Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma.

BACKGROUND: Neoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma (PDAC) but no standard of care exists. Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging preclinical activity in PDAC. We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy (IMRT) as neoadjuvant therapy in patients with localized or locally advanced PDAC. EXPERIMENTAL DESIGN: Treatment consisted of cetuximab load at 400 mg/m(2) followed by cetuximab 250 mg/m(2) weekly and gemcitabine 50 mg/m(2) twice-weekly given concurrently with IMRT to 54 Gy. Following therapy, patients were considered for resection. RESULTS: Thirty-seven patients were enrolled with 33 assessable for response. Ten patients (30%) manifested partial response and 20 (61%) manifested stable disease by RECIST. Twenty-five patients (76%) underwent resection, including 18/23 previously borderline and 3/6 previously unresectable tumors. Twenty-three (92%) of these had negative surgical margins. Pathology revealed that 24% of resected tumors had grade III/IV tumor kill, including two pathological complete responses (8%). Median survival was 24.3 months in resected patients. Outcome did not vary by epidermal growth factor receptor status. CONCLUSIONS: Neoadjuvant therapy with cetuximab/gemcitabine/IMRT is tolerable and active in PDAC. Margin-negative resection rates are high and some locally advanced tumors can be downstaged to allow for complete resection with encouraging survival. Pathological complete responses can occur. This combination warrants further investigation.

Endoscopic vs. laparoscopic gastrojejunostomy for duodenal obstruction: a randomized study in a porcine model.

BACKGROUND AND STUDY AIMS: Open or laparoscopic gastrojejunostomy is an established treatment for malignant duodenal obstruction but may be associated with significant morbidity and mortality. The purpose of this study was to develop a model for an entirely endoscopic gastrojejunostomy to treat duodenal obstruction, and to compare this with the laparoscopic technique. METHODS: During the first part of the study the endoscopic technique was developed and tested in porcine nonsurvival and survival experiments (n=12). During the second part of the study (n=10), endoscopic gastrojejunostomy for duodenal occlusion was compared with laparoscopic gastrojejunostomy in a survival randomized controlled trial (RCT). For both groups duodenal occlusion was achieved by the laparoscopic approach. RESULTS: In the RCT, the median times for laparoscopic vs. endoscopic gastrojejunostomy were 70 minutes (interquartile range [IQR] 65-75) vs. 210 minutes (IQR 197-220; P=0.01). There was a trend toward increased anastomotic diameter at necropsy in the laparoscopic group (2 cm, IQR 2-3) compared to the endoscopic group (1.8 cm, IQR 1.6-1.8; P=0.06). One animal in the endoscopic group died secondarily to bowel ischemia from volvulus of the jejunal loop. One animal in the laparoscopic group was prematurely sacrificed due to extensive pulmonary congestion and edema. All anastomoses were intact and patent. CONCLUSIONS: Purely endoscopic gastrojejunostomy using the developed technique and devices is feasible and can result in adequate relief of duodenal obstruction. Endoscopic anastomoses tend to be smaller than laparoscopic anastomoses, with the procedures being more time-consuming and associated with higher complication rates.

Effect of ischemia-reperfusion on the incidence of acute cellular rejection and timing of histologic hepatitis C virus recurrence after liver transplantation.

BACKGROUND: Because of a critical shortage of deceased donor (DD) livers, more extended criteria allografts are being utilized; these allografts are at increased risk for ischemia-reperfusion injury (IRI). We assessed whether, in a large cohort of patients transplanted for hepatitis C virus (HCV) either via a DD or live donor (LD), there was a relationship between the degree of IRI and the frequency and timing of acute cellular rejection (ACR) and histologic HCV recurrence. METHODS: During an 8-year study, patients were separated into four groups based on peak alanine aminotransferase (ALT) levels and three groups based on severity of IRI on postreperfusion liver biopsy. RESULTS: The mean follow-up time of 433 DD and 44 LD recipients was 1212 days. We noted a strong correlation in DD between peak ALT and the histologic degree of IRI (P = .01). There was no difference in the incidence or grade of ACR among the four groups. There was no correlation between the severity of IRI and the incidence or time to histologic recurrence of HCV. CONCLUSIONS: The magnitude of peak ALT correlated with the severity of IRI on postreperfusion liver biopsy. Among this large HCV cohort, there was no correlation between the severity of IRI and the incidence or timing of histologic HCV recurrence or incidence of ACR.

Parenchymal and nonparenchymal cellular responses in human hepatic regeneration.

To characterize cellular responses during hepatic regeneration, we examined 13 explant livers and 5 liver allografts by immunohistochemistry for cytokeratin 7, HepPar1, CD68, alpha-smooth muscle actin (alpha-SMA) and proliferating cell nuclear antigen as well as reticulin and Masson-trichrome staining. Within a week after liver damage, elongated CD68-positive cells were detected along the border of necrotic area. The number of alpha-SMA-positive cells was slightly increased along the sinusoids. Ductular proliferation or fibrosis was negligible. After one or two weeks, the size and number of CD68-positive cells were markedly increased. alpha-SMA-positive cells increased in number within lobules and portal tracts. Ductular proliferation occurred predominantly at the limiting plate or along the border of necrotic areas. After one month, necrotic parenchyma was replaced by many ductules, CD68-positive cells, alpha-SMA-positive cells. Nodules of regenerating hepatocytes and irregular fibrosis were diffusely present. Other nonparenchymal cells were not significantly changed. These observations indicate that chronological interaction between nonparenchymal and parenchymal cells occur during the course of human hepatic regeneration and suggest extensive porto-periportal fibrosis more than a few months after the onset of fulminant hepatitis is a major indicator of chronic functional impairment necessitating liver transplantation.

Hemangioma of the testis: report of unusual occurrences of cavernous hemangioma in a fetus and capillary hemangioma in an older man.

We report two cases of hemangiomata of the testes which occurred in a 17-week-old fetus and a 73-year-old man. To our knowledge, these are the first reported cases of cavernous hemangioma of the testis in a fetus and capillary hemangioma of the testis in an older man. Although a hemangioma of the testis is rare, it should be considered in the differential diagnosis of a testicular tumor. Ann Diagn Pathol 5:80-83, 2001.

Portal hypertension and hepatopulmonary syndrome in a middle-aged man with hepatitis B infection.

A 55-year-old Turkish man with a history of chronic hepatitis B for 35 years, presented with incapacitating fatigue and worsening shortness of breath. He was hospitalized several times because of hepatic encephalopathy. He underwent liver transplantation for a clinical diagnosis of Child's C cirrhosis complicated by hepatopulmonary syndrome. The explanted liver, however, was not cirrhotic and demonstrated features of hepatoportal sclerosis. Although treatment for hepatoportal sclerosis is relief of portal hypertension; in rare cases such as in this patient with liver failure, liver transplantation is indicated.

Hepatocellular carcinoma and non-Hodgkin lymphoma in a patient with chronic hepatitis C and cirrhosis.

Hepatitis C virus (HCV) is a hepatotropic virus, but its genome and replicative intermediates also have been detected in peripheral blood mononuclear cells in patients with chronic hepatitis C. Chronic HCV infection may lead to hepatocellular carcinoma and, in a small percentage of cases, to B-cell non-Hodgkin lymphoma. To our knowledge, coexistence of these 2 tumors has not been reported previously. We describe a case of chronic hepatitis C and cirrhosis with 2 small hepatocellular carcinomas and incidental non-Hodgkin lymphoma of a hilar lymph node found during liver transplantation. Although the mechanisms of HCV oncogenesis in hepatocellular carcinoma and in lymphoma are unclear, the presence of these 2 tumors in a single patient are in agreement with the tropism of HCV and its role in oncogenesis.

A 67-year-old man with hepatitis C virus infection and a liver tumor.

A 67-year-old man with no known liver disease was found to have an incidental tumor in the right liver lobe. His serum liver enzyme and alphafetoprotein were within normal limits, but he was found to be reactive for anti-HCV. The tumor was an intrahepatic cholangiocarcinoma. Since the only risk factor in this patient was hepatitis C infection, this case appears to support the recently suggested role of hepatitis C virus in the development of intrahepatic cholangiocarcinoma.

Primary hepatic marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in a patient with primary biliary cirrhosis.

Primary lymphoma of the liver is rare. Recently, marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type have been described in the liver. Most of these cases occurred without known underlying liver disease, while others were seen in patients with chronic hepatitis. A case of primary hepatic MALT lymphoma in a patient with primary biliary cirrhosis was reported recently. Some authors have proposed that chronic persistent immunogenic stimulation causes development of acquired MALT and subsequently MALT lymphoma, based on the observation of MALT lymphoma in association with infectious agents, such as Helicobacter pylori and hepatitis C virus, and autoimmune diseases, such as Hashimoto thyroiditis and Sjögren syndrome. Primary biliary cirrhosis is a chronic, progressive, cholestatic liver disease characterized by destruction of intrahepatic small to medium-sized bile ducts; this disease is mediated by a cytotoxic T-cell reaction. The prolonged immune activation in primary biliary cirrhosis may play a role in the lymphomagenesis of hepatic MALT lymphoma. We describe another case of primary hepatic MALT lymphoma, which was found incidentally in a patient with end-stage primary biliary cirrhosis. This case further supports the role of immunogenic stimulation in the pathogenesis of this particular low-grade B-cell lymphoma.

Expression of p53 and PCNA in cholangiocarcinoma and primary sclerosing cholangitis.

The aim of this study was to identify the pattern and significance of expression of p53 and PCNA in cholangiocarcinoma and primary sclerosing cholangitis. Histological sections from 18 patients with cholangiocarcinoma (3 of the cases were associated with primary sclerosing cholangitis), 10 patients with primary sclerosing cholangitis without cholangiocarcinoma, and 7 patients with cirrhosis without cholangiocarcinoma or primary sclerosing cholangitis were stained immunohistochemically for p53 and PCNA. Samples from 17 patients with cholangiocarcinoma (94%) stained positively for p53. Among these 17 cases, nontumorous bile duct epithelium was positive in 7 (including 3 cases with primary sclerosing cholangitis and 2 with carcinoma in situ), and were positive proliferating bile ductules in 4 cases. The single p53-negative cholangiocarcinoma did not show p53 positivity in either the bile duct epithelium or the proliferating bile ductules. Bile ductal and ductular cells in all 10 patients with primary sclerosing cholangitis without cholangiocarcinoma and in the 7 controls were not reactive for p53. All 18 samples from patients with cholangiocarcinoma (100%) were positive for PCNA protein. Bile duct epithelium was positive for PCNA in nine cases (90%) of primary sclerosing cholangitis without cholangiocarcinoma and in six (85%) controls. Our study showed a high rate of p53 expression (94%) in cholangiocarcinoma. The adjacent uninvolved bile duct epithelium was also immunoreactive for p53 in 7 of 17 patients (41%). These findings suggest an early p53 mutation in bile ductal cells in cholangiocarcinogenesis. Expression of p53 may potentially be used to identify or screen, by bile duct brushings, cases of primary sclerosing cholangitis suspected of harboring cholangiocarcinoma. Expression of PCNA was a universal feature in cholangiocarcinoma.

A 42-year-old woman with liver masses and long-term use of oral contraceptives.

A 42-year-old woman with a history of 25-year oral contraceptive use presented with abdominal pain and was found to have two exophytic liver masses. She had no known prior liver diseases, and her serum liver enzyme and AFP levels were normal. One of the masses was a hepatocellular adenoma and the other was a pigmented hepatocellular carcinoma. The exophytic appearance of both lesions was unusual. This case, once more, demonstrated the risk of hepatocellular adenomas to undergo malignant transformation. The reason for the brown pigment deposition in the hepatocellular carcinoma was not clear. The prognosis was expected to be excellent following complete surgical resection.

Recurring fibro-obliterative venopathy in liver allografts.

Recurrent diseases in liver allografts are not uncommon. These occur most frequently in those transplanted for viral hepatitis B and C. We report an unusual case of recurrent process in two consecutive liver allografts received by a 37-year-old woman, who previously had an unremarkable past medical history but developed a rapidly progressive cholestatic liver failure. Histopathologic examination of the native liver showed fibroocclusive lesions of both terminal hepatic venules and portal vein branches. The exuberant fibroobliterative process created dense fibrosis with whorled appearance, and broad fibrous septa connecting adjacent central areas, and sometimes bridging portal to central areas. Dense portal fibrosis resulted in compression atrophy and loss of bile ducts. The first allograft, which failed within 3 months, showed histopathologic findings similar to that of the native liver. A liver biopsy that was performed 20 months after the second liver transplant again showed similar histopathology. The histopathologic features and clinical presentation of this patient suggest an unusual form of recurring progressive fibroobliterative venopathy causing liver failure.