Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group.

PURPOSE: Pamidronate, an aminobisphosphonate, has been shown to lower the risk of skeletal complications associated with lytic bone lesions for up to 1 year in women with stage IV breast cancer who received chemotherapy. We studied the long-term effectiveness and safety of continued treatment with intravenous pamidronate infusions for up to 2 years. PATIENTS AND METHODS: Three hundred eighty-two women with metastatic breast cancer and lytic bone lesions who received chemotherapy were randomly assigned to receive either 90 mg of pamidronate or placebo intravenously every 3 to 4 weeks in this double-blind, multicenter, parallel-group trial. Patients were evaluated monthly for 2 years for skeletal complications, which included pathologic fractures, need for radiation or surgery to treat bone complications, spinal cord compression, and hypercalcemia. Bone pain, analgesic use, bone biochemical markers, performance status, quality of life, radiologic response in bone, and survival were also evaluated. RESULTS: As in the first year of treatment, the proportion of patients with any skeletal complication was significantly less for the pamidronate than the placebo group at 15, 18, 21, and 24 months (P < .001). The proportions of patients with any pathologic fracture (i.e., vertebral and nonvertebral fractures), need for radiation or surgery to treat bone complications, and hypercalcemia were also statistically less for the pamidronate than the placebo group. The median time to the first skeletal complication was 13.9 months in the pamidronate-treated women and 7.0 months in the placebo group (P < .001). Long-term treatment did not result in any unexpected adverse events. Survival did not differ between the two groups. CONCLUSION: The risk for osteolytic bone lesion complications in metastatic breast cancer was significantly decreased with monthly infusions of 90 mg of pamidronate, and this effect was maintained for at least 2 years. Pamidronate is a useful adjunct to standard chemotherapy in the palliative treatment of metastatic breast cancer.

Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group.

PURPOSE: To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma. PATIENTS AND METHODS: Patients with stage III myeloma and at least one lytic lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles. At study entry, the patients were stratified according to whether they were to receive first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy. Skeletal events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) and hypercalcemia were assessed monthly. RESULTS: The results of the first nine previously reported cycles are extended to 21 cycles. Of the 392 randomized patients, efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo. After 21 cycles, the proportion of patients who developed any skeletal event was lower in the pamidronate-group (P = .015). The mean number of skeletal events per year was less in the pamidronate-group (1.3) than in placebo-treated patients (2.2; P = .008). Although survival was not different between the pamidronate-treated group and placebo patients overall, stratum 2 patients who received pamidronate lived longer than those who received placebo (14 v 21 months, P = .041). Pamidronate was safe and well tolerated during the 21 cycles of therapy. CONCLUSION: Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients, and may improve the survival of patients on salvage therapy.

Imaging of fallopian tube tumors.

OBJECTIVE: The purposes of this study were to investigate the imaging findings in patients with primary fallopian tube neoplasms and to determine whether specific imaging features favor the preoperative diagnosis of fallopian tube tumors (FTT). MATERIALS AND METHODS: Computerized search of medical records from 1984 to 1994 identified 20 patients with a discharge diagnosis of primary fallopian tube carcinoma. Medical records, imaging studies, and pathology findings were reviewed. Eleven patients had available preoperative imaging. RESULTS: Seventeen of 20 patients with primary FTT had unilateral disease. Of these 17, preoperative imaging was available in nine, showing four solid adnexal masses, four complex cystic adnexal masses, and one normal adnexa. The preoperative imaging of these nine patients included six sonographic and five CT studies. Three patients with primary FTT had bilateral tumors, and preoperative imaging was available for two patients: Two sonographic studies and one CT study showed one complex cystic adnexal mass and three normal adnexa. CONCLUSION: Primary FTT commonly presents as an adnexal mass on preoperative imaging and mimics other pelvic malignancies, especially ovarian carcinoma. Making a specific preoperative diagnosis is difficult; however, because primary FTT is unlikely to be confused with a benign process, delay in diagnosis is rare.

Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group.

BACKGROUND: Bisphosphonates such as pamidronate disodium inhibit osteoclast-induced bone resorption associated with cancer that has metastasized to bone. METHODS: Women with stage IV breast cancer who were receiving cytotoxic chemotherapy and had at least one lytic bone lesion were given either placebo or pamidronate (90 mg) as a two-hour intravenous infusion monthly for 12 cycles. Skeletal complications, including pathologic fractures, the need for radiation to bone or bone surgery, spinal cord compression, and hypercalcemia (a serum calcium concentration above 12 mg per deciliter [3.0 mmol per liter] or elevated to any degree and requiring treatment), were assessed monthly. Bone pain, use of analgesic drugs, performance status, and quality of life were assessed throughout the trial. RESULTS: The efficacy of treatment was evaluated in 380 of 382 randomized patients, 185 receiving pamidronate and 195 receiving placebo. The median time to the occurrence of the first skeletal complication was greater in the pamidronate group than in the placebo group (13.1 vs. 7.0 months, P=0.005), and the proportion of patients in whom any skeletal complication occurred was lower (43 percent vs. 56 percent, P = 0.008). There was significantly less increase in bone pain (P=0.046) and deterioration of performance status (P=0.027) in the pamidronate group than in the placebo group. Pamidronate was well tolerated. CONCLUSIONS: Monthly infusions of pamidronate as a supplement to chemotherapy can protect against skeletal complications in women with stage IV breast cancer who have osteolytic bone metastases.

Endometrial polyps, hyperplasia, and carcinoma in postmenopausal women: differentiation with endovaginal sonography.

PURPOSE: To characterize endometrial polyps, hyperplasia, and carcinoma with endovaginal ultrasound in postmenopausal women. MATERIALS AND METHODS: Seventy-three postmenopausal women with abnormally thick endometria on endovaginal sonograms were retrospectively identified. The endometrial appearance was characterized as hyperechoic, containing cystic spaces, or heterogeneous. The final study group consisted of 68 women, in whom the pathologic and sonographic findings were correlated. RESULTS: Thirty sonograms showed hyperechoic endometria in women with hyperplasia (n = 8), polyps (n = 4), polyps and hyperplasia (n = 2), or atrophy, proliferative change, mild atypia, or normal endometria (n = 16); 27 sonograms showed cystic spaces in women with polyps (n = 21), carcinoma (n = 1), polyps and hyperplasia (n = 2), or atrophy (n = 3); and 11 sonograms showed heterogeneous endometria in women with endometrial carcinoma (n = 7), atrophy (n = 2), proliferative endometrium (n = 1), or secretory endometrium (n = 1). Cystic spaces were predictive of polyps (P = 1.19 x 10(-10)). CONCLUSION: Endovaginal sonography may be useful for differentiation of endometrial polyps, hyperplasia, and carcinoma.

Efficacy of sonographically guided biopsy of thyroid masses and cervical lymph nodes.

OBJECTIVE: We performed a prospective study in 96 patients to determine accuracy of sonographically guided fine-needle aspiration biopsy of thyroid masses and cervical lymph nodes. MATERIALS AND METHODS: Real-time sonography was used to guide biopsy of 112 cervical masses in 96 patients (71 patients with impalpable masses, 16 with failed unguided attempts, patient's or physician's preference in nine). The diameters of all masses were less than 3 cm, with a mean of 1.5 cm and a median of 1.5 cm. Twenty-nine masses measured 1 cm or less in diameter, 60 masses between 1.1 and 2.0 cm, and 23 masses between 2.1 and 3.0 cm. Cervical masses that were sampled by biopsy included 75 thyroid masses and 37 lymph nodes. RESULTS: Diagnostic specimens were obtained in 102 (91%) of 112 masses sampled. Sixty-eight (91%) of 75 biopsies of thyroid tissue and 34 (92%) of 37 biopsies of lymph nodes were diagnostic. Nondiagnostic thyroid biopsies included four of complex cysts and three of solid nodules. Sonographic follow-up (1 year) revealed no change or decrease in size of those seven lesions. Sixty of 68 diagnostic thyroid biopsies showed benign processes: 42 macrofollicular adenomas, six colloid adenomas, five microfollicular adenomas, four probable cases of thyroiditis, and three hemorrhagic cysts. The remaining eight diagnostic thyroid biopsies showed malignant processes: seven papillary carcinomas and one metastatic small-cell carcinoma. Of 34 diagnostic biopsies of lymph nodes, 26 showed malignant processes and eight showed benign processes. Surgery in the three patients with nondiagnostic biopsies of lymph nodes revealed two recurrent medullary cancers and one benign node. CONCLUSION: Sonographically guided fine-needle aspiration biopsy of neck masses has a high sensitivity (91%) and should be routinely used to evaluate indeterminate masses in the neck.

Fine-needle biopsy of cervical lymph nodes in patients with thyroid cancer: a prospective comparison of cytopathologic and tissue marker analysis.

Tissue levels of thyroglobulin (Tg) or calcitonin were compared with specimens from neck lymph node biopsy in patients with suspected recurrent differentiated (papillary or follicular) or medullary thyroid cancer. Thirty-six neck lymph node biopsies were performed in 29 patients. Tissue Tg levels were obtained from 31 specimens from patients with differentiated thyroid cancers, and tissue calcitonin levels were obtained from five specimens from patients with medullary cancer. Thirteen nodes were diagnosed as negative for cancer at surgery (n = 3) or follow-up sonography (n = 10). Malignant disease was confirmed at surgery in 23 of the 36 lymph nodes. Cytopathologic examination had a sensitivity of 91% and a specificity of 100%. Tissue Tg levels ranged from 0 to 3.5 ng/mL (mean, 1.5 ng/mL; median, 1.2 ng/mL) in 12 of the 13 benign lymph nodes and from 21 to 247,500 ng/mL (mean, 30,600 ng/mL; median, 2,330 ng/mL) in the 23 malignant nodes. Tissue calcitonin levels were elevated (range, 850-703,125 pg/mL; mean, 184,762 pg/mL; median, 17,538 pg/mL) in four malignant nodes and were normal (3.0 pg/mL) in one benign node. Diagnostic sensitivity of tissue markers was 91%. Specificity was 91%. The combined diagnostic sensitivity and specificity of tissue marker analysis and cytopathologic examination was 100%.

Optimal technique for detection of gallstones at injection cholecystography: in vitro analysis.

Injection cholecystography is often employed during invasive gallbladder procedures to determine the number of gallstones that are present. The authors undertook this study to define the optimal radiographic technique for performance of injection cholecystography. Condoms filled with 100 mL of contrast medium at four different iodine concentrations (30%, 15%, 7.5%, and 3.8% [wt/vol]) and containing up to five 4-mm-thick gallstones or a single 10-mm-thick gallstone were radiographed in a 20-cm-deep water bath by using four kilovolt peak settings (70, 80, 90, and 100 kVp). Images were read by three radiologists who were blinded to the radiographic technique. significantly (P less than .05) improved Decreasing iodine concentration significantly (P less than .05) improved detection of 4-mm-thick gallstones at a constant kilovolt peak setting. However, increasing the kilovolt peak setting while using the same concentration of contrast medium had no statistically significant influence on gallstone detectability, although radiologists did indicate a preference for the high-kilovolt peak technique. Results of the authors' experiments showed that for detection of small gallstones at injection cholecystography, use of a low-concentration contrast medium and a high kilovolt peak setting is the recommended radiographic technique.

Treatment of critically ill patients with sepsis of unknown cause: value of percutaneous cholecystostomy.

Because of the difficulty in diagnosing acute cholecystitis in critically ill patients with severe intercurrent illness by clinical and imaging methods or percutaneous aspiration of the gallbladder, a trial of percutaneous cholecystostomy was performed in 24 patients in the intensive-care unit with persistent, unexplained sepsis after a complete clinical, laboratory, and radiologic search showed no alternative source of infection. Persistent high fevers, despite antibiotic therapy, were present in all patients, with elevated WBC count in 18 patients, vague abdominal tenderness in 11, and septic shock requiring vasopressors in 15. Sonographically, all patients had distended, spherical gallbladders, six had gallstones, eight had wall thickening, three had pericholecystic fluid, and four had Murphy's sign. All patients were seen by a senior abdominal surgeon, who agreed to a trial of percutaneous cholecystostomy. Fourteen patients (58%) responded to percutaneous cholecystostomy, as evidenced by a decrease in WBC count, defervescence, and the ability to be weaned off vasopressors. Bile cultures were positive in four patients. Ten patients (42%) did not respond to percutaneous cholecystostomy; five eventually died of unrelated causes. A respiratory source of infection was eventually found in three of these 10 patients, with no proved source of infection in the remainder. No complications related to catheter insertion occurred in this group of patients. Bile leaks occurred in two patients when the percutaneous cholecystostomy catheter was removed, but without serious consequence. Our experience suggests that a lower threshold for performing percutaneous cholecystostomy in this difficult clinical subset of patients is worthwhile.

Benign and malignant adrenal masses: CT distinction with attenuation coefficients, size, and observer analysis.

In a retrospective study of adrenal masses evaluated with computed tomography (CT), lesion x-ray attenuation was compared with size and radiologists' interpretations in discriminating benign lesions from malignant ones. Unenhanced CT attenuation coefficient and size were analyzed electronically in 55 patients with 66 adrenal masses. There were 38 nonhyperfunctioning adenomas in 33 patients and 28 malignant masses in 22 patients. Primary extraadrenal malignancies were present in 45 of the 55 patients. Three blinded readers characterized the adrenal masses using a seven-point scale of certainty. Results were subjected to receiver operating characteristic (ROC) analysis. The mean CT attenuation coefficient for benign adrenal masses was -2.2 HU +/- 16.0 and was significantly different from the mean for malignant lesions (28.9 HU +/- 10.6). The area under the ROC curve for CT attenuation coefficients (0.91 +/- 0.04) was significantly larger than that for lesion size (0.84 +/- 0.05) or best observer interpretation (0.84 +/- 0.05). A threshold CT attenuation value of 0 HU had a sensitivity-to-specificity ratio of 47%:100% for characterizing benign adrenal masses, whereas a threshold attenuation of 10 HU had a ratio of 79%:96%.

Simulation of gallstone fragments by cavitation bubbles during extracorporeal shock wave lithotripsy: physical basis and in vitro demonstration.

During extracorporeal shock wave lithotripsy of gallstones, sonography often shows a swirling pattern of echogenic foci shortly after the application of shock waves. This effect has been thought to represent gallstone fragments in suspension. However, evidence suggests that this finding is in part due to cavitation, a physical phenomenon associated with the formation or movement of gas bubbles in the fluid-filled gallbladder. Condoms filled with degassed water and five human bile specimens were positioned in the focus of an MPL 9000 lithotriptor (Dornier Medical Systems, Munich). A solitary nonradiopaque gallstone was then added to a bile-filled condom, and the sonographic pattern was observed before and after fragmentation. The mean clearance time of the cavitation bubbles was 4 seconds for degassed water and 22 seconds for human bile. Gallstone fragments were distinguished from cavitation bubbles by their prolonged settling time (up to 30 minutes) along the dependent gallbladder wall.

Evaluation and treatment of the dominant dorsal duct syndrome (pancreas divisum redefined).

The controversial association of pancreatitis and pancreas divisum was studied in 100 patients (77 women, 23 men, median age 35) with episodic acute pancreatitis (49%) or "pancreatic pain" (51%). Seventy-one had classic pancreas divisum (type 1); 23 had only a dorsal duct with an absent Wirsung's duct (type 2); and 6 had a filamentous connection between the two duct systems (type 3). Accessory papilla sphincteroplasty was performed in 88 patients, with a mean follow-up of 53 months. The orifice was stenotic at the mucosal level in 66 patients. Seventy percent of patients have shown improvement: 85% if the accessory papilla was stenotic, compared with 27% if it was not (p less than 0.0001); and 82% with discrete attacks, compared with 56% with chronic pain (p = 0.002). Judged against intraoperative calibration of accessory papilla orifice diameter, ultrasonography with secretin stimulation was 78% sensitive for accessory papilla stenosis, with 3% false-positive results. Ultrasonography with secretin stimulation was the best predictor of surgical success: positive = 92% success (attacks or pain) versus negative = 40% success (64% with attacks; 21% with pain). There have been seven restenoses with six reoperations. We conclude that (1) pancreas divisum is but one variety of pancreatic anatomy characterized by a dominant dorsal duct and dependence on secretion through the accessory papilla; (2) accessory papilla stenosis appears to be a necessary cofactor to produce a morbid state, whether episodic pancreatitis or pancreatic pain; (3) presentation with pancreatitis and a positive result on the ultrasound-secretin test are the best predictors of successful accessory papilla sphincteroplasty.

Infected abdominal tumors: percutaneous catheter drainage.

Sixteen patients underwent percutaneous catheter drainage of infected primary (n = 9) or metastatic (n = 7) abdominal tumors. Twelve of the patients improved clinically, as evidenced by defervescence and decrease or normalization of leukocytosis. Four patients did not respond to catheter drainage and required surgery. Three of the twelve who improved underwent operations for attempts at surgical cure or debulking of tumor volume despite an initial "good" response to percutaneous drainage. Of the nine patients who did not undergo surgery after percutaneous drainage, four underwent catheter removal after 5 weeks of drainage and had no recurrence of infection, two remained alive with the catheter in place up to 8 months and 1 year after drainage, and two died with the catheter in place. One patient had the catheter removed inadvertently after 3 weeks of drainage and had recurrences that required replacement of the catheter until his death. The major differences between drainage of necrotic tumors and drainage of standard abscesses were the need for surgery in the majority of the cases and the fact that patients needed the catheters for continued palliation until their death.

Routine sonographic techniques fail to quantify gallstone size and number: a retrospective study of 111 surgically proved cases.

We analyzed sonographic images retrospectively to determine their value in quantifying gallstone size and number in 111 surgically proved stone-containing gallbladders for which routine preoperative sonograms were available. The number and size of of stones found on pathologic examination were correlated with the results of image analysis. In patients with more than one stone, observable size differences were recorded if the smallest stone diameter was less than 50% of the largest stone diameter. Estimates of gallstone size and number from preoperative sonograms were correct in only 23 (21%) of 111 cases. Stone size and number were overestimated as often as they were underestimated. Stones of a uniform size were recognized correctly in 59 (92%) of 64 cases. Stones of two different sizes were correctly identified in only 14 (30%) of 47 cases; the second, smaller stones were missed in 26 (79%) of 33 cases. These findings indicate poor sonographic characterization of gallbladder contents when imaging studies are performed solely to determine the presence or absence of gallstones.

Extracorporeal shock-wave lithotripsy of gallstones: Boston experience with the Dornier MPL 9000 lithotripter.

After the success of shock-wave therapy for fragmentation of renal stones, machines for shock-wave therapy of gallbladder stones were quick to follow. In Munich, gallstones were successfully treated in 174 of 175 patients who were also taking ursodiol to help solubilize the calculous rubble left after treatment. In Boston, of the initial 87 patients accepted, 58 were treated for a single stone (mean diameter 15.7 mm), 16 were treated for 2 stones, and 13 for 3 stones. Although reporting of exact results is not possible before the Food and Drug Administration issues a clearance, it is fair to say that both patients and physicians are generally pleased with the results.

Imaging of pancreatic neoplasms: comparison of MR and CT.

Thirty-two patients with pathologically proved pancreatic carcinomas or cystadenomas were evaluated with MR images obtained with T1-weighted spin echo (short TR/short TE), inversion recovery, and T2-weighted spin-echo (long TR/long TE) pulse sequences. CT was used as the reference standard to determine the ability of MR to delineate normal and abnormal pancreatic anatomy and thereby to exclude or detect pancreatic malignancy. Short TR/short TE spin-echo sequences were significantly better (p less than .05) than inversion recovery or T2-weighted spin-echo sequences in resolution of both normal and abnormal anatomy. Resolution of pancreatic anatomy correlated (r = .9) with the image signal-to-noise ratio. In seven (22%) of 32 cases, MR visualized pancreatic tumors better than CT did because it showed a signal intensity difference between the tumor and normal pancreatic tissue. Overall, the slight superiority of MR over CT for tumor visualization tended to occur in larger tumors and was not statistically significant. On T1-weighted images, 63% (20 of 32) of pancreatic tumors studied had lower signal intensities than normal pancreatic tissue, whereas on T2-weighted sequences (TE = 60, 120, and 180 msec) only 41% (13 of 32) of tumors had increased signal intensities. Currently available MR imaging techniques offer no significant advantages over CT for evaluating the pancreas for neoplasia.

The sonographic diagnosis of acute gangrenous cholecystitis: importance of the Murphy sign.

The sonographic Murphy sign is defined as the presence of maximal tenderness elicited by direct pressure of the transducer over a sonographically localized gallbladder. The reported prevalence of this sign is more than 95% in patients with acute cholecystitis. In this series of 18 patients with pathologically proved gangrenous cholecystitis, the sonographic Murphy sign was positive in only six (33%). Clinical examination showed a positive Murphy sign in eight patients (44%), diffuse abdominal pain in nine patients (50%), and no pain in one patient (6%). Other sonographic findings included pericholecystic fluid (10), thickening of the gallbladder wall (10), and a dilated gallbladder (five). Our experience suggests that the absence of the Murphy sign increases the possibility of gangrenous cholecystitis in patients with abdominal pain and sonographic findings of cholecystitis.