properties of this tumor, surgical resection and transplantation are rarely if ever viable therapeutic options. Other forms of liver-directed therapy have been attempted with limited success, having minimal efficacy and high morbidity. To date, there is no data available to determine if the various HCC subtypes respond to systemic therapy differently, so this may be the most reasonable approach. Left untreated, observed patients commonly progress to hepatic failure fairly rapidly.ConclusionInfiltrative HCC can be extremely subtle, and therefore difficult to detect, especially in the background of cirrhosis. Providers caring for patients with hepatitis, chronic liver disease, and cirrhosis must be extremely vigilant in the evaluation of surveillance imaging in order to potentially discover this HCC subtype as early as possible and initiate a multidisciplinary treatment plan.

Vascular reconstruction plays an important role in the treatment of pancreatic adenocarcinoma

OBJECTIVE Previous studies have proved the feasibility of performing a pancreaticoduodenectomy (Whipple operation) in patients with portal vein-superior mesenteric vein and hepatic artery invasion. We report our institutional experience with the use of a variety of vascular reconstructive methods during pancreatic resections for adenocarcinoma. METHODS A retrospective review was performed identifying all patients undergoing a Whipple operation or total pancreatectomy procedure from January 2003 to December 2013. All venous (portal vein-superior mesenteric vein) and arterial (superior mesenteric artery-hepatic artery) reconstructions were extracted and reviewed to determine survival and perioperative complications. RESULTS During the 10-year study period, 270 Whipple and total pancreatectomy procedures were performed, of which 183 were for adenocarcinoma of the pancreas. Of the 183 operations, a total of 60 (32.8%) vascular reconstructions were found, 49 venous and 11 arterial. Venous reconstruction included 37 (61.7%) primary repairs, four (6.7%) reconstructions with CryoVein (CryoLife, Inc, Kennesaw, Ga), three (5.0%) repairs with autologous vein patch, three (5.0%) autologous saphenous reconstructions, and two (3.33%) portacaval shunts. In addition, there were 11 (18.3%) arterial reconstructions (seven hepatic artery and four superior mesenteric artery). The 1-year survival for all reconstructions was 71.1%, which is equivalent to T3 lesions that did not receive vascular reconstruction (70.11%), with a median survival time of 575.28 days and 12 patients still alive. Survival time was comparable with each type of venous reconstruction, averaging 528 days (11 of 49 patients still alive). There was a total thrombosis rate of seven of 60 (11.6%), all of which were portal vein thrombosis: three in the primary repair group and four delayed thromboses seen in primary repair, CryoVein repair, and vein patch repair. There was no thrombosis in any patients after arterial reconstruction. CONCLUSIONS An aggressive approach for stage II pancreatic cancers with venous or arterial invasion can be performed with comparable results when it is executed by an experienced institution with skilled oncologic and vascular surgeons.

Assessing the Accuracy and Readability of Online Health Information for Patients With Pancreatic Cancer

IMPORTANCE The degree to which patients are empowered by written educational materials depends on the texts readability level and the accuracy of the information provided. The association of a websites affiliation or focus on treatment modality with its readability and accuracy has yet to be thoroughly elucidated. OBJECTIVE To compare the readability and accuracy of patient-oriented online resources for pancreatic cancer by treatment modality and website affiliation. DESIGN An online search of 50 websites discussing 5 pancreatic cancer treatment modalities (alternative therapy, chemotherapy, clinical trials, radiation therapy, and surgery) was conducted. The websites affiliation was identified. Readability was measured by 9 standardized tests, and accuracy was assessed by an expert panel. MAIN OUTCOMES AND MEASURES Nine standardized tests were used to compute the median readability level of each website. The median readability scores were compared among treatment modality and affiliation categories. Accuracy was determined by an expert panel consisting of 2 medical specialists and 2 surgical specialists. The 4 raters independently evaluated all websites belonging to the 5 treatment modalities (a score of 1 indicates that <25% of the information is accurate, a score of 2 indicates that 26%-50% of the information is accurate, a score of 3 indicates that 51%-75% of the information is accurate, a score of 4 indicates that 76%-99% of the information is accurate, and a score of 5 indicates that 100% of the information is accurate). RESULTS The 50 evaluated websites differed in readability and accuracy based on the focus of the treatment modality and the websites affiliation. Websites discussing surgery (with a median readability level of 13.7 and an interquartile range [IQR] of 11.9-15.6) were easier to read than those discussing radiotherapy (median readability level, 15.2 [IQR, 13.0-17.0]) (P = .003) and clinical trials (median readability level, 15.2 [IQR, 12.8-17.0]) (P = .002). Websites of nonprofit organizations (median readability level, 12.9 [IQR, 11.2-15.0]) were easier to read than media (median readability level, 16.0 [IQR, 13.4-17.0]) (P < .001) and academic (median readability level, 14.8 [IQR, 12.9-17.0]) (P < .001) websites. Privately owned websites (median readability level, 14.0 [IQR, 12.1-16.1]) were easier to read than media websites (P = .001). Among treatment modalities, alternative therapy websites exhibited the lowest accuracy scores (median accuracy score, 2 [IQR, 1-4]) (P < .001). Nonprofit (median accuracy score, 4 [IQR, 4-5]), government (median accuracy score, 5 [IQR, 4-5]), and academic (median accuracy score, 4 [IQR, 3.5-5]) websites were more accurate than privately owned (median accuracy score, 3.5 [IQR, 1.5-4]) and media (median accuracy score, 4 [IQR, 2-4]) websites (P < .004). Websites with higher accuracy were more difficult to read than websites with lower accuracy. CONCLUSIONS AND RELEVANCE Online information on pancreatic cancer overestimates the reading ability of the overall population and lacks accurate information about alternative therapy. In the absence of quality control on the Internet, physicians should provide guidance to patients in the selection of online resources with readable and accurate information.

Gd-EOB-DTPA-Enhanced MRI for Detection of Liver Metastases from Colorectal Cancer: A Surgeon’s Perspective!

Colorectal cancer affects over one million people worldwide annually, with the liver being the most common site of metastatic spread. Adequate resection of hepatic metastases is the only chance for a cure in a subset of patients, and five-year survival increases to 35% with complete resection. Traditionally, computed tomographic imaging (CT) was utilized for staging and to evaluate metastases in the liver. Recently, the introduction of hepatobiliary contrast-enhanced magnetic resonance imaging (MRI) agents including gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Eovist in the United States, Primovist in Europe, or Gd-EOB-DTPA) has proved to be a sensitive method for detection of hepatic metastases. Accurate detection of liver metastases is critical for staging of colorectal cancer as well as preoperative planning.

The Subspecialization of Surgery: A Paradigm Shift

General surgery has become increasingly fragmented into subspecialties and diseases previously treated by general surgeons are now managed by “specialists”. The Resident Education Committee of the Society for Surgery of the Alimentary Tract (SSAT) has reviewed the history of surgical training and factors that have contributed to this evolution to subsepcialization. As it is unlikely that this paradigm shift is reversible, a clear understanding of the contributing factors is essential. Herein, we present a timeline and taxonomy of forces in this evolution to subspecialization.

Refining indications for contemporary surgical treatment of renal cell carcinoma metastatic to the pancreas

BACKGROUND The pancreas is a rare location for metastatic disease, with only 2-11% of all pancreatic tumours being of non-primary origin. It is also uncommon for renal cell carcinoma (RCC) to metastasize to the pancreas (1-3% of cases) and, when it does, it typically occurs substantially after index nephrectomy. It is not known whether all pancreatic metastases need be resected because todays chemo- and biological therapies are increasingly effective in controlling advanced disease. METHODS Six patients with a variety of symptoms are discussed. Four patients presented with recurrent gastrointestinal bleeding, ranging from occult to life-threatening in severity. RESULTS The four patients with gastrointestinal bleeding had RCC metastases that had eroded into the duodenum and were successfully controlled by palliative pancreaticoduodenectomy or completion pancreatectomy. The other two patients were treated using different chemotherapeutic or biological agents. CONCLUSIONS Renal cell carcinoma metastases to the pancreas typically occur long after index nephrectomy. Although clinical presentation is variable, palliative resection should be reserved for those who develop complications, such as upper gastrointestinal bleeding, and, in other series, obstructive jaundice. Routine debulking resections do not appear to be indicated because current biological therapies effectively and reliably control disease over long periods.

Parathyroid carcinoma and neurofibromatosis

CASE REPORT A 31-year-old African-American female with neurofibromatosis presented to an outside hospital complaining of nausea, vomiting, fatigue, and mental status changes. At the time of admission, her serum calcium was elevated at 21.9 mg/dL, her parathyroid hormone (PTH) level was 466 pg/mL, and physical exam revealed café-au-lait spots (Fig 1) as well as a palpable neck mass. Her past medical history was notable only for multiple lower extremity orthopedic procedures to correct a discrepancy in leg length. There was no family history of multiple endocrine neoplasia syndromes (MEN) or parathyroid tumors. A CT scan of the neck showed a 2.2 3 2.3 cm mass adjacent to and involving the superior right thyroid lobe, and a sestamibi scan showed increased uptake in the right superior thyroid bed. The patient was transferred to our institution 4 days following her initial presentation. The physical findings were confirmed, and her serum calcium was 15.8 mg/dL, with a PTH level of 1967 pg/mL. Due to the unstable nature of her calcium levels, the decision was made to also treat with the calcimimetic cinacalcet, which has