Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial.

BACKGROUND: Prostate carcinoma is linked to osteoblastic metastasis. We therefore investigated the value of bone-targeted consolidation therapy in selected patients with advanced androgen-independent carcinoma of the prostate. METHODS: 103 patients received induction chemotherapy, consisting of ketoconazole and doxorubicin alternating with estramustine and vinblastine. After two or three cycles of induction chemotherapy, we randomly assigned 72 patients who were clinically stable or responders to receive doxorubicin with or without strontium-89 (Sr-89) every week for 6 weeks. FINDINGS: Overall 62 of the 103 (60%, 95% CI 50-70) patients had a 50% or greater reduction in serum prostate-specific antigen concentration that was maintained for at least 8 weeks, and 43 (42%, 32-52) had an 80% or greater reduction. 49 (52%) patients with bone pain at registration had complete resolution of pain. After follow-up of 67 patients until death, the estimated median survival for all 103 patients was 17.5 months (range 0.5-37.7). For the 36 patients randomly assigned to receive Sr-89 and doxorubicin, the median survival time was 27.7 months (4.9-37.7), and for the 36 who received doxorubicin alone it was 16.8 months (4.4-34.2) (p=0.0014). The hazard ratio was 2.76 (95% CI 1.44-5.29). INTERPRETATION: Bone-targeted consolidation therapy consisting of one dose of Sr-89 plus doxorubicin once a week for 6 weeks, when given to patients with stable or responding advanced androgen-independent carcinoma of the prostate after induction chemotherapy, improved overall survival.

Sentinel lymph node biopsy is accurate after neoadjuvant chemotherapy for breast cancer.

PURPOSE: Sentinel lymph node (SLN) biopsy has proved to be an accurate method for detecting nodal micrometastases in previously untreated patients with early-stage breast cancer. We investigated the accuracy of this technique for patients with more advanced breast cancer after neoadjuvant chemotherapy. PATIENTS AND METHODS: Patients with stage II or III breast cancer who had undergone doxorubicin-based neoadjuvant chemotherapy before breast surgery were eligible. Intraoperative lymphatic mapping was performed with peritumoral injections of blue dye alone or in combination with technetium-labeled sulfur colloid. All patients were offered axillary lymph node dissection. Negative sentinel and axillary nodes were subjected to additional processing with serial step sectioning and immunohistochemical staining with an anticytokeratin antibody to detect micrometastases. RESULTS: Fifty-one patients underwent SLN biopsy after neoadjuvant chemotherapy from 1994 to 1999. The SLN identification rate improved from 64.7% to 94.1%. Twenty-two (51.2%) of the 43 successfully mapped patients had positive SLNs, and in 10 of those 22 patients (45.5%), the SLN was the only positive node. Three patients had false-negative SLN biopsy; that is, the sentinel node was negative, but at least one nonsentinel node contained metastases. Additional processing revealed occult micrometastases in four patients (three in sentinel nodes and one in a nonsentinel node). CONCLUSION: SLN biopsy is accurate after neoadjuvant chemotherapy. The SLN identification improved with experience. False-negative findings occurred at a low rate throughout the series. This technique is a potential way to guide the axillary treatment of patients who are clinically node negative after neoadjuvant chemotherapy.

Relative contributions of technetium Tc 99m sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay to the surgical management of hyperparathyroidism.

HYPOTHESIS: Technetium Tc 99m sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay have been used to permit a directed operation in patients with hyperparathyroidism. We hypothesized that the coordinated use of these techniques might be particularly useful in patients who require a second operation for hyperparathyroidism. DESIGN: Retrospective analysis was performed to determine the specific contribution of these technologies to the surgical management of patients with hyperparathyroidism who underwent evaluation by at least 2 of these techniques between April 1996 and October 1999. SETTING: Patients were evaluated and treated by an endocrine tumor surgery group within a tertiary care referral center. PATIENTS: Coordinated application of 99mTc-sestamibi scintigraphy, intraoperative gamma probe detection, and/or the rapid parathyroid hormone assay was performed in 32 patients. RESULTS: Twenty-eight of 32 patients had primary hyperparathyroidism, 3 had multiple endocrine neoplasia type 1, and 1 had secondary hyperparathyroidism. The surgical procedure was an initial cervical exploration in 19 and a second operative procedure in 13. Parathyroidectomy was successful in all patients. A directed anatomic operation was performed in 24 patients, including 11 patients who underwent second operative procedures and 9 patients who underwent minimally invasive procedures under local anesthesia. A directed operation was facilitated by sestamibi scan in 22 of 24 patients, intraoperative gamma probe detection in 5 of 23 patients, and the rapid parathyroid hormone assay in 15 of 15 patients. CONCLUSIONS: Coordinated application of 99mTc-sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay allows for successful directed reoperative parathyroidectomy; a minimally invasive procedure may be performed in selected patients.

Determination of glomerular filtration rate using a dual-detector gamma camera and the geometric mean of renal activity: correlation with the Tc-99m DTPA plasma clearance method.

PURPOSE: In this study, the authors studied the use of a dual-detector gamma camera to measure the glomerular filtration rate (GFR). METHODS: Thirty-three patients with a wide range of renal function participated in this study. The GFR was measured using a dual-detector gamma camera by calculating the geometric mean of activity from each kidney and using an outline background. These results were compared with the GFR estimates obtained from Tc-99m DTPA plasma clearance using a multiple blood sample method. RESULTS: Correlation was excellent between GFR estimated using the dual-detector gamma camera and GFR measured using the plasma clearance of Tc-99m DTPA with multiple blood samples (r = 0.89). The correlation was especially strong in children younger than 13 years (r = 0.94). CONCLUSION: Measuring the GFR using a dual-detector gamma camera and calculating the geometric mean of renal activity yields relatively accurate results.

Role of indium-111 labelled platelet scintigraphy in the management of thrombocytopenic patients with malignant neoplasms.

This study was done to investigate the role of indium-111 labelled platelet scintigraphy in the treatment of thrombocytopenia in patients with malignant neoplasms. The study involved 20 consecutive patients with thrombocytopenia associated with malignant neoplasms of hematological disorders and without evidence of underproduction of megakaryocytes due to chemotherapy or bone marrow infiltration by the malignancy. Splenic sequestration of platelets was evaluated by measuring splenic uptake of 111In-labelled platelets, and findings were correlated with the outcome of splenectomy and medication. Of the 20 patients, 13 had splenic sequestration of platelets. Seven of the 13 patients underwent splenectomy; six of these seven patients experienced a complete response. The other six patients received medication only and showed no response. Of the seven patients without splenic sequestration of platelets, five received medication, and four of them responded to it. 111In-labelled platelet scintigraphy has a role in selecting appropriate therapy and predicting its efficacy in patients with thrombocytopenia associated with malignant neoplasms.

Prognosis and treatment of brain metastases in thyroid carcinoma.

We analyzed 47 cases of brain metastases from thyroid cancer seen at 1 institution over 5 decades. Brain metastases were a primary clinical feature at initial presentation in 15% of the cases, were identified during the subsequent course of the disease in 68%, and were only discovered at autopsy in 23%. The primary thyroid tumor was differentiated cancer in 68%, anaplastic cancer in 23%, and medullary cancer in 9%. Patients were typically older, with frequent evidence of aggressive disease and distant metastases at initial cancer diagnosis. Once brain metastases were diagnosed, disease-specific mortality was 78%, with a median product-limit survival of 4.7 months (67% and 12.4 months, respectively, for those with differentiated cancer). Resection of one or more foci of brain metastases significantly improved survival. The median disease-specific survival from diagnosis of brain metastases was 16.7 months for patients who underwent local excision of one or more brain metastases, compared with 3.4 months for those who did not (P < 0.05), independent of the presence of multifocal brain lesions. Recombinant human TSH safely stimulated radioiodine uptake for treatment of brain metastases in 1 patient. However, no evidence of survival benefit was found from radioiodine therapy, external beam radiotherapy, or chemotherapy. In summary, brain metastases from thyroid carcinoma are an extremely poor prognostic sign. Although selection bias and other unidentified factors inherent to retrospective analysis limit this conclusion, surgical resection of brain metastases may be associated with prolonged survival in differentiated carcinoma.

Phase II trial of hepatic arterial infusion of fluorouracil and recombinant human interferon alfa-2b for liver metastases of colorectal cancer refractory to systemic fluorouracil and leucovorin.

PURPOSE: To determine the toxicity, response rate, and survival in patients treated with hepatic arterial infusion (HAI) of fluorouracil (5-FU) plus recombinant human interferon alfa-2b (rIFN-alpha 2b) (Intron-A; Schering-Plough, Inc, Kenilworth, NJ) for colorectal carcinoma (CRC) liver metastases refractory to systemic 5-FU plus leucovorin (LCV). PATIENTS AND METHODS: Forty-eight patients were given a 6-hour HAI of rIFN-alpha 2b 5 MU/m2 followed by an 18-hour HAI of 5-FU, 1,500 mg/m2 daily for 5 days. Twenty-nine patients were treated through percutaneously placed catheters and 19 through implantable infusion pumps (Shiley Infusaid Inc, Noorwood, MA). Treatment cycles were repeated every 28 to 35 days. RESULTS: There were three (6.6%) complete remissions (CRs) and 12 (26.6%) partial remissions (PRs), for a CR plus PR rate of 33.3% among 45 assessable patients (95% confidence interval [CI], 20% to 49%). The median response duration was 7 months, while median survival duration was 15 months. Grade 3 to 4 treatment-related toxic effects included mucositis (40%), neutropenia (42%), and thrombocytopenia (12%). No hepatobiliary toxicity was encountered in any of the patients. Treatment was discontinued because of progressive liver disease in 23 patients and extrahepatic progression in 16, while six patients continue treatment through an infusaid pump. CONCLUSION: HAI of 5-FU plus rIFN-alpha 2b is well tolerated, devoid of hepatobiliary toxicity, and can produce a response rate of 33.3% among patients refractory to bolus intravenous (IV) 5-FU plus LCV. The lack of hepatobiliary toxicity may permit salvage HAI with floxuridine (FUDR) in patients whose liver tumors fail to respond to HAI of 5-FU plus rIFN-alpha 2b. Because diarrhea was not a common side effect of HAI of 5-FU plus rIFN-alpha 2b, it would be of interest to investigate whether alternating HAI of 5-FU and rIFN-alpha 2b with systemic irinotecan (CPT-11) will decrease the incidence of both hepatic and extrahepatic disease progression.

Synthesis, biodistribution, and estrogen receptor scintigraphy of indium-111-diethylenetriaminepentaacetic acid-tamoxifen analogue.

This study was aimed at developing a hydrophilic diethylenetriaminepentaacetic acid-tamoxifen (DTPA-Tam) analogue for use in imaging estrogen receptor positive (ER+) lesions. In rat uterine cytosol, the IC50 of DTPA-Tam conjugate was 1 microM and of tamoxifen, 2 microM. Biodistribution, autoradiography, and radionuclide imaging of 111In-DTPA-Tam in breast-tumor-bearing rats showed that tumor-to-tissue ratios increased steadily between 30 min and 48 h. The in vivo response of MCF-7 breast cancer xenografts to tamoxifen and DTPA-Tam in nude mice demonstrated that DTPA-Tam could reduce tumor growth rate. These results indicate that DTPA-Tam, a new hydrophilic ER+ ligand, might be useful in diagnosing ER+ lesions.

Strontium-89 combined with doxorubicin in the treatment of patients with androgen-independent prostate cancer.

We investigated the activity of a bone-targeting regimen consisting of strontium-89 and doxorubicin in the treatment of patients with androgen-independent prostate cancer. Three and 22 patients with androgen-independent prostate cancer and bone metastasis received doxorubicin at 15 mg/m(2) and 20 mg/m(2), respectively (intravenously by continuous infusion over 24 hours, once per week). All patients received strontium-89 55 µCi/kg, intravenously, every 3 months. Antitumor activity (a prostate specific antigen decrease of ≥75% from baseline) was seen in 32% of evaluable patients. Clinical benefit based on pain relief and performance improvement was achieved in 76% and 40% of patients, respectively. Strontium-89 combined with doxorubicin can be delivered with acceptable toxicities. Strontium-89 combined with doxorubicin is active in the treatment of androgen-independent prostate cancer and may be useful in future studies designed to optimize organ (bone)-specific therapies.

Value of SPECT imaging of the thoracolumbar spine in cancer patients.

The purpose of this study was to evaluate the usefulness of SPECT bone imaging in targeting the precise location of vertebral abnormalities to ascertain whether such knowledge would help in differentiating between metastatic and benign lesions. SPECT images of the thoracolumbar spine in 50 patients were correlated with plain x-rays, CT, MRI, PET, and bone scans and 6-month clinical follow-ups. SPECT images revealed 110 lesions, 35 of which were metastases. Twenty-four of 25 lesions involving the vertebral body with extension into posterior elements were metastases, as well as 10 of 39 lesions found in the vertebral body and 1 of 4 found in the spinous process. All lesions limited to the anterior aspect of the vertebral body (13/13), facet joints (23/23), and intervertebral disk space (6/6) were benign. In conclusion, SPECT imaging of the thoracolumbar spine is helpful in determining the precise anatomic location of vertebral abnormalities, and knowledge of the location can be used to determine whether these abnormalities in cancer patients are benign entities or metastases.

Rapid identification of common human pathogens by high-resolution proton magnetic resonance spectroscopy.

Routine procedures for recovery of bacteria from clinical specimens involve culturing the latter on various nonselective and selective agar media. The bacteria are then identified by means of biochemical and immunological test procedures. Reduction of the time required to identify the bacteria is highly desirable for rapid clinical diagnosis. Towards this end the potential of proton nuclear magnetic resonance (NMR) spectroscopy for providing a "fingerprint" within the proton spectrum of five bacterial genera, reflecting their characteristic cell wall constituents, has been investigated. Establishing a database of high-resolution proton NMR spectra of a large number of bacterial species is a prerequisite for attaining this objective. A database has been established for five common human pathogens: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. On the basis of the presence of characteristic resonances in their spectra, a simple algorithm has been developed to differentiate and identify these microorganisms. The NMR spectra of E. coli and S. aureus showed no dependency on the type of growth medium, growth density, or incubation time.

Nuclear hepatobiliary imaging.

Recent improvements in hepatobiliary radiopharmaceuticals and the high prevalence of biliary tract disease have resulted in a larger role for hepatobiliary imaging in clinical applications. The use of hepatobiliary imaging in assessing hepatic blood flow, hepatocyte function, biliary drainage, and complications in patients with jaundice or abdominal pain or surgery, as well as its primary use in diagnosing acute cholecystitis, is discussed.

Evaluation of soft tissue injury by Tc-99m bone agent scintigraphy.

Six patients with soft tissue injury secondary to different etiologic factors are presented. The degree and extent of tissue necrosis was precisely identified by scintigraphy. In two of these, radionuclide imaging helped to establish accurately the level of amputation that resulted in appropriate wound healing.

Bone scintigraphy in calcific discitis of childhood.

The bone scintigraphic findings of calcific discitis of childhood is described and one new case is presented. A brief review of the value of bone scintigraphy in the diagnosis of this syndrome as well as pathogenesis, clinical course, and treatment is provided.

Cavernous sinus syndrome as the presentation of malignant lymphoma: case report and review of the literature.

Cavernous sinus syndrome (CSS) is an unusual presentation of malignant lymphoma. We report a patient with lymphoma that presented with CSS, and we review the literature on nine other reported cases. Sharp retroorbital pain, paraesthesia around the orbit, and complete 6th nerve palsy were dominant presenting symptoms. In all cases, the tumor developed on the right side. The computed tomographic scan was abnormal in only two of the nine patients during the early stages of the disease. The dominant histological type was large cell lymphoma. The mean age of the patients was 45 years. The mean survival time after the first presenting symptom was 8.7 months. Two of the reported patients as well as our patient had disseminated disease, which became evident at autopsy.