Orbital-dependent modifications of electronic structure across the magnetostructural transition in BaFe2As2.

Laser angle-resolved photoemission spectroscopy (ARPES) is employed to investigate the temperature (T) dependence of the electronic structure in BaFe2As2 across the magnetostructural transition at T{N} approximately 140 K. A drastic transformation in Fermi surface (FS) shape across T{N} is observed, as expected by first-principles band calculations. Polarization-dependent ARPES and band calculations consistently indicate that the observed FSs at k{z} approximately pi in the low-T antiferromagnetic state are dominated by the Fe3d{zx} orbital, leading to the twofold electronic structure. These results indicate that magnetostructural transition in BaFe2As2 accompanies orbital-dependent modifications in the electronic structure.

A multi-center phase I study of clofarabine, etoposide and cyclophosphamide in combination in pediatric patients with refractory or relapsed acute leukemia.

This Phase I study of clofarabine with etoposide and cyclophosphamide for children with relapsed/refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicities and the recommended phase 2 doses (RP2Ds). All three drugs were administered for five consecutive days in induction and four consecutive days in consolidation, for a maximum of eight cycles. A total of 25 patients (20 ALL and 5 AML) were enrolled in five cohorts. An MTD was not reached. The RP2Ds of clofarabine, cyclophosphamide and etoposide were 40, 440 and 100 mg/m(2)/day, respectively. Complete remission (CR) was achieved in 10 patients (ALL: nine; AML: one), and CR without platelet recovery in six patients (ALL: two; AML: four) for an overall response rate of 64% (ALL: 55%; AML: 100%). Of the 16 responders, 9 patients proceeded to hematopoietic stem cell transplantation. In conclusion, the combination of clofarabine, etoposide and cyclophosphamide was well tolerated and effective in pediatric patients with relapsed/refractory leukemia. Of note, the phase II portion of the trial was amended after the occurrence of unexpected hepatotoxicity. The ongoing phase II study will evaluate the efficacy and safety of this regimen in ALL patients.

Anterior pedicle screw fixation for multilevel cervical corpectomy and spinal fusion.

BACKGROUND: Prevention of graft dislodgement in multilevel cervical corpectomy and fusion has been an unresolved problem. Anterior plate fixation has a significant failure rate. External support with a halo-vest is uncomfortable for patients. In the present study, we report a new surgical technique of anterior pedicle screw (APS) fixation for multilevel cervical corpectomy and spinal fusion, and describe the safety and utility of the system. METHOD: After cervical corpectomy, the pedicles on the right side were visualised under oblique fluoroscopy. Guide wires were inserted into the pedicles from the inner wall of the excavated vertebral body until they were hidden in the pedicles. After a fibula autograft was placed, the graft was penetrated in the reverse direction by the guide wires. After drilling and tapping, cannulated screws were inserted into the pedicles through the grafted fibula along the guide wires. FINDINGS: In 9 patients with cervical myelopathy, the surgery was accomplished with a fibula autograft using APS fixation. A total of 22 APSs were inserted, and 21 screws were placed precisely in the pedicles. There were no neurovascular complications. Patients were allowed to ambulate without a halo-vest on the second day after the surgery. Post-operatively, no dislodgement of the grated fibula occurred, and all patients improved neurologically. CONCLUSIONS: The insertion of APSs is feasible and safe. APS fixation enables us to obtain rigid fixation anteriorly, and we propose that APS fixation is an attractive option for multilevel cervical corpectomy and fusion.

Paclitaxel for the treatment of progressive or recurrent childhood brain tumors: a pediatric oncology phase II study.

PURPOSE: To assess the efficacy and define the toxicity of paclitaxel given at a dosage of 350 mg/m2 every 3 weeks as a 24-hour continuous infusion to children with recurrent or progressive primary brain tumors. PATIENTS AND METHODS: Seventy-three eligible patients, ages 4 months to 19 years, with progressive or recurrent primary brain tumors were treated according to a Pediatric Oncology Group (POG) phase II protocol with paclitaxel (POG 9330). Tumor histologic strata included: astrocytoma (n = 4), malignant glioma (n = 13), medulloblastoma (n = 16), brain stem glioma (n = 15), ependymoma (n = 13), and miscellaneous histologies (n = 12). All patients had previous histologic confirmation of a primary intracranial or spinal cord tumor with magnetic resonance imaging or computed tomography documentation of unequivocally measurable progressive or recurrent disease. All patients had received previous therapy including surgery, radiation therapy, and/or chemotherapy, but no patient had been previously treated on more than one phase II trial. Paclitaxel was administered as a 24-hour intravenous infusion at a dosage of 350 mg/m2 every 3 weeks. Neurologic and neuroradiologic reevaluations were performed after every second course. Patients were allowed to continue therapy for a total of 18 cycles in the absence of progressive disease or unacceptable toxicity. RESULTS: Seventy-five patients were enrolled onto the POG 9330 protocol; two ineligible patients were removed from the study before receiving any therapy. Of the 73 eligible patients, 72 were evaluable for toxicity and 70 were either fully or partially evaluable for disease response. There was one complete response and three partial responses (5.7%). Twenty patients had stable disease for more than 2 months. Toxicities included mild nausea, central nervous system toxicity, myelosuppression, and febrile neutropenia, including one septic death. One grade 2 and two grade 3 allergic reactions occurred. No cardiac toxicities or arthralgias were reported. CONCLUSION: Paclitaxel is well tolerated in children with recurrent or progressive brain tumors at this dosage and schedule and may result in short-term disease stabilization in this patient population. The lack of a significant number of patients with measurable disease regression, however, precludes it from being identified as an active agent when administered as a single agent by 24-hour continuous infusion.

Multidisciplinary management of pediatric low-grade gliomas.

Low-grade gliomas comprise a heterogeneous group of tumors accounting for 30% to 40% of all primary central nervous system (CNS) neoplasms in the pediatric population. Management of these patients has evolved significantly over the past 2 decades, the present emphasis being on surgery. Adjuvant therapies, such as radiation and/or chemotherapy are generally withheld until symptomatic or radiographic progression is evident. The goal of surgery is gross total resection, while preserving maximal neurologic function. The goal of radiation and chemotherapy is to provide symptom and tumor control with minimal acute and late toxicities. Chemotherapy has the additional goal of deferring radiation to allow maximal development and maturation of the child's CNS. The incorporation of these 3 modalities into the overall care of the pediatric low-grade glioma patient involves the multidisciplinary input of the neurosurgeon, radiation oncologist, and pediatric neuro-oncologist both at time of diagnosis and throughout the course of their disease.

A detrimental effect of a combined chemotherapy-radiotherapy approach in children with diffuse intrinsic brain stem gliomas?

PURPOSE: To compare the proportion of patients that survive at least 1 year following treatment with hyper-fractionated radiotherapy (HRT) to a dose of 70.2 Gy on Pediatric Oncology Group (POG) study #8495 with that of patients treated with similar radiotherapy plus cisplatinum given by continuous infusion on weeks 1, 3, and 5 of radiotherapy on POG #9239. METHODS AND MATERIALS: The eligibility criteria for the two studies were identical and included age 3 to 21 years, previously untreated tumor involving the brain stem of which two-thirds was in the pons, history less than 6 months, and clinical findings typical for diffuse intrinsic brain stem glioma, including cranial nerve deficits, long tract signs, and ataxia. The outcome of 57 patients who were treated at the 70.2 Gy dose level of POG #8495 between May 1986 and February 1988 was compared with that of 64 patients treated with identical radiotherapy plus cisplatinum on POG #9239 between June 1992 and March 1996. RESULTS: The number of patients accrued to POG #9239 was determined to guarantee that the probability was at least 0.80 of correctly detecting that the 1-year survival rate exceeded that of patients on POG #8495 by 0.2. However, the z value for this test was -1.564, giving a p value of 0.9411. That is, there is almost sufficient evidence to conclude that survival for patients receiving HRT plus cisplatinum on POG #9239 was worse than that for patients receiving the same radiotherapy alone on POG #8495. CONCLUSION: The finding that patients who received cisplatinum given as a radiosensitizing agent concurrent with HRT fared less well than those receiving the same dose of HRT alone was unexpected and is clearly a cause for concern as many current protocols for patients with diffuse intrinsic brain stem gliomas call for use of chemotherapeutic and/or biological agents given concurrent with radiotherapy.

Oral methotrexate for recurrent brain tumors in children: a Pediatric Oncology Group study.

PURPOSE: Children with recurrent or progressive central nervous system (CNS) tumors have an unfavorable prognosis. Based on Pediatric Oncology Group (POG) institutional pilot data, low-dose oral methotrexate (MTX) was studied. METHODS: Eight dosages of MTX 7.5 mg/m2 every 6 hours were administered on a weekly schedule for as long as 18 months. Patients in six different brain tumor strata were accrued. RESULTS: The response rates (complete or partial responses) were as follows: astrocytoma 2 of 10, malignant glioma 1 of 19, medulloblastoma 0 of 18, brainstem tumor 0 of 12, ependymoma 1 of 7, and miscellaneous histologic types 0 of 12. The main toxicities, mucositis, myelosuppression, and hepatic transaminase elevation were considered tolerable. CONCLUSION: Low-dose oral MTX showed no significant activity against malignant glioma, medulloblastoma, brainstem tumors, and miscellaneous histologic types. Indeterminate but low response rates were observed in children with astrocytoma and ependymoma. This regimen will not be recommended for front-line therapy.

Topotecan for the treatment of recurrent or progressive central nervous system tumors - a pediatric oncology group phase II study.

Topotecan was studied as a 72 h infusion given every 3 weeks. Treatment began at a dose of 1.0 mg/m2/day and was increased to 1.25 mg/m2/day after the first 6 patients tolerated this higher dose without excessive toxicities. Eighty-eight evaluable children were accrued in 6 strata. There were no complete nor partial responses. Twenty subjects had stable disease (astrocytoma 5/11, malignant glioma 5/13, medulloblastoma 0/12, brain stem tumor 4/19, ependymoma 5/17, and miscellaneous histologies 1/16). Two patients (astrocytoma, ependymoma) completed the maximum 18 topotecan courses. The remaining 68 children developed progressive disease within 2 months. Myelosuppression was the main toxicity. Grade 4 leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 18, 32, 5, and 23 participants, respectively. It was concluded that topotecan as given according to this schedule showed insufficient activity to promote it to frontline protocol usage.

Cyclophosphamide for the treatment of progressive low-grade astrocytoma: a Pediatric Oncology Group phase II Study.

PURPOSE: Results of a phase II trial of cyclophosphamide (CPM) for children with progressive low-grade astrocytoma are reported. PATIENTS AND METHODS: Fifteen patients with a median age of 39 months (range, 2 to 71) were included in this study. The tumors of 11 children were located in the optic pathway, hypothalamus, or thalamus. Four courses of intravenous CPM 1.2 g/m2 were administered every 3 weeks during the upfront window portion of this protocol. Subsequently, chemotherapy was to continue with CPM, vincristine, and carboplatin for 2 years. RESULTS: By study design, the first 14 patients were centrally reviewed after completion of the initial 4 CPM courses. Toxicity was primarily hematologic. One patients had a complete response, 8 had stable disease, and 5 had progressive disease (PD). The excessive number of children with PD prompted study closure. CONCLUSION: CPM as used in this protocol showed insufficient activity against astrocytoma to justify further patient accrual.

There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy.

PURPOSE: In June 1992, POG began accrual to a phase III study, POG-9239, designed to compare the time to disease progression, overall survival, and toxicities observed in children with newly diagnosed brainstem tumor treated with 100 mg/m2 of infusional cisplatin and randomized to either conventional vs. hyperfractionated radiotherapy. METHODS AND MATERIALS: Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the pons. Histologic confirmation of diagnosis was not mandatory, provided that the clinical and MRI scan findings were typical for a diffusely infiltrating pontine lesion. Treatment consisted of a six-week course of local field radiotherapy with either once a day treatment of 180 cGy per fraction to a total dose of 5400 cGy (arm 1) or a twice a day regimen of 117 cGy per fraction to a total dose of 7020 cGy (the second of the three hyperfractionated dose escalation levels of POG-8495) (arm 2). Because of previously reported poor results with conventional radiotherapy alone, cisplatin was included as a potential radiosensitizer in an attempt to improve progression-free and ultimate survival rates. Based on results of the phase I cisplatin dose escalation trial, POG-9139, 100 mg/m2 was chosen for this trial and was delivered by continuous infusion over a 120-hour period, beginning on the first day of radiotherapy and repeated during weeks 3 and 5. One hundred thirty eligible patients were treated on protocol, 66 on arm 1 and 64 on arm 2. RESULTS: The results we report are from time of diagnosis through October 1997. For patients treated on arm 1, the median time to disease progression (defined as time to off study) was 6 months (range 2-15 months) and the median time to death 8.5 months (range 3-24 months); survival at 1 year was 30.9% and at 2 years, 7.1%. For patients treated on arm 2, the corresponding values were 5 months (range 1-12 months) and 8 months (range 1-23 months), with 1- and 2-year survival rates at 27.0% and 6.7%, respectively. Evaluation of response by MRI at 4 or 8 wks post treatment was available in 108 patients and revealed a complete response in 1 patient of each Rx arm, a partial response (> 50% decrease in size) in 18 patients of arm 1 and 15 patients of arm 2, minimal to no response (stable) in 25 patients of arm 1 and 23 patients of arm 2, and progressive disease in 13 patients of arm 1 and 12 patients of arm 2. The pattern of failure was local in all patients. Morbidity of treatment was similar in both Rx arms, with no significant toxicity (including hearing loss) reported. Autopsy was performed in 6 patients, and confirmed the presence of extensive residual tumor in these cases. CONCLUSION: The major conclusion from this trial is that the hyperfractionated method of Rx 2 did not improve event-free survival (p = 0.96) nor did it improve survival (p = 0.65) over that of the conventional fractionation regimen of Rx 1, and that both treatments are associated with a poor disease-free and survival outcome.

A phase II study of every other day high-dose ifosfamide in pediatric brain tumors: a Pediatric Oncology Group Study.

Despite reported activity in many other solid tumors, high-dose ifosfamide produces few objective responses in recurrent pediatric brain tumors. Alkylating agents such as cyclophosphamide (CYCLO) possess good activity in many of solid tumors, including brain tumors. Although Ifosfamide (IFOS), a structural congener of CYCLO, has been suggested to have greater activity in several tumors, its activity in brain tumors is uncertain. We conducted a phase II trial of every-other day IFOS (3 gm/M2/qod x 3) in 87 recurrent pediatric brain tumors. Responses were evaluable in 71 patients. Partial responses occurred in 1/6 patients with low grade astrocytoma, 1/16 with malignant glioma, 1/16 with medulloblastoma, 1/3 with pineoblastoma and 1/12 patients with ependymoma. No responses occurred among 10 patients with brain stem gliomas or 8 patients with other brain tumors. Despite the poor objective response rate, 23/71 patients were clinically and imaging stable for periods of 8-62 weeks. There was no relationship between prior CYCLO treatment and subsequent response or failure with IFOS. The predominant toxicity was myelosuppression. Although generally reversible, prolonged suppression and sepsis were responsible for the deaths of 3 heavily pretreated patients. Renal toxicity was uncommon; 2 patients had grade III, and one grade IV renal tubular dysfunction. One patient had grade IV hematuria. Neurotoxicity was less common than in studies of daily ifosfamide; only 1 patient had grade IV neurotoxicity. Three patients had grade III or IV IFOS related hyponatremia. Despite the good stable disease rate, the poor rate of objective response suggests that IFOS monotherapy possesses little clinically meaningful activity in brain tumors.

Hyperfractionated irradiation and concurrent cisplatin in brain stem tumors: a Pediatric Oncology Group pilot study (9139).

A phase I Pediatric Oncology Group Study was performed combining 7,020 cGy hyperfractionated irradiation (117 cGy twice daily separated by 6 h) with increasing concurrent doses of cisplatin given with the intent of radiosensitization as treatment for children with newly diagnosed brain stem tumors. Cisplatin was infused over 120 h on weeks 1, 3, and 5 during a 6-week radiotherapy course. The following cisplatin dose levels were studied: (1) 50 mg/m2/120 h, (2) 75 mg/m2/120 h and (3) 100 mg/m2/120 h. Sixteen of 17 children completed therapy. One child expired after 2 days of treatment secondary to massive intratumoral hemorrhage. At cisplatin dose level 3 (100 mg/m2/120 h), grade 2-4 myelosuppression was encountered in 3 of 5 evaluable patients. Otherwise, no other excessive toxicities, including renal and ototoxicity, were noted.

Effect of isosorbide dinitrate infusion on the canine left ventricular force-length relationship.

Recently, the slope (Ec) of the left ventricular (LV) end-systolic force-diameter (Fes-Des) relationship has been proposed as a new index for assessing myocardial contractility. Using this relationship, the effects of ISDN on LV myocardial contractility were evaluated in 10 healthy adult mongrel dogs. After the intravenous infusion of propranolol and atropine to produce autonomic blockade, the inferior vena cava was gradually occluded for 20 sec to decrease preload while the dogs were kept apneic. The LV diameter was measured by ultrasonic crystals and LV pressure was measured by a micromanometer. After the control measurements, the dogs received intravenous ISDN (1, 5, 10, or 50 micrograms/kg/min), and inferior vena caval occlusion was repeated. Ec and the extrapolated diameter intercept (D0) of the LV Fes-Des relationship were determined for each dog from the end-systolic data. The differences in heart rate between the control state and ISDN infusion at any dose were not statistically significant. The Ec and D0 values also showed no significant changes with ISDN infusion (Ec: 80 +/- 19, 83 +/- 20, 84 +/- 17, 82 +/- 24, and 87 +/- 24 g/cm for 0, 1, 5, 10, and 50 micrograms/kg/min, respectively. D0: 1.38 +/- 0.42, 1.38 +/- 0.40, 1.38 +/- 0.38, 1.34 +/- 0.40, and 1.36 +/- 0.40 cm for 0, 1, 5, 10, and 50 micrograms/kg/min, respectively). These findings suggested that intravenous ISDN did not affect myocardial contractility in the normal in situ canine left ventricle.

[The effect of propranolol on the myocardial force-length relationship in the in situ canine left ventricle].

The effect of beta-adrenoceptor blockade on the wall performance of the in situ canine left ventricle (LV) was evaluated based on the LV end-systolic force-diameter (Fes-Des) relation in 10 healthy mongrel dogs. LV diameter was measured with ultrasonic crystals, and LV pressure was measured with a micromanometer. Preload was altered by inferior vena caval (IVC) occlusion. In the control contractility state, the IVC was occluded for 7 sec. Blockade of the cardiac beta-adrenergic nerves was induced with 2 mg/kg propranolol i.v.. Slopes (Ec) and extrapolated diameter intercepts (D(o)) of the LV Fes-Des relation were obtained from end-systolic data of the control contractility state and after the infusion of propranolol. Ec was used as an index for the inotropic state of the myocardium of the LV wall. IVC occlusion during 7 sec under the control contractility state produced little change in the heart rate. Thus, IVC occlusion for 7 sec avoided the major reflex change of autonomic tone. After the infusion of propranolol, the heart rate and Ec both decreased by 24 and 43% of the control value, respectively; whereas, D(o) was not significantly altered. Therefore, it was suspected that the cardiac beta-adrenergic nerve played an important role in maintaining myocardial contractility state of the in situ canine LV wall.

Time-varying myocardial elastance of canine left ventricle.

A formula was derived from an active cross-bridge model for expressing the "time-varying myocardial elastance" of the left ventricular (LV) wall. To assess the validity of this model's predictions of the behavior of the intact left ventricle, eight healthy beagles were instrumented with ultrasonic crystals to measure LV diameter and a micromanometer for LV pressure measurement. During ejecting beats starting from short end-diastolic myocardial lengths, the predicted values for myocardial elastance and force closely approximated the measured values for the instantaneous external load-muscle length ratio and the external load, respectively. However, in cycles starting from long end-diastolic lengths, the predicted myocardial elastance and force values deviated from the actual values during the shortening phase of LV contraction. The differences between myocardial elastance and external load-muscle length ratio as well as those between force and external load during the shortening phase (shortening deactivation) appeared to result from an internal load in the shortening myocardium that was closely related to the product of instantaneous myocardial force and shortening velocity. Thus this model may provide reasonable approximations of myocardial elastance and force in the intact LV wall. In addition, time-varying myocardial elastance might reflect time-dependent changes in calcium activation.

Slope of human left ventricular end-systolic force-length relation is independent of myocardial length.

We have introduced a new contractility index (Ec), i.e., the slope of the left ventricular (LV) end-systolic force-length (Fes-Les) relation. To examine whether Ec was dependent on the LV wall myocardial length, 16 normal hearts of human subjects were evaluated to determine the LV end-systolic force-dimension (Fes-Des) and pressure-dimension (Pes-Des) relations (dimension denotes the distance between the LV septum and posterior wall). LV end-systolic pressures and dimensions were estimated simultaneously by intra-arterial cannulation and LV echocardiography. In seven subjects, the effect of a dobutamine infusion was also assessed. The Fes-Des relation was found to be nearly linear. Slopes and extrapolated dimension intercepts were obtained for the LV Fes-Des and Pes-Des relations [Ec, slope of LV Pes-Des relation (Es), and extrapolated dimension intercept of LV Fes-Des (Do), and of Pes-Des relation (D'o), respectively]. Es showed a hyperbolic relation to the baseline LV Des, whereas Ec was unrelated to it. The average variation for Ec (9.5%) was smaller than that for Es (22.5%). Dobutamine infusion increased Ec, Es, and D'o, whereas Do was not changed. Thus the assumption of linearity of the LV Fes-Les relation was found to be reasonable in normal human hearts. Do appears to provide a more accurate parameter than D'o for estimating the actual unstressed myocardial length, whereas Ec could possibly serve as an index of LV wall performance in the normal human heart that is independent of myocardial length and nearly constant between individuals.

Afterloading increases the left ventricular end-systolic force-length relation slope in dogs.

We evaluated the effects of pressure loading produced by gradual aortic occlusion on left ventricular (LV) myocardial contractility by assessing changes in the slope of the LV end-systolic force-diameter (Fes-Des) relation. Eleven adult mongrel dogs were prepared with ultrasonic crystals for measuring LV diameter and a micromanometer for measuring LV pressure. Preload was decreased by vena caval occlusion (VCO), and afterload was increased by aortic occlusion (AOO). The slopes (Ec) and extrapolated diameter intercepts (Do) of the LV Fes-Des relation were determined for each dog from the end-systolic data obtained during VCO and AOO. During VCO and also AOO, the heart rate showed little change (134 +/- 18 vs. 134 +/- 16 bpm in VCO, 135 +/- 16 vs. 132 +/- 17 bpm in AOO). The values of Ec and Do during VCO were 62.8 +/- 15.6 g/cm and 1.20 +/- 0.36 cm, respectively, while during AOO the respective values were 122.6 +/- 18.6 g/cm and 1.66 +/- 0.38 cm. Ec and Do were both significantly increased during AOO in comparison with VCO (p less than 0.001). These results suggest that gradual aortic occlusion increases LV myocardial contractility in anesthetized, open-chest dogs under autonomic blockade. This phenomenon might be related to length-dependent calcium activation.

Hepatoblastoma characterized by trisomy 20 and double minutes.

Karyotypic study of two hepatoblastomas revealed trisomies for chromosome 20 and the presence of double minutes (dmin). These cases are the second and third examples of trisomy 20 in hepatoblastoma and are the first examples of dmins in this rare childhood tumor.

[Deterioration of myocardial contractility induced by nitroglycerin infusion in a case of ischemic cardiomyopathy].

To evaluate left ventricular (LV) contractility in a 42-year-old woman with ischemic cardiomyopathy, the brachial arterial pressure and LV end-systolic dimension were simultaneously measured using arterial cannulation and LV echocardiography. Blood pressure progressively decreased with the intravenous infusion of nitroglycerin. When the infusion rate reached 4 micrograms/kg/min, the LV end-systolic dimension increased from 63 mm (control) to 66 mm in association with a decrease in blood pressure (from 137 to 120 mmHg) and heart rate (from 103 to 100 bpm). With the infusion of dobutamine (1.5 micrograms/kg/min), the blood pressure increased to 126 mmHg and the LV end-systolic dimension decreased to 57 mm. These findings suggest that nitroglycerin reduced LV myocardial contractility in this patient. Thus, during the intravenous administration of nitroglycerin (especially in patients with ischemic heart disease), the infusion rate should be carefully determined.