Survival after resection of perihilar cholangiocarcinoma-development and external validation of a prognostic nomogram.

BACKGROUND: The objective of this study was to derive and validate a prognostic nomogram to predict disease-specific survival (DSS) after a curative intent resection of perihilar cholangiocarcinoma (PHC). PATIENTS AND METHODS: A nomogram was developed from 173 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA. The nomogram was externally validated in 133 patients treated at the Academic Medical Center (AMC), Amsterdam, The Netherlands. Prognostic accuracy was assessed with concordance estimates and calibration, and compared with the American Joint Committee on Cancer (AJCC) staging system. The nomogram will be available as web-based calculator at mskcc.org/nomograms. RESULTS: For all 306 patients, the median overall survival (OS) was 40 months and the median DSS 41 months. Median follow-up for patients alive at last follow-up was 48 months. Lymph node involvement, resection margin status, and tumor differentiation were independent prognostic factors in the derivation cohort (MSKCC). A nomogram with these prognostic factors had a concordance index of 0.73 compared with 0.66 for the AJCC staging system. In the validation cohort (AMC), the concordance index was 0.72, compared with 0.60 for the AJCC staging system. Calibration was good in the derivation cohort; in the validation cohort patients had a better median DSS than predicted by the model. CONCLUSIONS: The proposed nomogram to predict DSS after curative intent resection of PHC had a better prognostic accuracy than the AJCC staging system. Calibration was suboptimal because DSS differed between the two institutions. The nomogram can inform patients and physicians, guide shared decision making for adjuvant therapy, and stratify patients in future randomized, controlled trials.

Prospective study of outcomes after percutaneous biliary drainage for malignant biliary obstruction.

BACKGROUND: Percutaneous biliary drainage (PBD) is used to relieve malignant bile duct obstruction (MBO) when endoscopic drainage is not feasible. Little is known about the effects of PBD on the quality of life (QoL) in patients with MBO. The aim of this study was to evaluate changes in QoL and pruritus after PBD and to explore the variables that impact these changes. MATERIALS AND METHODS: Eligible patients reported their QoL and pruritus before and after PBD using the Functional Assessment of Cancer Therapy-Hepatobiliary instrument (FACT-HS) and the Visual Analog Scale for Pruritus (VASP). Instruments were completed preprocedure and at 1 and 4 weeks following PBD. RESULTS: A total of 109 (60 male/49 female) patients enrolled; 102 (94%) had unresectable disease. PBD was technically successful (hepatic ducts cannulated at the conclusion of procedure) in all patients. There were 2 procedure-related deaths. All-cause mortality was 10% (N = 11) at 4 weeks and 28% (N = 31) at 8 weeks post-PBD with a median survival of 4.74 months. The mean FACT-HS scores declined significantly (P < .01) over time (101.3, 94.8, 94.7 at baseline, 1 week, 4 weeks, respectively). The VASP scores showed significant improvement at 1 week with continued improvement at 4 weeks (P < .01). CONCLUSIONS: PBD improves pruritus but not QoL in patients with MBO and advanced malignancy. There is high early mortality in this population.

Regional chemotherapy for unresectable primary liver cancer: results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival.

BACKGROUND: This study reports the results of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (dex) in patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) and investigates dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) assessment of tumor vascularity as a biomarker of outcome. PATIENTS AND METHODS: Thirty-four unresectable patients (26 ICC and eight HCC) were treated with HAI FUDR/dex. Radiologic dynamic and pharmacokinetic parameters related to tumor perfusion were analyzed and correlated with response and survival. RESULTS: Partial responses were seen in 16 patients (47.1%); time to progression and response duration were 7.4 and 11.9 months, respectively. Median follow-up and median survival were 35 and 29.5 months, respectively; 2-year survival was 67%. DCE-MRI data showed that patients with pretreatment integrated area under the concentration curve of gadolinium contrast over 180 s (AUC 180) >34.2 mM.s had a longer median survival than those with AUC 180 <34 mM.s (35.1 versus 19.1 months, P = 0.002). Decreased volume transfer exchange between the vascular space and extracellular extravascular space (-DeltaK(trans)) and the corresponding rate constant (-Deltak(ep)) on the first post-treatment scan both predicted survival. CONCLUSIONS: In patients with unresectable primary liver cancer, HAI therapy can be effective and safe. Pretreatment and early post-treatment changes in tumor perfusion characteristics may predict treatment outcome.

Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC).

BACKGROUND: The incidence of gallbladder cancer (GBC) in the US is 1.2/100,000. This report examines the patterns of presentation, adjuvant treatment and survival of a large cohort of patients with GBC evaluated at MSKCC over a 10-year period. METHODS: A retrospective analysis of patients referred to MSKCC with a diagnosis of GBC between January 1995 and December 2005 was performed. Patients were identified from the MSKCC cancer registry. Information extracted included, demographics, clinical and pathological stage, surgical management, pathology, adjuvant and palliative therapy, date of relapse, death or last follow-up. Date of diagnosis was defined as date of surgery or biopsy. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Four hundred thirty-five GBC cases were identified: 285 (65.5%) females,150 (34.5%) males. Median age 67 years (range 28-100). Pathology: 88% adenocarcinoma, 4% squamous, 3% neuroendocrine, 2% sarcoma. 36.6% presented as AJCC Stage IV. 47% were discovered incidentally at laparoscopic cholecystectomy. One hundred thirty-six of these were re-explored, of whom 100 (73.5%) had residual disease. Of those who underwent curative resections (N = 123), 8 (6.5%) received adjuvant chemotherapy, 8 (6.5%) chemoradiation alone and 8 (6.5%) both chemoradiation and systemic chemotherapy. Median overall survival for the cohort was 10.3 months (95% CI 8.8-11.8) with a median follow up of 26.6 months. The median survival for those presenting with stage Ia-III disease was 12.9 months (95% CI 11.7-15.8 months) and 5.8 months (95% CI 4.5-6.7) for those presenting with stage IV disease. Median survival was 15.7 months (95% CI 12.4-18.4) for those discovered incidentally at laparoscopic cholecystectomy. For those who underwent re-exploration, median survival was 14.6 months (95% CI 12.6-18.3) if residual disease was present, and 72 months (95% CI 34 to infinity) if no evidence of disease. The median survival for those who received adjuvant therapy was 23.4 months (95% CI 15.7-47). CONCLUSIONS: GBC is commonly diagnosed incidentally (47%). Re-exploration reveals a high incidence of residual disease (74%). Median survival is better for patients who have no evidence of disease on re-exploration (72 months) compared to those with residual disease detected (P < 0.0001). Overall prognosis is poor. Although we did not observe a survival benefit for those who received adjuvant therapy, the study did not have sufficient power to address this question. In addition, the number of patients who received adjuvant therapy was small with marked heterogeneity in clinical and therapeutic details, precluding any definitive conclusions being drawn. Prospective randomized trials of adjuvant therapy are needed in this disease.

Rates and patterns of recurrence for percutaneous radiofrequency ablation and open wedge resection for solitary colorectal liver metastasis.

INTRODUCTION: The purpose of this study was to compare rates and patterns of disease progression following percutaneous, image-guided radiofrequency ablation (RFA) and nonanatomic wedge resection for solitary colorectal liver metastases. METHODS: We identified 30 patients who underwent nonanatomic wedge resection for solitary liver metastases and 22 patients who underwent percutaneous RFA because of prior major hepatectomy (50%), major medical comorbidities (41%), or relative unresectability (9%). Serial imaging studies were retrospectively reviewed for evidence of local tumor progression. RESULTS: Patients in the RFA group were more likely to have undergone prior liver resection, to have a disease-free interval greater than 1 year, and to have had an abnormal carcinoembryonic antigen (CEA) level before treatment. Two-year local tumor progression-free survival (PFS) was 88% in the Wedge group and 41% in the RFA group. Two patients in the RFA group underwent re-ablation, and two patients underwent resection to improve the 2-year local tumor disease-free survival to 55%. Approximately 30% of patients in each group presented with distant metastasis as a component of their first recurrence. Median overall survival from the time of resection was 80 months in the Wedge group vs 31 months in the RFA group. However, overall survival from the time of treatment of the colorectal primary was not significantly different between the two groups. CONCLUSIONS: Local tumor progression is common after percutaneous RFA. Surgical resection remains the gold standard treatment for patients who are candidates for resection. For patients who are poor candidates for resection, RFA may help to manage local disease, but close follow-up and retreatment are necessary to achieve optimal results.

Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer.

PURPOSE: Patients who undergo resection of liver metastases from colorectal cancer have an average 2-year survival of 65%. With hepatic arterial infusion (HAI) plus systemic fluorouracil and leucovorin, 2-year survival increased to 86%. For further improvement in both local and systemic control, combinations of new systemic drugs with HAI are being explored. The purpose of this study was to determine the maximum-tolerated dose (MTD) of systemic irinotecan (CPT-11) and HAI floxuridine (FUDR) plus dexamethasone (DEX) as combination adjuvant therapy after liver resection. PATIENTS AND METHODS: Ninety-six patients who underwent complete resection of liver metastases from colorectal cancer were treated with six monthly cycles of HAI FUDR plus DEX for 14 days of each 4-week cycle plus escalating doses of systemic CPT-11. The primary end points of the phase I/II study were the MTD and efficacy of this regimen. RESULTS: The MTD for combined systemic CPT-11 and HAI FUDR was CPT-11 at 200 mg/m2 every other week and FUDR at 0.12 mg/kg x pump volume / pump flow rate. The dose-limiting toxicities were diarrhea and neutropenia. With a median follow-up time of 26 months, the 2-year survival rate is 89%. All of the 27 patients who were treated at the MTD are alive. CONCLUSION: In patients who undergo resection of liver metastases from colorectal cancer, adding systemic CPT-11 to HAI therapy in an adjuvant regimen is feasible. This regimen seems to have comparable activity to fluorouracil and leucovorin, but further studies are needed to assess whether it improves local control or decreases extrahepatic recurrences.

Liver resection for colorectal metastases.

PURPOSE: More than 50,000 patients in the United States will present each year with liver metastases from colorectal cancers. The current study was performed to determine if liver resection for colorectal metastases is safe and effective and to evaluate predictors of outcome. MATERIALS AND METHODS: Data for 456 consecutive resections performed between July 1985 and December 1991 in a tertiary referral center were analyzed. RESULTS: The perioperative mortality rate was 2.8%, with a mortality rate of 4.6% for resections that involved a lobectomy or more. The median hospital stay was 12 days and only 9% of patients were admitted to the intensive care unit. The 5-year survival rate is 38%, with a median survival duration of 46 months. By univariate analysis, nodal status of the primary lesion, short disease-free interval before detection of liver metastases, carcinoembryonic antigen (CEA) level greater than 200 ng/mL, multiple liver tumors, extrahepatic disease, large tumors, or positive resection margin was predictive of poorer outcome. Sex, age greater than 70 years, site of primary tumor, or perioperative transfusion was not predictive of outcome. By multivariate analysis, positive margin, size greater than 10 cm, disease-free interval less than 12 months, multiple tumors, and extrahepatic disease were independent predictors of poorer outcome. Short disease-free interval or multiple tumors were nevertheless associated with a 5-year survival rate greater than 24%. CONCLUSION: Liver resection for colorectal metastases is safe and effective therapy and currently represents the only potentially curative therapy for metastatic colorectal cancer. The only absolute contraindication to resection is extrahepatic disease. A randomized trial to examine efficacy of surgical resection cannot ethically be performed. Liver resection should be considered standard therapy for all fit patients with colorectal metastases isolated to the liver.

Intrabiliary growth of metastatic colonic adenocarcinoma: a pattern of intrahepatic spread easily confused with primary neoplasia of the biliary tract.

Because of its propensity to spread along epithelial surfaces, colonic adenocarcinoma can mimic other neoplasms. For example, colonic adenocarcinoma can grow along the surface of the urinary bladder and can simulate primary bladder neoplasia, and metastatic colonic adenocarcinoma can grow along alveolar walls and can mimic primary lung neoplasia. Intraepithelial spread along bile ducts, however, is not a well-recognized behavior of hepatic metastases. Indeed, dysplastic change in the epithelium lining the biliary tract is sometimes used to discriminate primary biliary neoplasms from metastatic adenocarcinoma. We report on eight cases of colonic adenocarcinoma metastatic to the liver that demonstrated prominent spread throughout the biliary tree along intact basement membranes. Morphologically, this pattern closely resembled high-grade dysplasia (i.e., carcinoma in situ) of the extrahepatic and intrahepatic bile ducts. Clinically, two of the tumors were mistaken for primary biliary neoplasia because of the common radiologic finding of intrabiliary masses with distended bile ducts. A definite diagnosis of metastatic carcinoma was established by careful attention to the medical history, thorough evaluation of the morphologic features, and histologic comparison with the primary colon cancer. For patients with a history of colonic adenocarcinoma, consideration of a liver metastasis is appropriate even when certain histologic and radiographic features point to a neoplasm of biliary origin.

Effect of orthotopic liver transplantation and chemical denervation of the liver on the activities of hepatic monoamine oxidase and catechol-O-methyltransferase.

The denervation of some tissue is associated with a fall in the activities of monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). Here we report on the effect of orthotopic liver transplantation and chemical denervation of the liver on the enzymes. Liver transplantation was performed on Lewis rats (n = 7). Denervation (n = 8) was by intraportal injection of 6-hydroxydopamine (75 mg/kg). A control group (n = 8) was also included. The norepinephrine content of the transplanted and denervated livers was reduced by greater than 99% (P < 0.001) and 95% (P < 0.001), respectively. The activity of hepatic COMT (substrate: catechol [5 mM] was not affected by transplantation or denervation. The activity of MAO with 0.1 mM 5-hydroxytryptamine (5-HT) (substrate for MAO-A) and with 0.01 mM 2-phenylethylamine (substrate for MAO-B) were not affected by denervation. In the transplanted liver, the activity of MAO with 5-HT and 2-phenylethylamine was increased by 26% (P < 0.05) and by 53% (P < 0.001), respectively. The ratios of the activities of the A to B forms of MAO (approximately 70% A to 30% B) was not affected by either procedure. Enzyme sensitivity for MAO inhibitors clorgyline and deprenyl were not significantly altered by transplantation. The concentration of plasma norepinephrine in the transplantation group was significantly lower than either the control (P < 0.001) or denervation groups (P < 0.05). We conclude from our results that the metabolism of circulating catecholamines by the liver is unlikely to be impaired after liver transplantation.

Uptake of a colloid in rat liver following intravenous intrasplenic and intramesenteric injection.

Intramesenteric and intrasplenic injections of 99mTc-sulfur colloid in the rat resulted in significant differences between the mean uptakes in only some of the liver lobes. More important were the wider interlobular variations seen in the intrasplenic and intramesenteric routes of injection compared with the intravenous route. It is suggested that these differences result from laminar blood flow in the portal vein. In the light of our findings, previous evidence must be considered inconclusive. Laminar flow appears to vary between individual animals and may also vary from time to time in the same animal. Caution is therefore advised when other than systemic routes of injection are used.

In vivo assessment of liver size in the rat.

In vivo assessment of liver mass in the rat was achieved using several parameters obtained by scintigraphy, including one computed using a Nuclear Data 50:50 analysis system. All correlated well with the directly measured liver weight. The simplest parameter, the area of the anterior view measured from the Polaroid scintigraph, was therefore the one preferred. The results so obtained were compared with those derived from the relationship between liver and body weights. It is suggested that this accurate in vivo measurement of liver mass is of value in the study of the pathophysiology of this organ.

The effect of propranolol on the hyperaemic response of the hepatic artery to portal venous occlusion in the dog.

1. It has been reported that activation of beta-adrenoceptors may be responsible for the hyperaemic response of the hepatic artery to portal venous blood flow reduction. 2. The effect of beta-adrenoceptor blockade on the hepatic arterial response to portal vein occlusion was investigated in 6 anaesthetized dogs. A side-to-side portacaval shunt was established to prevent loss of venous return and arterial blood pressure during periods of portal occlusion. Measurements of hepatic arterial and portal venous blood flows were made by use of electromagnetic flow probes. 3. Intravenous propranolol injection, at a dose sufficient to block the vasodilator effect of low doses of exogenous adrenaline, did not alter the magnitude of the hyperaemic response of the hepatic artery. Propranolol also produced no change in baseline portal venous pressure. 4. It is concluded that hepatic beta-adrenoceptors are unlikely to be involved in the arterial response to portal occlusion. The absence of any reduction in basal portal venous pressure by propranolol is of interest in view of the current application of the drug in the treatment of patients with portal hypertension.

Clear cell papillary carcinoma of the liver: an unusual variant of peripheral cholangiocarcinoma.

Cholangiocarcinomas may be extrahepatic or intrahepatic; the latter are further divided into hilar and peripheral types. Peripheral cholangiocarcinomas often resemble adenocarcinomas arising in other organs. Although clear cell changes may occur in hepatocellular carcinoma and extrahepatic cholangiocarcinoma, peripheral cholangiocarcinomas with clear cell change are rare. In such cases, an extrahepatic primary carcinoma must be excluded. We present a patient with a large, clear cell papillary carcinoma in the liver. Extensive workup of the patient for other possible primary sites including kidneys, adrenals, thyroid, prostate, or urinary bladder failed to indicate any other neoplasm. The patient is alive without evidence of disease 30 months after complete resection. The histological, immunohistochemical, and electron microscopic results were most consistent with a neoplasm in the cholangiocarcinoma family. To the best of our knowledge, a clear cell papillary peripheral cholangio carcinoma has not been described previously. This neoplasm may be related to the recently described clear cell carcinomas of the gallbladder and extrahepatic bile ducts.

The pathology of the atrophy/hypertrophy complex (AHC) of the liver. A light microscopic and immunohistochemical study.

The term, atrophy/hypertrophy complex (AHC) of the liver, denotes a distinct combination of hepatic atrophy and hypertrophy occurring in situations of significant impairment of bile flow and/or portal or hepatic venous blood flow. In the lobes or segments concerned atrophy ensues, whereas areas not or less involved develop compensatory hypertrophy, resulting in a characteristic gross deformity of the organ and, in some instances, in rotation of the liver around a virtual hilar axis. As recognition and early detection of AHC have a strong implication on the treatment of several hepatobiliary diseases, adequate combined clinical, radiological and histopathological strategies have to be used in order to arrive at a correct diagnosis. The present investigation was designed to analyze the morphology of AHC in detail and to define lesion patterns having the highest predictive value. For atrophy, the following features were highly characteristic: 1) Advanced septal fibrosis with or without nodular change of parenchyma; 2) Biliary piecemeal necrosis with formation of vascular structures; 3) Ductular proliferations, frequently extending into septa and involving the parenchyma; 4) Capillarization of sinusoids with type IV collagen deposition in Disse's space; 5) Factor VIII-associated antigen expression by sinusoidal endothelia; 6) a seemingly paradoxical increase of proliferative activity of hepatocytes as based on PCNA staining. The severity of lesions in atrophy was related to the type of underlying disease, in that the changes were clearly more expressed in situations of longstanding obstruction due to benign disease. Using a set of well-defined morphological parameters, atrophy can be reproducibly distinguished from hypertrophy in biopsy material from AHC.

Prolyl hydroxylase in the skin of patients with obstructive jaundice.

Prolyl hydroxylase was estimated in the skin of 24 jaundiced patients and 25 non-jaundiced patients. The activity of this enzyme was markedly reduced in the skin of the jaundiced patients.

Structural aspects of the liver in patients with biliary disease and portal hypertension.

Structural changes were examined in liver tissue from 28 patients with chronic bile duct obstruction in whom portal hypertension was diagnosed. Extrahepatic portal occlusion was found in three patients and cirrhosis of the liver in two. In the remaining 23 patients diffuse hepatocyte hyperplasia and portal fibrosis were observed, but a normal spatial relation between portal tracts and hepatic venous radicles was, for the most part, retained. Liver tissue was also examined from a group of 76 patients with chronic bile duct obstruction in whom there was no indication of portal hypertension but some evidence of hepatocyte hyperplasia and fibrosis. Both these features were much less extensive than the changes seen in the group of patients ostensibly suffering from portal hypertension. The findings suggest that the combination of portal hypertension and chronic bile duct obstruction may not imply the unremitting, progressive, and irreversible changes that accompany cirrhosis because the normal vascular relations are retained. In the light of increasing experimental and clinical evidence of the resorption of collagen and the remodelling of hepatic plates it seems that the structural abnormalities in duct obstruction may substantially regress.

A case of veno-occlusive disease of the liver in Britain associated with herbal tea consumption.

Veno-occlusive disease of the liver with clinical and pathological features similar to those of the condition occurring in the Caribbean is described in a young woman resident in Britain. The diagnosis was made from liver biopsies and hepatic venography and was confirmed at necropsy. Small amounts of pyrroliziding alkaloids were recovered from a sample of mate (Paraguay) tea, owned by the patient, to which she was addicted. It seems probable that the consumption of large amounts of this tea over a period of years was the cause of the hepatic disease.

A critical comparison of the value of pregnancy-associated alpha2-glycoprotein and carcinoembryonic antigen assays in patients with colorectal cancer.

Absolute serum concentrations of pregnancy-associated alpha2-glycoprotein (alpha2-PAG) and carcinoembryonic antigen (CEA) were compared in 54 patients before and after surgery for colorectal cancer. Preoperatively, elevated levels of alpha2-PAG were found in 32 (59%) and of CEA in 35 (65%). Postoperatively, elevated alpha2-PAG levels were found in 10 of 18 patients (56%) without clinical evidence of recurrence whereas elevated CEA levels were present in three (16%). In patients who developed clinical evidence of tumour recurrence, alpha2-PAG levels were elevated in 8 of 13 (62%) while CEA levels were uniformly abnormal. It is concluded that, in this cross-sectional study, measurement of alpha2-PAG concentrations is less reliable than CEA in the detection of tumour recurrence after apparently curative surgery for colorectal cancer.