Imaging Surveillance of Hypervascular Liver Lesions in Non-Cirrhotic Patients.

A consensus surveillance protocol is lacking for non-cirrhotic patients with hypervascular liver lesions presumed to represent hepatocellular adenomas. Patients with hypervascular liver lesions <5 cm not meeting criteria for focal nodular hyperplasia or hepatocellular carcinoma underwent surveillance with contrast-enhanced magnetic resonance imaging (MRI) 6, 12, and 24 months after baseline imaging. If lesions remained stable or decreased in size, then surveillance imaging was discontinued. Between 2011 and 2014, 116 patients with hypervascular liver lesions were evaluated. Seventy-nine patients were eligible for the surveillance protocol. Median follow-up was 24 months (range, 1-144 months). One patient (1 %) continued oral contraceptive pill (OCP) use and presented with hemorrhage requiring embolization 5 months after initial diagnosis. Ten patients (13 %) underwent elective embolization or surgical resection for size ≥5 cm. The remaining 68 patients (86 %) continued surveillance without hemorrhage or malignant transformation. Risk factors for requiring intervention during the surveillance period included younger age, larger lesion size, and estrogen use (all p < 0.05). Patients with hepatocellular adenomas <5 cm can safely be observed after discontinuing OCP with serial imaging 6, 12, and 24 months after diagnosis. If lesions remain stable or decrease in size, then longer-term surveillance is unlikely to identify patients at risk for complications.

Neoadjuvant interferon-based chemoradiation for borderline resectable and locally advanced pancreas cancer: a Phase II pilot study.

OBJECTIVES: Neoadjuvant chemoradiotherapy (CRT) is a viable treatment strategy for patients with pancreatic cancer. This study was conducted to evaluate the Virginia Mason Protocol (5-fluorouracil, cisplatin, interferon-α and radiation) given in the neoadjuvant setting for the treatment of locally advanced pancreatic cancer. METHODS: A Phase II pilot study evaluating interferon-based neoadjuvant CRT in patients with locally advanced pancreatic cancer was performed. RESULTS: A total of 23 patients were enrolled. The mean age of the patients was 58.6 years. Of the 23 patients, seven (30.4%) completed all treatments. In the remaining 16 (69.6%) patients, treatment was interrupted as a result of toxicity. The most commonly reported effects of toxicity were leucopoenia/cytopoenia (n = 19, 82.6%) and gastrointestinal effects (n = 19, 82.6%). Surgical resection was successful in seven (30.4%) patients. Margins were negative in six (85.7%) of these seven patients. Positive lymph nodes were identified in three (42.9%) of seven patients. Overall survival was 11.5 months. Surgery provided improved survival (22.6 months) compared with CRT alone (8.8 months). Disease-free survival in resected patients was 17.2 months. CONCLUSIONS: Interferon-based neoadjuvant CRT may allow for resection of locally advanced pancreatic cancer, but with significant toxicity. In the absence of surgical resection, survival remains dismal.

The robotic Whipple: operative strategy and technical considerations.

Advances in robotic surgery have allowed the frontiers of minimally invasive pancreatic surgery to expand. We present a step-by-step approach to the robotic Whipple procedure. The discussion includes port setting and robotic docking, kocherization and superior mesenteric vein identification, portal dissection, releasing the ligament of Treitz, uncinate dissection, and reconstruction. A brief report of our initial 2-year experience with the robotic Whipple procedure is also presented.

Multi-institutional tumor banking: lessons learned from a pancreatic cancer biospecimen repository.

Clinically annotated pancreatic cancer samples are needed for progress to be made toward developing more effective treatments for this deadly cancer. As part of a National Cancer Institute-funded program project, we established a biospecimen core to support the research efforts. This article summarizes the key hurdles encountered and solutions we found in the process of developing a successful multi-institution biospecimen repository.

Analysis of the plasma peptidome from pancreas cancer patients connects a peptide in plasma to overexpression of the parent protein in tumors.

Blood circulates through nearly every organ including tumors. Therefore, plasma is a logical source to search for tumor-derived proteins and peptides. The challenge with plasma is that it is a complex bodily fluid composed of high concentrations of normal host proteins that obscure identification of tumor-derived molecules. To simplify plasma, we examined a low molecular weight (LMW) fraction (plasma peptidome) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. In the plasma peptidome of patients with ductal adenocarcinoma of the pancreas (DAP), a prominent peptide was identified from the QSOX1 parent protein. This peptide is stable in whole blood over 24 h and was present in 16 of 23 DAP patients and 4 of 5 patients with intraductal papillary mucinous neoplasm (IPMN). QSOX1 peptides were never identified in the plasma peptidome from 42 normal healthy donors using the same methods. Immunohistochemical staining of DAP tissue sections with anti-QSOX1 antibody shows overexpression of QSOX1 in tumor but not in adjacent stroma or normal ducts. Three of four pancreas tumor cell lines also express QSOX1 protein by Western blot analysis. This is the first report of QSOX1 peptides in plasma from DAP patients and makes the rare connection between a peptide in plasma from cancer patients and overexpression of the parent protein in tumors.

Successful treatment of metastatic pancreatic adenocarcinoma with combination chemotherapy regimens.

Pancreatic adenocarcinoma is the fourth leading cause of cancer deaths in the United States. Current 5-year survival is less than 4%, highlighting the dire need for effective treatment. We report the case of a 41-year-old woman who was diagnosed with advanced metastatic well-to-moderately differentiated mucinous adenocarcinoma of the pancreas, involving the liver and peritoneal cavity. She agreed to receive novel combination chemotherapy rather than the standard-of-care treatment. This patient was treated with three unique combination regimens. Complete response of multiple liver and peritoneal metastases and reduction in size with increasing calcification of the pancreatic mass occurred in this patient after 18 months of treatment. This report documents the individual response to effective and well-tolerated treatment regimens integrating available drugs.

Selective internal radiation therapy-induced extrahepatic injury: an emerging cause of iatrogenic organ damage.

Selective internal radiation therapy (SIRT) using Yttrium microspheres is a novel therapeutic approach to the localized treatment of hepatic tumors. It provides a distinct advantage over conventional external beam radiation in that its targeted nature allows the directed delivery of high doses of radiation to tumors while sparing the surrounding uninvolved hepatic parenchyma. Numerous studies have evaluated the safety and efficacy of SIRT, and it has been used to treat both primary and metastatic hepatic malignancies. However, SIRT is not without risk of complications, and has been known to cause various toxicities due to extrahepatic SIRT microsphere deposition. Reports of such injury have been only sparsely described in the pathology literature to date, and surgical pathologists therefore remain largely unaware of this phenomenon, which can potentially lead to misdiagnosis. Herein, we review the histopathology and pathophysiology of extrahepatic SIRT microsphere migration as a cause of iatrogenic tissue injury, highlighted by 3 examples of gastritis and 1 case of cholecystitis.

Clinical utility of endoscopic ultrasound in solid pancreatic mass lesions deemed resectable by computer tomography.

CONTEXT: Appropriate surgical exploration and resection of pancreatic carcinoma depends on accurate preoperative evaluation. OBJECTIVE: Determine the accuracy of endoscopic ultrasound in predicting the need for surgical exploration in patients with solid pancreatic masses deemed by computer tomography to be resectable without venous grafting (absence of distant metastatic disease or major vascular involvement). PATIENTS: All patients between March 2000 and November 2003 with focal pancreatic mass lesions deemed to be surgically resectable by computer tomography. Forty-nine patients participated (29 males, 20 females; age range: 40-86 years). INTERVENTION: Preoperative linear-array endoscopic ultrasound. MAIN OUTCOME MEASURE: Surgical pathology compared to computer tomography and endoscopic ultrasound results. RESULTS: Out of the 49 patients, 33 (67.3%) had pancreatic neoplasms and 16 (32.7%) had chronic pancreatitis. Endoscopic ultrasound correctly diagnosed all 16 patients with chronic pancreatitis. Endoscopic ultrasound correctly identified 18 (54.5%) of those with neoplasms as having unresectable disease while 6 (18.2%) patients were appropriately identified as resectable by endoscopic ultrasound. The remaining 9 patients (27.3%) were deemed resectable by endoscopic ultrasound, but were unresectable at the time of surgery. None of the patients were falsely designated as unresectable by endoscopic ultrasound. CONCLUSION: Endoscopic ultrasound is an important compliment to computed tomography in predicting resectability and in avoiding nontherapeutic laparotomy of solid pancreatic neoplasms. Moreover, endoscopic ultrasound classification did not discourage surgery of resectable pancreatic masses.

Staged laparoscopic infusion of hyperthermic intraperitoneal chemotherapy after cytoreductive surgery.

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPC) is a promising treatment for patients with peritoneal malignancies. Traditionally, HIPC is performed concurrently with cytoreductive surgery. However, this strategy is associated with significant morbidity and mortality. In this report, we describe our initial experience with staged laparoscopic infusion of HIPC. Five patients underwent complete open cytoreductive surgery followed by staged laparoscopic HIPC several weeks later. Primary malignancies included adenocarcinoma of the ileum (one patient), adenocarcinoma of the appendix (three patients), and adenocarcinoma of the gallbladder (one patient). At a subsequent operation, we performed laparoscopic HIPC. Quality of life was measured with the Functional Assessment of Cancer Therapy-Colon Subscale (FACT-C). Mean inflow and outflow cannula temperatures were 42.1 degrees C and 40.5 degrees C, respectively. Mean peritoneal perfusion flow rates were 689.8 ml/minute. The hospital stay for all patients was 1 to 2 days. One patient developed postoperative cellulitis, one patient died of progressive tumor, and four patients are alive without tumor progression. Quality-of-life measurements had returned to baseline 4 months after treatment. Staged laparoscopic HIPC after open cytoreductive surgery is safe, feasible, and can achieve uniform temperatures and perfusion flow rates. Although the results of this pilot study are encouraging, additional studies are required to determine long-term survival and quality of life.

Biliary cystadenomas: hormone receptor expression and clinical management.

Biliary cystadenomas with mesenchymal stroma are neoplasms whose growth may be hormone sensitive. This study profiled the immunohistochemistry of these lesions to clarify the pathophysiology and define clinical management. Twelve patients with biliary cystadenomas were identified. Tissue was tested with a panel of probes including estrogen and progesterone receptors and compared to pancreatic and ovarian cystadenomas. Epithelial ER, PR, CD117, or SMA expression was negative in all three tumors. Epithelial CD10 expression was seen in 60% biliary, 75% pancreatic, and 0% ovarian tumors. Biliary cystadenoma stromal expression was ER+ (70%), PR+ (60%), CD10+ (40%), and c-kit+ (0%). Symptoms were seen in 92% patients. Percutaneous sclerotherapy and incomplete resection were associated with recurrence. Enucleation was the least morbid surgical technique. A role for hormonally mediated growth of biliary cystadenomas occurring through the stroma, rather than the epithelium, is suggested. Management remains complete surgical resection.

Hypothermic maintenance of hepatocyte spheroids.

Primary hepatocytes form spheroids under some culture conditions. These spheroids exhibit many tissue-like ultrastructures and retain many liver-specific functions over a long period of time. They are attractive for many applications employing liver cells. The ability to maintain their viability and functions at a reduced temperature to allow for transportation to the site of their application will facilitate their use. Furthermore, with their structural and functional similarity, they could possibly be used as a model system for studying various liver ischemias. The effect of hypothermic treatment was assessed by oxygen consumption rate, ATP, H2O2, and caspase 8 content, as well as albumin and urea synthesis, during and posttreatment. No single outcome variable gives a superlative quantification of hypothermic damage. Taken together, the hypothermic treatment can be seen as increasingly damaging as the temperature decreases from 21 degrees C to 15 degrees C and 4 degrees C. The addition of the chemical protectants glutathione, N-acetyl-L-cystein (NAC), and tauroursodeoxycholic acid (TUDCA) decreased the damaging effect of hypothermic treatment. This protection effect was even more profound when spheroids were preincubated with the protectant for 24 h, and was most prominent at 4 degrees C. The viability of the hypothermically treated hepatocyte spheroids was confirmed by laser scanning confocal microscopy. The method reported provides a means of maintaining spheroids' viability and may allow for their distribution to application sites at a distance.

Postoperative severe microangiopathic hemolytic anemia associated with a giant hepatic cavernous hemangioma.

Complications related to liver hemangioma are rare. We herein describe the case of a patient with three giant cavernous hemangiomas of the liver, of which two were resected for symptoms. A significant microangiopathic hemolytic anemia occurred in the early postoperative period, leading to acute renal failure and necessitating blood transfusions. The systematic evaluation of hemolytic processes in the postoperative patient is described. Surgeons should be aware of the potential for hemolytic complications after major surgery when giant hepatic hemangiomas are present.

A modern approach to malignant hilar biliary obstruction.

Management of patients with malignant hilar biliary obstruction is challenging for all specialists involved in their care. Evaluation should focus on potential surgical resection, which offers the principal chance of cure; liver transplantation is offered as an experimental treatment at a few centers. Attempt at curative surgical resection is appropriate for selected tumors and often requires partial hepatectomy. Diagnosis and staging is now facilitated by the use of magnetic resonance cholangiopancreatography (MRCP), spiral computed tomography, and endoscopic ultrasonography, which should largely supplant invasive cholangiography. Use of endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography should be limited primarily to palliation of jaundice in patients with unresectable tumors and to establish tissue diagnoses in ambiguous cases. Palliation of jaundice is optimal with self-expanding metallic stents. Safe and effective drainage can be achieved by using MRCP for targeted endoscopic placement of unilateral metal stents in most cases, with bilateral stents rarely required unless undrained ducts are contaminated. Other palliative modalities for bile duct tumors include surgical bypass, intraluminal and external beam radiation therapy, chemotherapy, and photodynamic therapy.

Laparoscopic stapled left lateral segment liver resection--technique and results.

Because of the favorable anatomy of the left lateral segment of the liver, a totally laparoscopic approach to resection is feasible. Herein we describe a technique for laparoscopic stapled resection of the left lateral segment of the liver, including the necessary anatomic criteria for a safe operation and data on clinical outcome. Five patients at our center underwent laparoscopic exploration, ultrasound examination, and resection of segments II and III. After complete mobilization of the left lateral segment and minimal portal dissection, the totally laparoscopic resections were performed with two endoscopic staple loads (4.5 mm x 60 mm) applied sequentially across the portal pedicle and the left hepatic vein. The mean operative time was 182 minutes (range 130 to 240 minutes), blood loss was 41 ml (range 25 to 50 ml), and length of hospital stay was 2.2 days (range 1 to 3 days). All three patients with malignancy had negative surgical margins. All five patients returned to normal activity or work by 1 week postoperatively. There were no complications. Patients with isolated malignant and benign diseases of the left lateral segment of the liver are candidates for totally laparoscopic resection, if evaluation demonstrates a normal liver character and hepatic parenchymal thickness less than 3 cm overlying the ligamentum venosum groove. Such patients benefit from the minimally invasive approach, with no compromise in the surgical result as compared to the open approach.

Radiofrequency ablation causes 'thermal fixation' of hepatocellular carcinoma: a post-liver transplant histopathologic study.

Radiofrequency ablation (RFA) is increasingly used to treat hepatocellular carcinoma (HCC) in patients awaiting a liver transplant. Despite its increasing use, detailed histologic information is scarce regarding the nature of RFA-treated lesions. We identified four chronic hepatitis C patients who had RFA of their HCC before their liver transplant. For these four patients, we conducted a detailed histopathologic analysis of the treated lesions in their explanted livers. The five lesions included immediate (4 d) and long-term (14 months) post-RFA specimens. Of the five lesions, four were completely ablated. The one incompletely ablated lesion was also treated with chemoembolization. In the acute post-RFA period, a zone of interstitial hemorrhage occurred at the outer boundary of the lesion. Differing from classic tissue necrosis, the treated lesions all showed 'thermal fixation', with preserved tissue architecture and microscopic cellular detail. The cellular staining characteristics faded with time, but the treated tissue became brittle, resisted tissue breakdown, and generated a minimal wound healing response. At the periphery of the lesion, the fibrous septae of the cirrhotic liver and vascular structures appeared to demarcate or limit progression of the ablation front. A narrow hypocellular fibrous boundary with a focal 'foreign body' giant cell-type reaction developed around the edge of the ablation zone. Thus, RFA can produce immediate and complete thermal fixation of select lesions with an appropriate liver margin and can provide a satisfactory treatment option for select HCC patients before a liver transplant.

Hepatic encephalopathy secondary to transtumoral portal-hepatic venous shunting.

Intrahepatic portal-systemic shunts causing hepatic encephalopathy are very rare. This is a case report of a patient with hepatic metastases of a pancreatic islet cell tumor that manifested with transtumoral shunts leading to hepatic encephalopathy. The diagnosis was confirmed with Doppler ultrasound and initially treated with selective transhepatic portal vein embolization followed by hepatic artery embolization, and eventually radiofrequency ablation of the largest metastases. Despite excellent short-term palliation, symptom recurrence necessitated liver resection, the results of which proved durable. A multidisciplinary treatment plan for the identification and management of potentially salvageable encephalopathy in similar patients is described.

Cyclooxygenase-2 inhibition augments the hepatic antitumor effect of oral Salmonella typhimurium in a model of mouse metastatic colon cancer.

INTRODUCTION: Oral inoculation with a nontoxic, attenuated strain of Salmonella typhimurium reduces tumor burden and improves survival in a mouse model of metastatic colon cancer. These effects are likely mediated by S. typhimurium-induced increases in hepatic natural killer leukocytes. Cyclooxygenase-2 inhibitors may mediate antitumor effects through antiangiogenic, immune, or proapoptotic pathways. We hypothesized that cyclooxygenase-2 inhibitors would act synergistically with S. typhimurium, resulting in additional antitumor effects. METHODS: Four groups of mice were studied: control, S. typhimurium alone, cyclooxygenase-2 inhibitor alone, and S. typhimurium plus cyclooxygenase-2 inhibitor. Mice were given normal drinking water (control, S. typhimurium alone) or water with 1,600 parts per million cyclooxygenase-2 inhibitor (cyclooxygenase-2 inhibitor alone, and S. typhimurium plus cyclooxygenase-2 inhibitor) and orally inoculated with saline (control, cyclooxygenase-2 inhibitor alone) or 10(9) S. typhimurium (S. typhimurium alone, S. typhimurium plus cyclooxygenase-2 inhibitor). Twenty-four hours later, all mice underwent laparotomy, and 5 x 10(4) MCA38 murine adenocarcinoma cells were injected into the spleen. On Day 14, hepatic tumor number and tumor volume was quantitated and hepatic leukocytes were analyzed by flow cytometry. RESULTS: Compared with control mice orally inoculated with saline, S. typhimurium-treated mice had fewer and smaller tumors; mice treated with cyclooxygenase-2 inhibitor alone had tumor burden similar to control mice, and mice treated with S. typhimurium plus cyclooxygenase-2 inhibitor had fewer and smaller tumors compared with all other groups. Increased liver natural killer cells and decreased CD4+ and CD8+ T cells were observed in both S. typhimurium-treated groups. No alterations in hepatic leukocyte phenotype were observed in mice receiving cyclooxygenase-2 inhibitor alone. CONCLUSION: Oral cyclooxygenase-2 inhibitor appeared to act synergistically with S. typhimurium to reduce tumor burden. This combination therapy may have clinical application in the treatment or prevention of hepatic metastases associated with colorectal cancer.

Local, intrahepatic, and systemic recurrence patterns after radiofrequency ablation of hepatic malignancies.

The objective of this study was to describe the recurrence patterns in patients with unresectable hepatic malignancies treated with radiofrequency ablation (RFA). As RFA is applied more widely to patients with hepatic tumors, a better understanding of the biologic behavior of these tumors and the risk of recurrence, both in the liver and systemically, is needed. A multidisciplinary team evaluated patients referred for RFA and followed them prospectively to assess local, intrahepatic, and extrahepatic disease recurrence and complication rates. Forty-five patients with 143 lesions and a minimum follow-up of 6 months (median 19.5 months) were treated. Overall, 7.7% of treated lesions had local recurrence. New intrahepatic disease was seen in 49% of patients, and 24% had evidence of new systemic tumor progression. Patients with colorectal metastatic lesions > or =4 cm at the time of the first RFA were more likely to present with local recurrence (P = 0.048). Complications occurred in 27% of patients. Although RFA has a satisfactory local failure rate and safety profile, the patient population being treated is at high risk of developing new disease. Multimodality adjuvant therapy will be necessary to realize the full potential of hepatic malignancy control with RFA.