Cortical axon sub-population maintains density, but not turnover, of en passant boutons in the aged APP/PS1 amyloidosis model.

Synaptic dysfunction is one of the key mechanisms associated with cognitive deficits observed in Alzheimer's disease (AD), yet little is known about the presynaptic axonal boutons in AD. Focusing on cortical en passant boutons (EPBs) along axons located in the motor, sensory and prefrontal regions of the cerebral cortex in the APP/PS1 mouse model of AD, we investigated structural properties of EPBs over the lifespan and in response to a midlife environmental enrichment (EE) intervention. At 3, 12, and 18-22 months and following 6 months of midlife EE, we found that EPBs showed remarkable resilience in preserving overall synaptic output, as evidenced by the maintained density of EPBs along the axon shaft across all experimental conditions. Using cranial window imaging to monitor synaptic changes in real time, we report that despite maintaining a stable synaptic density, the dynamic fraction (gains and losses) of EPBs was significantlyreduced at 10-13 months of age in APP/PS1 axons compared to age matched controls.

Percutaneous tumor ablation: increased necrosis with combined radio-frequency ablation and intratumoral doxorubicin injection in a rat breast tumor model.

PURPOSE: To determine whether a combination of intratumoral doxorubicin injection and radio-frequency (RF) ablation increases tumor destruction compared with RF ablation alone in an animal tumor model. MATERIALS AND METHODS: R3230 mammary adenocarcinoma 1.2-1.5-cm- diameter nodules (n = 110) were implanted subcutaneously in 84 female Fischer rats. For initial experiments (n = 46), tumors were treated with (a) conventional, monopolar RF (250 mA +/- 25 [SD] at 70 degrees C +/- 1 for 5 minutes) ablation alone; (b) direct intratumoral doxorubicin injection (volume, 250 microL; total dose, 0.5 mg) alone; (c) combined therapy (doxorubicin injection immediately followed by RF ablation); (d) RF ablation and injection of 250 microL of distilled water; or (e) no treatment. In subsequent experiments, amount of doxorubicin (0.02-2.50 mg; n = 40 additional tumors) and timing of doxorubicin administration (2 days before to 2 days after RF ablation; n = 24 more tumors) were varied. Pathologic examination, including staining for mitochondrial enzyme activity and perfusion, was performed, and the resultant tumor destruction from each treatment was evaluated. RESULTS: Coagulation diameter was 6.7 mm +/- 0.6 for tumors treated with RF ablation alone and 6.9 mm +/- 0.7 for those treated with RF ablation and water (P =.52), while intratumoral doxorubicin injection alone produced only 2.0-3.0 mm of coagulation (P <.001). Increased coagulation was observed only with combined doxorubicin injection and RF therapy (P <.001). Coagulation was dependent on concentration and timing of doxorubicin administration, with greatest coagulation (11.5 mm +/- 1.1) observed for doxorubicin administered within 30 minutes of RF ablation. CONCLUSION: Adjuvant intratumoral doxorubicin injection increases coagulation in solid tumors compared with RF ablation alone. Increased tumor destruction is also seen when doxorubicin is administered after RF ablation, which suggests that RF ablation may sensitize tumors to chemotherapy. Such combination therapies may, therefore, offer improved methods for ablating solid tumors.

A phase II trial of irinotecan (CPT-11) for unresectable biliary tree carcinoma.

BACKGROUND: Unresectable adenocarcinomas of the biliary tree have a very poor prognosis. No good chemotherapeutic regimen is available. Irinotecan has not yet been fully tested in this disease. We evaluated its activity in unresectable bile duct cancers. PATIENTS AND METHODS: Twenty-five consecutive eligible patients at our two institutions were treated with irinotecan at a starting dose of 125 mg/m2. A cycle consisted of once-a-week treatments for four consecutive weeks, followed by two weeks of rest. All patients were required to have histologically confirmed diagnosis, clinically documented metastatic or unresectable carcinoma and measurable disease. Patients were evaluated for response, toxicity, and survival. RESULTS: A total of 83 cycles of therapy were delivered. Two patients had a partial response (8%; 95% confidence interval (CI): 0%-18%) and ten additional patients had stable disease for at least two months (40%; 95% CI: 20.8%-59.2%). The therapy was well tolerated, with moderate myelosuppression and diarrhea as the main toxicities. The overall median survival was 10 months. CONCLUSIONS: Irinotecan has minimal activity in biliary tree carcinomas, but is well tolerated with appropriate supportive care, and produces occasional objective responses.

A phase II study of irinotecan in patients with advanced hepatocellular carcinoma.

BACKGROUND: Advanced hepatocellular carcinoma has a poor prognosis. In a Phase II clinical trial, two academic centers assessed irinotecan, a topoisomerase-1 inhibitor with broad spectrum clinical activity, in patients who had advanced hepatocellular cancer. METHODS: Patients who had had up to one prior chemotherapy regimen were eligible. Bidimensionally measurable disease, a good performance status, and adequate major organ function were required. At a starting dose of 125 mg/m2, irinotecan was administered weekly for 4 weeks followed by a 2 week break, which constituted 1 treatment cycle. Patients were restaged radiologically after two cycles of therapy. Dose attenuations were made as indicated for toxicity. RESULTS: Fourteen patients were enrolled over a 10-week period in 1997. There were ten males and four females. The median age was 58 years (range, 38-74 yrs). The Eastern Cooperative Oncology Group median performance status was 1 (range, 0-1). Two patients had prior chemotherapy (14%), and 1 patient (7%) had had radiation. A total of 30 cycles of therapy were delivered (median, 1; range, 1-6). Considerable toxicity was observed, mostly neutropenia, diarrhea, nausea, vomiting, and fatigue. All patients required at least one dose attenuation for toxicity. One partial response (7%; confidence interval, 0-20%) was noted to last 7 months. One patient had transient stable disease, and all others (86%) had progression of disease as their best response. CONCLUSIONS: Irinotecan had modest activity in advanced hepatocellular cancer. Toxicity was substantial, presumably reflecting impaired underlying liver function or poor ability to metabolize and eliminate the drug. The current study indicated that continued new therapy assessment is warranted for this disease.

Cost-effectiveness of hepatic arterial chemoembolization for colorectal liver metastases refractory to systemic chemotherapy.

PURPOSE: To calculate the cost-effectiveness of hepatic arterial chemoembolization (HACE) for the treatment of colorectal liver metastases (CLM) over a range of survival benefits and to determine the survival benefit that HACE must confer to meet three thresholds of cost-effectiveness. MATERIALS AND METHODS: A spreadsheet model was used to estimate the marginal direct cost of HACE compared with palliative care from a payer's perspective. Medicare reimbursement amounts represented costs, while probabilities of reembolization and complications were obtained from records of patients who underwent HACE. Marginal cost-effectiveness was calculated from marginal direct cost by varying the survival benefit of HACE compared with palliative care from 0 to 24 months. Break-even analyses were conducted to determine the survival benefit at which the cost-effectiveness of HACE would decrease below three threshold values derived from a literature review. RESULTS: The marginal cost-effectiveness of HACE compared with palliative care, given survival benefits of 3, 6, and 12 months, was $82,385, $41,193, and $21,045 per life-year (LY) gained, respectively. Cost-effectiveness thresholds of $20,000 (strict), $50,000 (moderate), and $100,000 (generous) per LY gained required survival benefits of 12.63, 4.94, and 2.47 months, respectively, more than the expected baseline. CONCLUSION: The cost-effectiveness of HACE for the treatment of CLM varies considerably according to the anticipated survival benefit. Results of future randomized controlled trials must demonstrate a survival benefit of nearly 5 months for HACE to meet the moderate cost-effectiveness standard of $50,000 per LY gained.

Chemoembolization of hepatic neoplasms: safety, complications, and when to worry.

Chemoembolization of the liver for unresectable malignancy, although controversial, is being used with increasing frequency. Chemoembolization can be difficult, and there is great potential for causing complications. There are also findings after chemoembolization, particularly on computed tomographic scans, that may appear to indicate complications but are common and of no concern. Chemoembolization requires an understanding of the congenital and acquired variations of arterial anatomy that may be seen supplying the liver. Assessment of the patency of the portal vein is also required. An abnormal portal vein demands significant changes in technique to allow safe chemoembolization. Partial or complete occlusion of the portal vein is associated with significantly decreased survival but does not prevent a worthwhile response to chemoembolization and is not an absolute contraindication. The presence of chemoembolization material in the gallbladder is not uncommon; with the technique used by the authors, the chemoembolization material infrequently causes cholecystitis or gallbladder infarction. Extrahepatic chemoembolization material is commonly seen in other organs but usually does not cause problems, presumably because the dose deposited outside the liver is small compared with the dose delivered to the liver. Other complications include pseudocirrhosis, liver infarction and abscess formation, carcinoid crisis, hepatorenal syndrome, and liver rupture.

A phase II trial of 5-fluorouracil, leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma.

BACKGROUND: Unresectable adenocarcinoma of the biliary tree are associated with a very poor prognosis. 5-fluorouracil (5-FU) combination regimens have produced objective response rates in approximately 10-20% of patients. Leucovorin increases the selective cytotoxicity of 5-FU. There also are encouraging reports of carboplatin in combination with 5-FU in other gastrointestinal tract malignancies. METHODS: Fourteen consecutive eligible patients were treated with a combination of carboplatin, 300 mg/m2, intravenously (i.v.) on Day 1 only and 5-FU, 400 mg/m2, i.v. with leucovorin, 25 mg/m2, i.v. on Days 1-4. All patients were required to have a histologically confirmed diagnosis and measurable disease. Patients were evaluated for response, survival, and toxicity. RESULTS: A total of 48 cycles of therapy were delivered. The median survival was 5 months. One patient achieved complete remission and two others partial remission, for a total response rate of 21.4%. Four additional patients had stable disease for a median duration of 4 months. The therapy was well tolerated, with moderate myelosuppression as the main dose-limiting toxicity. CONCLUSIONS: The current combination regimen of leucovorin-modulated 5-FU with carboplatin is well tolerated with appropriate supportive care, produces significant objective responses in 21% of patients with biliary tree carcinoma, and should be considered for the treatment of this disease.

Selective chemoembolization in the management of hepatic metastases in refractory colorectal carcinoma: a phase II trial.

PURPOSE: Metastatic involvement of the liver frequently determines the evolution of the clinical picture in colorectal cancer patients. We examined the efficacy and toxicity of chemoembolization in this setting, identifying prognostic factors to define patients most likely to benefit from the procedure. METHODS: Forty patients underwent chemoembolization of metastatic liver lesions from colorectal carcinoma. Selective angiography of the hepatic artery was performed to identify the feeding vessels of the metastatic lesions. The injected chemoemulsion consisted of 1,000 mg of 5-fluorouracil, 10 mg of mitomycin C, and 10 ml of ethiodized oil in a total volume of 30 ml. Gelfoam embolization then followed, until stagnation of blood flow was achieved. Patients were evaluated for response, overall survival, and toxicities. RESULTS: Overall median survival from date of first chemoembolization was ten months. Factors that predicted a longer median survival included favorable performance status (24 months), serum alkaline phosphatase and lactate dehydrogenase levels less than three times normal (24 and 12 months, respectively), and metastatic disease confined to the liver (14 months). Most patients tolerated the procedure well. The most common side effects were transient fevers, abdominal pain, and fatigue. Three patients died within one month from the procedure. CONCLUSION: This study suggests that chemoembolization of hepatic metastases in colorectal cancer should be further evaluated; it may be beneficial in patients who have failed systemic chemotherapy, have a good performance status, and have metastatic disease confined to the liver.

Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival.

BACKGROUND: The purpose of this study was to investigate prognostic factors at presentation and the survival of North American patients with hepatocellular carcinoma (HCC). METHODS: A retrospective analysis of medical records was performed for 314 patients identified through the Tumor Registry as having been evaluated for hepatocellular carcinoma at the Deaconess Hospital, Boston, Massachusetts, from 1986 through 1995. Clinical characteristics were noted, including age, sex, TNM staging, serum biochemistries, serum alpha-fetoprotein (AFP), patency of portal vasculature, cirrhosis, history of alcohol abuse, hepatitis-B or C positivity, hemochromatosis, treatment received, and ultimate survival from the date of diagnosis. RESULTS: Overall median survival was 10 months. The presence of cirrhosis, a history of alcohol abuse, low albumin, high bilirubin, abnormal AFP, and portal vein obstruction (PVO) were each associated with significantly shorter survival, as was advanced stage. Only albumin, AFP, and PVO were independent risk factors by multiple regression analysis. Patients undergoing surgery had the longest median survival (45 months), followed by those receiving chemoembolization (14 months). Those patients who were untreated or received systemic chemotherapy alone had significantly shorter survivals (2-4 months). CONCLUSIONS: Despite the difference in the underlying etiology of HCC in this population compared with Asian patients, poor prognostic indicators are similar. In this large series of patients at a single Northeastern hospital, analysis of presenting clinical characteristics was found to offer useful prognostic information.

Multimodality treatment of hepatocellular carcinoma in a hepatobiliary specialty center.

OBJECTIVES: To review the experience of the treatment of hepatocellular carcinoma by a single multimodality team during a 6-year period, including all patients who were referred for possible surgical intervention, to evaluate prognostic factors at presentation, and to determine the results of the different modalities of treatment that were used. DESIGN: Retrospective study of 154 patients who were referred to our Hepatobiliary Surgical Unit with the diagnosis of hepatocellular carcinoma from January 1988 through August 1995. SETTING: Tertiary care center. RESULTS: Methods of treatment included surgical resection (n=49), transplantation (n=22), hepatic artery chemoembolization (n=30), systemic chemotherapy (n=25), and no treatment (n=22). Predictive prognostic factors included coexisting cirrhosis, symptoms at presentation, and abnormal liver function test results. Unfavorable tumor characteristics were size (diameter, >5 cm) and multicentricity. For patients who underwent surgical exploration, advanced staging according to the manual of the American Joint Committee on Cancer, vascular invasion, and a margin of less than 1 cm in the group for patients who underwent resection impacted negatively on the prognosis. The median survival (42.4 months) for the group of patients who underwent resection was significantly higher than that for the groups of patients who did not undergo resection. Chemoembolization was associated with significantly better survival results than was systemic chemotherapy. CONCLUSIONS: Hepatic resection offers the best chance at cure for patients with hepatocellular carcinoma. The high association between hepatocellular carcinoma and cirrhotic liver disease makes surgical resection, even in favorable tumor types, a difficult task based on low hepatic reserve whose tumors are considered unresectable can be considered for chemoembolization. Liver transplantation should be reserved for selected patients with cirrhotic liver disease who have tumors (diameter, <5 cm) in the contest of neoadjuvant protocols.

Chemoembolization for hepatocellular carcinoma: epinephrine followed by a doxorubicin-ethiodized oil emulsion and gelatin sponge powder.

PURPOSE: This study evaluates chemoembolization (CE) of the liver with minimal vasoconstriction followed by selective intraarterial delivery of an emulsion of iopamidol, doxorubicin, and ethiodized oil and temporary occlusion of hepatic artery with gelatin sponge powder in patients with hepatocellular carcinoma. PATIENTS AND METHODS: Since 1988, 30 patients with nonresectable hepatocellular carcinoma underwent CE with the above protocol. Intraarterial epinephrine (0.5-1 microgram diluted in 10 mL of saline) was rapidly injected directly into the proper hepatic artery or selectively into the right or left hepatic arteries and was followed by 40-60 mg of doxorubicin dissolved in 10 mL of iopamidol and emulsified in 20 mL of ethiodized oil. The chemoembolic mixture was injected at the rate of arterial flow. Liver function and clotting parameters were monitored three times a day until there was a downward trend toward preembolic levels. Computed tomography (CT) was performed immediately after embolization and at 1-3-month intervals. Embolization was repeated when CT demonstrated recurrent or progressive disease. RESULTS: Disease recurred or progressed in 11 patients at 2-17 months after embolization. CE was repeated in four patients; one individual underwent three embolizations. Re-embolization was performed up to 14 months after initial embolization (median, 10 months). Five patients (16.7%) died within 1 month of embolization. Ten patients died at 3-33 months after CE. Two of these patients died of cirrhosis at 6 and 14 months, without evidence of recurrent tumor. Fifteen patients remain alive 5-28 months after CE. Kaplan-Meier estimation of probability of survival curves demonstrates a median survival of 14 months. Sixty-one percent of patients were alive at 1 year and 36% at 2 years after the procedure. CONCLUSION: CE with use of the above technique is effective for palliating inoperable hepatocellular carcinoma. It causes a significant prolongation of survival over the expected 18-24 weeks in untreated patients; this may occur because high doses of chemotherapeutic agents are delivered and come in contact with the tumor for a longer period, followed by ischemia brought about by temporary arterial occlusion.