Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma.

PURPOSE: To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naive or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS: This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. RESULTS: An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naive and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. CONCLUSION: Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.

Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy.

PURPOSE: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody, Rituxan (Rituximab, IDEC-C2B8; IDEC Pharmaceuticals Corporation, San Diego, CA), and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. PATIENTS AND METHODS: Forty patients with low-grade or follicular B-cell non-Hodgkin's lymphoma received six infusions of Rituxan (375 mg/m2 per dose) in combination with six doses of CHOP chemotherapy. RESULTS: The overall response rate was 95% (38 of 40 patients). Twenty-two patients experienced a complete response (55%), 16 patients had a partial response (40%), and two patients, who received no treatment, were classified as nonresponders. Medians for duration of response and time to progression had not been reached after a median observation time of 29 + months. Twenty-eight of 38 assessable patients (74%) continued in remission during this median follow-up period. The most frequent adverse events attributable to CHOP were alopecia (38 patients), neutropenia (31 patients), and fever (23 patients). The most frequent events attributed to Rituxan were fever and chills, observed primarily with the first infusion. No quantifiable immune response to the chimeric antibody was detected. In a subset of 18 patients, the bcl-2 [t(14;18)] translocation was positive in eight patients; seven of these patients had complete remissions and converted to polymerase chain reaction (PCR) negativity by completion of therapy. CONCLUSION: This is the first report demonstrating the safety and efficacy of Rituxan anti-CD20 chimeric antibody in combination with standard-dose systemic chemotherapy in the treatment of indolent B-cell lymphoma. The clinical responses suggest an additive therapeutic benefit for the combination with no significant added toxicity. The conversion of bcl-2 from positive to negative by PCR in blood and/or marrow suggests possible clearing of minimal residual disease not previously demonstrated by CHOP chemotherapy alone.

Cathepsin D and dynamic magnetic resonance imaging gadolinium enhancement in malignant and benign breast lesions.

Our purpose was to determine whether the expression of cathepsin D, a proteolytic enzyme implicated in basement membrane degradation, is associated with dynamic magnetic resonance imaging (MRI) enhancement of breast lesions. Forty-five patients with 48 breast lesions underwent gadolinium-enhanced spoiled gradient recalled echo MRI followed by excisional biopsy and cathepsin D staining and semiquantitative measurement in the lesions. There was no significant difference in cathepsin D staining of 25 malignant and 23 benign breast lesions. A significant association was seen between high cathepsin D staining and positive axillary lymph nodes in invasive carcinomas. Nine of nine (100%) node-positive carcinomas had high cathepsin D, as compared to three of seven (43%) node-negative carcinomas (P = 0.02). No significant associations were observed between cathepsin D staining and MRI enhancement amplitude, rate, or washout. Cathepsin D has no effect upon MRI gadolinium enhancement of malignant and benign breast lesions but is associated with positive axillary lymph nodes in invasive carcinomas.

Copper(II) bis(thiosemicarbazone) complexes as potential tracers for evaluation of cerebral and myocardial blood flow with PET.

Wider application of positron emission tomography would be facilitated by the availability of positron-emitting radiopharmaceuticals labeled with nuclides, like 62Cu, that are available from parent/daughter generator systems. Using a longer-lived copper isotope (67Cu) we have examined three derivatives of copper(II) pyruvaldehyde bis(thiosemicarbazone) as potential tracers for evaluation of cerebral and myocardial blood flow: Cu(PTS), Cu(PTSM), and Cu(PTSM2) (where PTS = pyruvaldehyde bis(thiosemicarbazone), PTSM = pyruvaldehyde bis(N4-methylthiosemicarbazone), and PTSM2 = pyruvaldehyde bis(N4-dimethylthiosemicarbazone). All three lipophilic radiocopper complexes were obtained in high yield via a procedure that could be adapted to a "kit" formulation. In animal model systems Cu(PTSM) and Cu(PTSM2) show excellent uptake in the brain and heart following i.v. injection. These tracers differ in that Cu(PTSM) exhibits microsphere-like retention in the brain and heart, whereas Cu(PTSM2) substantially clears from these organs. The relative cerebral pharmacokinetics of [67Cu]Cu(PTSM) and [67Cu]Cu(PTSM2) are consistent with their known reactivity towards intracellular sulfhydryl groups.

Radioimmunoscintigraphy (RIS) with bectumomab (Tc99m labeled IMMU-LL2, Lymphoscan) in the assessment of recurrent non-Hodgkin's lymphoma (NHL).

UNLABELLED: The efficacy of a Tc99m-labeled anti-lymphoma antibody fragment, bectumomab [LymphoScan], was retrospectively examined in the staging of recurrent or newly diagnosed non-Hodgkin's lymphoma (NHL) [7 patients] and to assess targeting before radioimmunotherapy (RIT) [14 patients]. Performance was graded relative to conventional imaging. Tumors included 7 low-grade, 11 intermediate-grade, and 3 high-grade histologic subtypes. Computed x-ray tomography, radiogallium imaging, FDG-PET, and bone marrow biopsy defined 117 sites. Bectumomab revealed 56% of these sites. In 4 patients bectumomab uncovered five sites not evident by conventional imaging. In addition, it uncovered one site in the brain, an area not covered in the standard work-up of asymptomatic patients. Bectumomab imaging most often failed in central abdominal and thoracic locations, and excelled in revealing disease in the head and neck. Relative to Ga67 citrate imaging, the performance of bectumomab was variable, with no clear relation to anatomic location; there was better targeting of low and intermediate grade NHL. Radiogallium out-performed bectumomab imaging in 23 sites, 19 of which were in patients with high or intermediate-grade disease. Bectumomab was superior to radiogallium at six sites, five of which involved low-grade tumor. CONCLUSION: Bectumomab shows promise as a pre-RIT probe for targeting of B-cell NHL. It excelled at defining small volume, low-grade disease. However, as a purely diagnostic agent, its performance was variable.

Lower extremity deep venous thrombosis in cancer patients: correlation of presenting symptoms with venous sonographic findings.

We sought to determine how rates of sonographically detected deep venous thrombosis correlate with presenting symptoms in cancer patients. We performed venous sonography in 588 cancer patients with clinically suspected lower extremity deep venous thrombosis. Results were correlated with clinical findings. Deep venous thrombosis was diagnosed in 32% of patients with unilateral lower extremity symptoms and in 17% of patients with bilateral symptoms. Patients with unilateral symptoms of pain and swelling, swelling alone, or pain alone had significantly different rates of deep venous thrombosis (47%, 31%, and 16%, respectively). In patients with bilateral leg symptoms, deep venous thrombosis was significantly more likely when symptoms were not bilaterally symmetric.

Splenic enlargement in neonates during ECMO.

PURPOSE: To determine whether hepatosplenomegaly was a reproducible finding in seven neonates who were being treated with extracorporeal membrane oxygenation (ECMO) for respiratory failure. MATERIALS AND METHODS: The authors measured splenic and hepatic dimensions with ultrasound (US) at the time ECMO was initiated and then every 24-48 hours until decannulation. Splenic volume and the index of hepatic size were calculated by using published formulas. RESULTS: Splenic volume increased in all seven patients from 8.3 cm3 +/- 1.7 to 16.4 cm3 +/- 4.4 (P < or = .001). Hepatic size did not change markedly. CONCLUSION: Hemolysis, leukopenia, and platelet activation occur during ECMO. Rapid splenic enlargement may be secondary to sequestration of red cells, platelets, and other hematologic elements that have been damaged in the ECMO circuit. Since the liver does not also increase in size, the splenic enlargement is unlikely to be the result of passive congestion.

Heterogeneity of heparan sulfate proteoglycans synthesized by PYS-2 cells.

Antibodies to the basement membrane proteoglycan produced by the EHS tumor were used to immunoprecipitate [35S]sulfate-labeled protoglycans produced by PYS-2 cells. The immunoprecipitated proteoglycans were subsequently fractionated by CsCl density gradient centrifugation and Sepharose CL-4B chromatography. The culture medium contained a low-density proteoglycan eluting from Sepharose CL-4B at Kav = 0.18, containing heparan sulfate side chains of Mr = 35-40,000. The medium also contained a high-density proteoglycan eluting from Sepharose CL-4B at Kav = 0.23, containing heparan sulfate side chains of Mr = 30,000. The corresponding proteoglycans of the cell layer were all smaller than those in the medium. Since the antibodies used to precipitate those proteoglycans were directed against the protein core, this suggests that these proteoglycans share common antigenic features, and may be derived from a common precursor which undergoes modification by the removal of protein segments and a portion of each heparan sulfate chain.

Combined CT venography and pulmonary angiography: how much venous enhancement is routinely obtained?

OBJECTIVE: Combined CT venography and helical pulmonary angiography is a new diagnostic test that permits radiologists to check both the pulmonary arteries for embolism and the deep veins of the abdomen, pelvis, and legs for thrombosis in a single examination. The purpose of this study was to determine the degree of venous enhancement routinely obtained using this combined CT examination. MATERIALS AND METHODS: We identified all patients at a single institution who, during a 29-month period, had symptoms suggestive of pulmonary embolism and who underwent CT venography and helical pulmonary angiography. The examinations were performed after the patients received a rapid (3--5 mL/sec) IV injection of 150 mL of nonionic contrast medium (240 mg I/mL). CT venography of the abdomen, pelvis, and lower extremities was performed as follows: Beginning 3 min after the start of contrast medium infusion for helical CT pulmonary angiography, 1-cm axial images obtained at 5-cm intervals were acquired from an area ranging from the diaphragm to the calves. Patients who had evidence of deep venous thrombosis on CT scans were excluded from further analysis. The venous portions of the remaining 429 examinations were retrospectively reviewed at a CT console or workstation by one of two radiologists, and Hounsfield unit measurements were recorded from the inferior vena cava as well as from the right and left external or internal iliac, common femoral, superficial femoral, and popliteal veins. A single Hounsfield unit measurement was obtained from the center of each vessel using a region of interest that was approximately half the diameter of the vessel. Mean Hounsfield unit measurements were then calculated for these venous stations. RESULTS: Mean Hounsfield unit measurements at the inferior vena cava and at the right and left external or internal iliac veins were 97, 95, and 95 H, respectively. Mean measurements at the common femoral veins were 95 H for both the right and left; the mean measurements at the superficial femoral veins were 91 H for both the right and left, and those at the popliteal veins were 97 H for the right and 94 H for the left. CONCLUSION: CT venography of the abdomen, pelvis, and lower extremities begun 3 min after the start of contrast medium infusion for helical CT pulmonary angiography routinely produced high mean levels of venous enhancement.

Combined CT venography and pulmonary angiography in suspected thromboembolic disease: diagnostic accuracy for deep venous evaluation.

OBJECTIVE: Combined CT venography and pulmonary angiography is a new diagnostic test that evaluates both pulmonary embolism and deep venous thrombosis (DVT) in a single study. Our purpose was to compare the CT venous findings with lower extremity venous sonography. SUBJECTS AND METHODS: Seventy-one consecutive patients with suspected pulmonary embolism underwent helical CT pulmonary angiography during rapid i.v. infusion of contrast medium. Axial scans at 5-cm intervals from the patient's upper calves to the diaphragm were generated 3.5 min after the beginning of contrast medium injection. CT venous phase images were interpreted prospectively and compared with subsequent bilateral lower extremity venous sonography performed within 12 hr. RESULTS: DVT was revealed by CT venous phase images in 19 patients, 12 of whom also had pulmonary embolism. CT and sonographic findings correlated exactly in the femoropopliteal deep venous system, where most pulmonary emboli originate. CT venous phase images also revealed pelvic extension of DVT in six patients and isolated vena cava thrombus in one patient. CONCLUSION: CT venous phase imaging at the time of CT pulmonary angiography is comparable with venous sonography in the evaluation of femoropopliteal DVT. The iliac veins and vena cava, vessels poorly shown on sonography but sometimes the source of significant pulmonary emboli, are also depicted by CT venography.

Angiogenesis and dynamic MR imaging gadolinium enhancement of malignant and benign breast lesions.

PURPOSE: To determine whether dynamic magnetic resonance (MR) imaging enhancement parameters are associated with vessel density of malignant and benign breast lesions. MATERIALS AND METHODS: Forty-five patients with 48 breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo (SPGR) MR imaging followed by excisional biopsy and Factor VIII staining and vessel density measurement in the lesions. RESULTS: The vessel densities were not significantly different in 25 malignant breast lesions as compared to 23 benign breast lesions. Among all 48 lesions, greater MR enhancement showed an association with increased vessel density. Seventy-four percent of all lesions with MRI enhancement amplitude greater or equal to three times post-precontrast ratio had vessel densities greater than the median of 172 as compared to 34% of lesions with enhancement amplitude less than three times, p = 0.02. The rate and washout of MR enhancement showed no significant association with vessel density. CONCLUSION: Although there is an overall significant association between greater MRI enhancement amplitude and vessel density, MRI gadolinium enhancement of breast lesions is not an accurate predictor of vessel density.

Invasive breast carcinoma: analysis of dynamic magnetic resonance imaging enhancement features and cell proliferative activity determined by DNA S-phase percentage.

BACKGROUND: There is little information regarding associations between magnetic resonance imaging (MRI) enhancement and biologic parameters of breast carcinoma. A prospective study was undertaken to correlate MRI dynamic contrast enhancement features with cell proliferative activity, as determined by DNA S-phase percentage. METHODS: Seventeen patients with invasive breast cancer underwent MRI at 1.5 tesla using a dynamic gadolinium-enhanced spoiled gradient recall echo technique. DNA analysis of samples of the excised lesions was then performed using flow cytometry. RESULTS: Invasive carcinomas with high DNA S-phase percentages (> or = 6.9%, the median value in this study), a measure of increased cell proliferation, were associated with a peripheral MRI enhancement pattern in 4 of 6 (67%) lesions compared with 0 of 11 carcinomas with lower DNA S-phase percentages (< or = 6.9%) (P = 0.006). There was no significant association between a high DNA S-phase percentage and greater MRI enhancement amplitude, rate, or washout. There was no significant association between aneuploid DNA content and any MRI enhancement feature. CONCLUSIONS: Increased cell proliferation in invasive breast carcinoma, as determined by high DNA S-phase percentage, is significantly associated with a peripheral MRI enhancement pattern but unrelated to greater MRI enhancement amplitude, rate, or washout.

A pilot study of cryochemotherapy for hepatic metastases from colorectal cancer.

Cryosurgery of hepatic metastases from colorectal carcinoma is a form of local therapy for unresectable disease. After curative resection, failures occur in the liver, and at extrahepatic sites. This pilot study evaluated the toxicity and tolerance to cryotherapy and intraoperative chemotherapy for unresectable hepatic metastases from colorectal cancer. If after exploratory celiotomy for potential curative resection of hepatic metastases the patient was deemed unresectable because of location and/or number of lesions, cryosurgery and intraoperative chemotherapy with systemic 5-fluorouracil 600 mg/m2 and leucovorin 500 mg/m2 was performed. Four patients were treated with cryochemotherapy. All patients developed toxicity. Two patients developed grade II leukopenia on Postoperative Days 2 and 12, and grades II and III diarrhea on Postoperative Days 5 and 7, respectively. Grade III hyperbilirubinemia and thrombocytopenia occurred in one patient on Postoperative Days 3 and 7. Acute respiratory distress syndrome, postoperative ileus, and grade II mucositis occurred in one patient each. All patients had delays and dose reductions on their subsequent chemotherapy treatments secondary to toxicity. Two patients had disease progression, one had stable disease. and one is "disease free." Combining the tumoricidal effects of chemotherapy and cryosurgery is in theory a good concept. However, the toxicity of 5-FU and leucovorin is enhanced by this approach.

Deep venous thrombosis with suspected pulmonary embolism: detection with combined CT venography and pulmonary angiography.

PURPOSE: To determine the frequency and location of deep venous thrombosis at computed tomographic (CT) venography after CT pulmonary angiography in a large series of patients clinically suspected of having pulmonary embolism and to compare the accuracy of CT venography with lower-extremity venous sonography. MATERIALS AND METHODS: Venous phase images were acquired from the diaphragm to the upper calves after completion of CT pulmonary angiography in 650 patients (373 women, 277 men; age range, 18-99 years; mean age, 63 years) to determine the presence and location of deep venous thrombosis. Results of CT venography were compared with those of bilateral lower-extremity venous sonography in 308 patients. RESULTS: A total of 116 patients had pulmonary embolism and/or deep venous thrombosis, including 27 patients with pulmonary embolism alone, 31 patients with deep venous thrombosis alone, and 58 patients with both. Among 89 patients with deep venous thrombosis, thrombosis was bilateral in 26, involved the abdominal or pelvic veins in 11, and was isolated to the abdominal or pelvic veins in four. In patients in whom sonographic correlation was available, CT venography had a sensitivity of 97% and a specificity of 100% for femoropopliteal deep venous thrombosis. CONCLUSION: Combined CT venography and pulmonary angiography can accurately depict the femoropopliteal deep veins, permitting concurrent testing for venous thrombosis and pulmonary embolism. CT venography also defines pelvic or abdominal thrombus, which was seen in 17% of patients with deep venous thrombosis.

Clinicopathologic effects of cryotherapy on hepatic vessels and bile ducts in a porcine model.

BACKGROUND: The proximity of a hepatic tumor to major vessels and bile ducts limits the use of cryotherapy because of the potential damage to these structures. However, the effects of cryotherapy on major hepatic vessels and bile ducts are not well understood. METHODS: Nine pigs underwent laparotomy and intraoperative ultrasound to identify hepatic vessels larger than 5.0 mm. Cryotherapy consisting of two freeze-thaw cycles was performed, incorporating the identified vessel. In four pigs the Pringle maneuver was performed to determine the effects of partial vascular occlusion on the hepatic parenchyma and structures undergoing cryotherapy. The animals were sacrificed 30 days postoperatively, and the livers were processed for histologic examination. RESULTS: Eight of the nine livers had vessels larger than 5.0 mm incorporated into the iceball, with all vessels having evidence of infarction but remaining patent. All the livers had major bile ducts incorporated in the iceball, with eight having evidence of infarction. The Pringle maneuver had no real effect on the degree of vessel and bile duct infarction. There was no incidence of hepatic bleeding, liver fracture, bile leak, or hemobilia. CONCLUSIONS: Cryotherapy results in the infarction of major hepatic vessels and bile ducts but can be safely performed in the porcine model. Proximity of tumors to major vascular and biliary structures may not be a contraindication to the use of cryotherapy. Further studies are necessary to determine whether cryotherapy can be used in humans.

Extra-thoracic findings on the venous phase of combined computed tomographic venography and pulmonary angiography.

A growing consensus is that pulmonary embolism and thrombosis represent different aspects of the same disease, and a single study that accurately defines both pulmonary emboli and deep venous thrombosis would be a desirable examination. The purpose of this pictorial review is to demonstrate the extra-thoracic findings on the venous phase of such a study, which combines computed tomographic venography and pulmonary angiography.

Response criteria for NHL: importance of 'normal' lymph node size and correlations with response rates.

BACKGROUND: Oncologic literature cites many different definitions of critical response measurements. PATIENTS AND METHODS: Response criteria (RC) for non-Hodgkin's lymphoma (NHL) were developed by lymphoma experts, endorsed by international lymphoma clinicians, and applied to a 166-patient rituximab (Rituxan, MabThera) trial by a third-party, blinded panel of NHL experts (LEXCOR). Retrospectively, we analyzed this data using variations of the original RC and comparing with recently published RC. RESULTS: The definition of a 'normal' lymph node affected the complete response (CR) rate (< or = 1.0 x 1.0 cm, 6%; < or = 1.5 x 1.5 cm, 18%; < or = 2.0 x 2.0 cm, 28%); overall response rate (ORR) was not affected. CR rates increased progressively without > or = 28 days response confirmation: 12% vs. 6% (< or = 1.0 x 1.0 cm), 26% vs. 18% (< or = 1.5 x 1.5 cm), and 36% vs. 28% (< or = 2.0 x 2.0 cm). CR rate and duration of response (DR) were unaffected when only the six largest, rather than all lesions, were measured. When the new RC were applied, CR rate (32%) was higher and DR (13.9 months) and time to progression (15.6 months) were shorter in complete responders. CONCLUSIONS: Standard RC must be consistently and rigorously applied for accurate comparisons between studies.

Suspect breast lesions: findings at dynamic gadolinium-enhanced MR imaging correlated with mammographic and pathologic features.

PURPOSE: To prospectively correlate dynamic contrast enhancement at magnetic resonance (MR) imaging with mammographic and pathologic features of suspect breast lesions. MATERIALS AND METHODS: Forty-nine patients with 51 breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo (SPGR) MR imaging at 1.5 T, as well as excisional biopsy or cyst aspiration. RESULTS: Twenty-two of 22 (100%) invasive carcinomas 8 mm or more in diameter, including three (12%) not evident on dense mammograms, enhanced 2.0 or more times the unenhanced intensity. One of three predominantly ductal carcinomas in situ and 10 of 26 (38%) benign lesions enhanced 2.0 or more times. Time-intensity curves were not statistically significantly different among enhancing carcinomas, fibroadenomas, or other benign lesions and showed no statistically significant correlations with pathologic size, nodal status, or hormone receptor status of invasive carcinomas. CONCLUSION: MR imaging enhancement of 2.0 or more times had high sensitivity (100%) for invasive carcinomas 8 mm or more in diameter, with moderate specificity (65%). Time-intensity curves showed no significant difference between enhancement of benign and malignant lesions.

Safety and efficacy of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: results of the U.S. multicenter phase III clinical trials (safety).

The short-term safety of mangafodipir trisodium (MnDPDP) injection was studied in 546 adults with known or suspected focal liver lesions. An initial contrast-enhanced computed tomography examination was followed by unenhanced magnetic resonance imaging (MRI), injection of MnDPDP (5 micromol/kg), and enhanced MRI. Adverse events were reported for 23% of the patients; most were mild to moderate in intensity, did not require treatment, and were not drug related. The most commonly reported adverse events were nausea (7%) and headache (4%). The incidence of serious adverse events was low (nine events in six patients) and not drug related. Injection-associated discomfort was reported for 69% of the patients, and the most commonly reported discomforts included heat (49%) and flushing (33%). Changes in laboratory values and vital signs were generally transient, were not clinically significant, and did not require treatment. There were no clinically significant short-term risks from exposure to MnDPDP.