Methodologic and Clinical Validation of the TIMI Myocardial Perfusion Grade in Acute Myocardial Infarction

Improved microvascular perfusion using the TIMI myocardial perfusion grade (TMPG) has been related to reduced in hospital, 30-day and 2-year mortality following thrombolytic administration. We sought to validate this measure using the more quantitative technique of digital subtraction angiography (DSA) and to correlate TMPG with ST segment resolution. DSA was used to analyze films from the LIMIT AMI acute myocardial infarction trial of front loaded r-tPA and rhuMAb CD18. Dye kinetics were also characterized using DSA in 88 arteries from patients without acute coronary syndromes in the absence of an obstructive lesion. Compared to normal patients, microvascular perfusion was reduced in acute myocardial infarction patients on DSA as demonstrated by a reduction in peak Gray (brightness) (p < 0.0001), the rate of rise in Gray/sec (p < 0.0001), the blush circumference (p < 0.0001), and the rate of growth in circumference (cm/sec) (p < 0.0001). However, while DSA perfusion was impaired overall in the setting of acute myocardial infarction, TMPG grade 3 in the setting of acute myocardial infarction did not differ from that in normal patients when studied quantitatively as shown by similar rates of growth in brightness and circumference (p = NS). ST resolution and the TMPG were significantly associated (p = 0.04). Compared to normal patients, acute myocardial infarction reduces the peak brightness of the myocardium, the rate of rise in brightness, the circumference of blush and the rate of growth in circumference as assessed using digital subtraction angiography. However, acute myocardial infarction patients with TMPG 3 had rates of growth in brightness and circumference that were nearly identical to normal patients. Thus, DSA validates that TMPG 3 is associated with normal kinetics of myocardial perfusion, and this likely accounts for the low (0.7%) 30 day mortality observed among those patients with TFG 3 and TMPG 3.     

Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma

European and American investigators have reported response rates of 38% to 83% for ifosfamide alone in pretreated sarcomas. In a phase II trial of ifosfamide 2.0g/m2 days 1 to 4 with mesna uroprotection in 124 patients with previously failed sarcomas, four (3%) responded completely (95% exact confidence interval, 1% to 8%) and 26 (21%) had a complete or partial response (95% exact confidence interval, 14% to 29%). The median time to progression was 5 and 9 months for partial and complete responders, respectively. In the subset of soft tissue sarcomas, the response rate for the patients receiving bolus administration was 26%, compared with 9% for the patients receiving a continuous infusion schedule (P = .03). The response rates among patients with soft tissue and bony sarcomas with a performance score of 0-2 and 0-1 prior to chemotherapy administration were 20% and 40%, respectively. Somnolence or confusion developed in 19%. Neurotoxicity was significantly associated with poor performance status (P less than .01), elevated creatinine (P less than .01), and low bicarbonate levels (P = .05). A serum bicarbonate less than 20 developed in 31% of the patients and was significantly associated with older age (P = .01), elevated creatinine (P = .02), and female sex (P = .06). Hematuria was significantly associated with no uroprotection (the first four patients did not receive mesna because it was unavailable), but was not associated with prior cyclophosphamide, pelvic radiotherapy, age, or bolus v continuation infusion schedule. Thus, ifosfamide is active in failed sarcomas and warrants further study in previously untreated patients with sarcoma.     

Serum erythropoietin levels in patients receiving intensive chemotherapy and radiotherapy

To investigate the potential role of recombinant human erythropoietin (rhEpo) in patients receiving intensive cytotoxic therapy, we measured the endogenous levels of Epo in 31 patients undergoing bone marrow transplantation (BMT). Seventeen patients underwent allogeneic BMT and 14 underwent autologous BMT. On average, 10 +/- 4 units of red blood cells (RBCs) were transfused per patient. The mean RBC transfusion requirement of the autologous BMT patients was significantly greater than that of the allogeneic recipients (12 +/- 3 v 8 +/- 4, P less than .01), although both groups were maintained at comparable hematocrits. Epo levels were measured by radioimmunoassay (RIA). For each patient, baseline serum Epo levels were determined at time of admission to the hospital. Subsequent samples were collected within 24 hours of completing chemotherapy and/or radiotherapy, and on days 7, 14, and 28, after BMT. Hematocrits (Hcts) were measured daily. All patients had an initial serum creatinine less than or equal to 1.5 mg/dL. Despite considerable differences in absolute Epo levels among individuals, a characteristic pattern was observed. Following admission to the hospital and initiation of cytotoxic therapy, the average Hct decreased and the average Epo level initially increased. The mean serum Epo levels peaked on day 7 post-BMT (284 +/- 190 mU/mL) and fell steadily thereafter. While the average Hcts on day 7 and on day 28 post-BMT were not significantly different (28 +/- 4.6% v 29 +/- 3.3%, respectively), the average serum Epo levels decreased fourfold (P less than .01) during this same period. Moreover, day 28 post-BMT mean Epo levels were inappropriately low (P less than .05) when compared with a reference population with bone marrow failure and normal controls who had not received cytotoxic therapy. We conclude that the endogenous Epo response appears to be blunted during the 3 to 4 weeks immediately post-BMT. Therefore, clinical trials assessing the efficacy of the administration of rhEpo in the treatment of anemias associated with cytotoxic therapy are warranted.     

Bone metastases in pheochromocytoma: comparative studies of efficacy of imaging

Bone is the most common site of metastasis from pheochromocytoma. Now that the effects of hypercatecholaminemia can be adequately controlled with adrenergic blockade, pathologic fractures are becoming an increasingly significant cause of morbidity in patients with metastatic pheochromocytoma. Bone metastases from pheochromocytoma have not been extensively reevaluated since the advent of computed tomography (CT), high-resolution bone scintigraphy, and iodine 131 MIBG scintigraphy. Plain radiographs, CT scans, bone scans, and I-131 MIBG scans of 38 patients with pheochromocytoma bone metastasis were reviewed. The axial skeleton was the most common site of metastasis. Metastases typically appeared expansile and mixed lytic-sclerotic on radiographs. Bone scintigraphy was the most sensitive modality for detecting bone metastasis, with 74% of all alleged lesions being identified. In screening for bone metastasis from pheochromocytoma, bone scanning in conjunction with I-131 MIBG scanning is recommended, followed by scan- and symptom-directed radiography and - where a question still exists - CT.     

A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy.

PURPOSE: The study was designed to determine the duration of complete response (CR) for patients with unresectable or metastatic breast cancer treated with high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) while responding to conventional-dose therapy. METHODS: Eligibility criteria included histologically documented metastatic or unresectable breast cancer, at least a partial response (PR) to conventional-dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m3, and physiologic age between 18 and 55 years. Patients with inadequate renal, hepatic, pulmonary, and/or cardiac function or tumor involvement of marrow or CNS were excluded. Cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 were given by continuous infusion over 4 days. After recovery, sites of prior bulk disease were to be radiated or resected if feasible. RESULTS: Of 29 registered patients, one died of toxicity (3%; hemorrhage). CRs and PRs continued a median of 16 and 5 months after transplant, respectively (26 and 9 months from initiation of chemotherapy for metastatic disease). Of 10 patients transplanted in CR, four have not progressed at 17 to 31 months after transplantation (25 to 43 months after beginning standard-dose therapy). One of four patients with uptake on bone scan as their only sites of residual disease before transplant and one of three who converted from PR to CR with transplant have not progressed at 27 and 29 months, respectively, after transplant. CONCLUSIONS: CTCb is an intensification regimen with a low mortality that delivers a significantly increased dose of agents with known activity at conventional doses in breast cancer. Although the duration of PR is short as expected, CRs appear to be durable.     

Behavioral and physiological consequences of suckling in rat and human newborns

Suckling, in addition to yielding milk, water and calories, exerts profound behavioral effects on newborn rats and humans. In particular, suckling induces feelings of calm, reduces heart rate and metabolic rate, causes infants to bring their hands to their mouths and elevates the pain threshold. These changes are mediated by opioid and non-opioid systems, each having its own separate behavioral and neurological characteristics. The implications of suckling-induced changes for long-term motivational and cognitive change are discussed.     

Increase in circulating colony-forming units-granulocyte-macrophage during large-volume leukapheresis: evaluation of a new cell separator

Peripheral blood stem cell (PBSC) collection was evaluated in two groups of normal donors who underwent large-volume leukapheresis on a blood cell separator. In Group A (n = 10), a 3-hour leukapheresis was performed. An average of 11.8 L of blood was processed with a mean flow rate of 66 mL per minute and a collection rate of 3 mL per minute. The PBSC product contained a mean 1.4 x 10(10) mononuclear cells (MNCs) (lymphocytes and monocytes), 1.27 x 10(6) colony-forming units-granulocyte-macrophage (CFUs-GM), and an average hematocrit of 4 percent (0.04). Postapheresis blood counts showed significant reductions in MNCs (19%) and platelets (45%) (p less than 0.005). Twenty-four hours later, the MNCs had returned to preapheresis levels. The platelet count returned to baseline only after 7 days. Circulating CFUs-GM remained stable for 3 days after apheresis but were increased twofold by Day 7 after apheresis (p = 0.025). Varying the product hematocrit from 1 percent (0.01) to 13.3 percent (0.13) did not change the number of CFUs-GM collected per MNC. In Group B (n = 4), an average of 18.5 L of blood was processed with a mean flow rate of 94 mL per minute and a collection rate of 3 mL per minute. The PBSC product was collected as four sequential samples and assayed for MNCs and CFUs-GM. Total MNCs averaged 1.7 x 10(10) (an increase of 21% relative to Group A) and CFUs-GM averaged 3.08 x 10(6) (an increase of 143%). Mean MNCs did not vary significantly among the four samples. However, CFUs-GM collected per minute (relative to the first sample) did show 1.26-fold (p = 0.001), 1.86-fold (p = 0.011), and 2.52-fold (p = 0.04) increases in the second, third, and fourth samples. These data suggest that MNCs and committed progenitor cells are recruited during large-volume leukapheresis. Moreover, there is a twofold increase in circulating CFUs-GM 1 week after apheresis.     

Intracranial circulation: preliminary clinical results with three- dimensional (volume) MR angiography

The authors assessed the clinical utility of a magnetic resonance angiography technique in the evaluation of intracranial circulation. Eighteen patients with a low likelihood of cerebrovascular disease (control group) and 40 patients with suspected cerebrovascular disease were imaged with a FISP (fast imaging with steady precession) sequence (repetition time of 50 msec, echo time of 15 msec, velocity compensation in the read and section-select directions with acceleration compensation in the read direction, 15 degrees anisotropic volume, and a 1.25-mm partition thickness). Ninety-four percent of images in the control group and 72% of images in the group with cerebrovascular disease were considered useful for diagnosis. This technique can provide accurate images of intracranial circulation and can be performed in conjunction with two-dimensional spin-echo or gradient-echo imaging. It was most useful in the evaluation of patent intracranial aneurysms, vessel displacement, and large-vessel occlusive disease. Disadvantages included limited field of view, persistent signal voids, limited spatial resolution, and inadequate depiction of lesions with slow flow.