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Objectives: Cytoplasmic clusterin (Clusterin), a ubiquitous multifunctional secretory sulfated glycoprotein, plays a role in apoptosis and is reportedly overexpressed in a variety of tumors. The role of Clusterin in pancreatic neuroendocrine tumors (PNETs) has not been investigated. In this study, Clusterin expression was evaluated in a subset of PNETs, and the results were correlated with the clinical-pathological features of the tumors., Methods: Fifty-nine surgical cases were used to evaluate the immunohistochemical expression of Clusterin in PNETs. Using the avidin-biotin complex method, tissue sections from each case were stained with a rabbit anticlusterin antibody (Abcam, Cambridge, Mass). The immunohistochemical reactions were qualitatively and semiquantitatively evaluated by 2 pathologists., Results: Strong Clusterin reactivity was identified in 36 (61%) of 59 PNETs. In 23 (39%) of 59 cases, the Clusterin score was 3 or less. Clusterin expression scores significantly associated with tumor size (P = 0.03) and with tumor stage (P = 0.02). The immunohistochemical score index did not correlate with tumor grade (P = 0.15)., Conclusions: We report the expression of Clusterin in PNETs. The correlation of Clusterin with tumor size and stage suggests involvement of this molecule in pancreatic neuroendocrine tumor progression. Clusterin may represent a new target of therapy for PNETs.

Objectives: Pancreatic endocrine carcinomas (PECAs) are uncommon, with an incidence of 1 per 100,000. Past studies of chemotherapy and hepatic arterial embolization have described median survival durations of approximately 2 to 3 years. Overall survival from time of diagnosis of metastases has never been reported in a large cohort of patients. Our objective was to evaluate the stage-specific prognosis of patients with metastatic PECAs and to assess the impact of clinical and pathologic prognostic factors., Methods: We evaluated all cases of differentiated, metastatic PECAs seen at the H. Lee Moffitt Cancer Center between the years 1999 and 2003, measuring survival from time of diagnosis of metastases., Results: Ninety cases of metastatic PECAs were identified. Median overall survival was 70 months, and the 5-year survival rate was 56%. Age, sex, and tumor type (functional vs nonfunctional) did not impact prognosis. Tumor grade, however, was highly prognostic for survival., Conclusions: Median overall survival is 70 months (5.8 years) among patients with metastatic PECAs. This prolonged survival duration may reflect the impact of multimodality treatments. Tumor grade (low vs intermediate grade) represents a highly significant prognostic factor.

Objective: The purpose of this study is to report the spectrum of MR findings of pancreatic islet cell carcinoma., Materials and Methods: The MR scans of 33 patients with islet cell carcinoma were retrospectively reviewed. Magnetic resonance detected the primary tumor in 21 of 27 patients (78%) who had not had prior resection of their primary tumor. Mean tumor diameter was 7.1 cm (range 3.5-13.0 cm)., Results: In all patients, the primary tumor on T1-weighted images (TR/TE = 250/15) was of signal intensity equal to or lower than that of the adjacent normal pancreas. The primary tumor on T2-weighted images (TR/TE = 2,000/> or = 100) was of signal intensity the same as or higher than fat in 18 of 21 patients (86%) and had mixed signal intensity in the other 3 (14%). Hepatic metastases were found in 28 of 33 patients (85%). Liver metastases were categorized as "usual" (variably circumscribed, homogeneous lesions of medium signal intensity on T2-weighted images) in 19 of 28 patients (68%), necrotic in 8 of 28 (29%), hemorrhagic in 3 of 28 (11%), and calcified in 1 of 28 (4%). Extrahepatic metastases were found in 18 of 33 patients (55%)., Conclusion: We conclude that MRI is an excellent modality for the diagnosis and routine follow-up of patients with islet cell carcinoma.

Background: The carcinoid syndrome is a rare cause of acquired valvular heart disease. Although the typical echocardiographic features of carcinoid heart disease are well recognized, this large series provides new information about unusual manifestations of the disease as well as the role of Doppler echocardiography., Methods and Results: Between 1980 and 1989, 132 patients with carcinoid syndrome underwent echocardiographic study. The echocardiographic, Doppler, and clinical features of the 74 patients (56%) with echocardiographic evidence of carcinoid heart disease are described. Among these patients, 97% had shortened, thickened tricuspid leaflets. Tricuspid regurgitation was present in all 69 patients with carcinoid heart disease who underwent Doppler examination, and it was of moderate or severe degree in 62 patients (90%). Severe tricuspid regurgitation was characterized by a dagger-shaped Doppler spectral profile with an early peak pressure and rapid decline. The pressure half-time was prolonged (mean, 116 msec), which is consistent with associated tricuspid stenosis. The pulmonary valve appeared thickened, retracted, and immobile in 36 patients (49%) and was diminutive to the extent of not being visualized in an additional 29 patients (39%). Among the 47 patients who underwent Doppler evaluation of the pulmonary valve, regurgitation was present in 81%, and stenosis was present in 53%. Left-sided valvular involvement was present in five patients (7%), four of whom had patent foramen ovale or carcinoid tumor involving the lung. Previously undescribed myocardial metastases were present in three patients (4%) and were confirmed by biopsy in each case. Small pericardial effusions were present in 10 patients (14%). Patients with and without echocardiographic evidence of carcinoid heart disease did not differ with regard to sex, age, location of the primary tumor, duration of diagnosis, or duration of symptoms of carcinoid syndrome. However, the mean pretreatment level of urinary 5-hydroxyindoleacetic acid was higher in patients with carcinoid heart disease than in patients without carcinoid heart disease (270 versus 131 mg/24 hrs, p < 0.001). The symptom of dyspnea was more prevalent among patients with carcinoid heart disease than in patients without the disease (54% versus 27%, p = 0.003); as expected, heart murmurs were also noted more frequently in patients with disease (92% versus 43%, p < 0.0001). Treatment regimens and response to therapy were similar in the two groups. Survival of patients with echocardiographic evidence of carcinoid heart disease was reduced compared with those without cardiac involvement (p = 0.0003). ECG and chest roentgenographic findings in patients with carcinoid heart disease were nonspecific., Conclusions: The broad spectrum of carcinoid heart disease is detailed in this large series. This includes not only right-sided valvular lesions but also left-sided involvement, pericardial effusion, and myocardial metastases.

Neuroendocrine tumors are a group of malignancies that arise from primitive neuroectodermal cells. There is, however, considerable variation in the location and clinical behavior of these tumors. They are often difficult to distinguish from other malignancies and difficult to classify. Recent advances in molecular genetics have attempted to resolve some issues regarding accurate diagnosis, classification into prognostic subgroups, and understanding of basic common mechanisms underlying the development of these tumors. Correlation of morphologic changes with molecular changes induced by some potential therapeutic differentiating agents may lead to more rational therapy for these malignancies.

We report a retrospective review of our experience with close observation after orchiectomy in clinical stage I nonseminomatous germ cell tumors (NSGCT) of the testis during a 10-year period. Twenty-four patients were followed between 1977 and 1986 for a median duration of 47 months (24-112 months). Six of 24 (25%) relapsed at a median of 3.5 months (2-46 months) after orchiectomy; all of these were treated with chemotherapy and are in complete remission at a median of 55 months (27-69 months) after diagnosis of recurrence. Eighteen other (75%) who did not relapse are without evidence of disease at a median of 39 months (24-112 months) after orchiectomy. Orchiectomy alone followed by close observation in clinical stage I NSGCT is a reasonable approach in reliable patient populations at well-equipped centers where adequate follow-up is possible.

One hundred fifty-one women with advanced breast cancer who had failed prior chemotherapy were randomized to monthly courses of doxorubicin (60 mg/m2 I.V. day 1, observation after 500 mg/m2) or doxorubicin (40 mg/m2 I.V. day 1; maximum 500 mg/m2) and mitolactol (135 mg/m2 orally, days 1-10; 180 mg/m2 after maximum doxorubicin). Median survival times were 232 days for doxorubicin and 225 days for doxorubicin + mitolactol, and median times to progression were 112 days and 97 days, respectively. Results are inconsistent with a 25% improvement in survival or time to progression for doxorubicin + mitolactol (p = 0.04 and 0.02, respectively, adjusted for stratification factors but not multiple testing). Regression rates for all patients, both measurable and evaluable, were 30% for doxorubicin alone and 26% for doxorubicin + mitolactol. Regression rates were significantly higher in patients with measurable indicator lesions. Cardiac toxicity was seen in four patients, all of whom were receiving doxorubicin alone. It appears that the combination of doxorubicin + mitolactol is not substantially more effective than doxorubicin alone in women with advanced breast cancer and prior chemotherapy exposure.

A clinical trial of 5-day Cisplatin combined with loading course 5-fluorouracil (5-FU) was conducted in 37 patients with advanced colorectal carcinoma. Objective tumor responses were seen in 10 of 34 patients (29%) who had not received prior chemotherapy. The estimated median survival for previously untreated patients is 26 weeks measured from the onset of therapy. Toxicity consisted primarily of leukopenia, vomiting, and reversible renal insufficiency. This combination of cisplatin and intensive course 5-FU has demonstrated Phase II activity in patients with advanced colorectal cancer. A controlled trial is now in progress to prospectively compare this regimen with full dose single agent 5-FU.

A phase II study of ADAH was conducted in thirty patients with biopsy-prove metastatic or recurrent colorectal carcinoma in order to define its benefits and toxicity. Doses were adjusted by leukocyte nadirs. No patients met the criteria for complete or partial response.