In vivo magnetic resonance imaging and surgical histopathology of intracardiac masses: distinct features of subacute thrombi.

We evaluated intracardiac masses in vivo, in situ and histologically to determine tissue properties revealed by magnetic resonance (MR) imaging. In 15 consecutive patients scheduled for cardiotomy, the cardiac chambers were studied preoperatively with MR imaging and echocardiography. Visual examination of one or more chambers was performed during cardiotomy for mitral valve replacement, aneurysmectomy, atrial septal repair and atriotomy. Six thrombi (1 atrial appendage, 5 ventricular) and 2 atrial myxomas were removed and subjected to histological analysis. All masses were detected preoperatively by MR imaging. The smallest was a subacute 3-mm mural clot in the left ventricle and was undetected by transesophageal and transthoracic echocardiography. The 3 subacute clots had homogeneously low MR signals, did not enhance with gadolinium and exhibited magnetic susceptibility effects; histopathology confirmed these clots to be avascular and laden with dense iron deposition related to hemoglobin breakdown products. The 3 organized clots had intermediate and heterogeneous MR signals and multiple areas of gadolinium enhancement. The 2 myxomas had low MR signals and gadolinium enhancement in the core and septal attachment; these areas had dense neovascular channels. Subacute thrombi appear to have MR features that are distinct from organized thrombi and myxomas, and MR images of subacute thrombi contrast sharply with normal cardiac structures, enabling detection of thin mural clots that may be echographically occult. These findings may be of value, because a subacute clot may be more likely than an organized thrombus to give rise to an embolus.

Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy.

In 1997, the National Cancer Institute (NCI) led an effort to revise and expand the Common Toxicity Criteria (CTC) with the goal of integrating systemic agent, radiation, and surgical criteria into a comprehensive and standardized system. Representatives from the Radiation Therapy Oncology Group (RTOG) participated in this process in an effort to improve acute radiation related criteria and to achieve better clarity and consistency among modalities. CTC v. 2.0 replaces the previous NCI CTC and the RTOG Acute Radiation Morbidity Scoring Criteria and includes more than 260 individual adverse events with more than 100 of these applicable to acute radiation effects. One of the advantages of the revised criteria for radiation oncology is the opportunity to grade acute radiation effects not adequately captured under the previous RTOG system. A pilot study conducted by the RTOG indicated the new criteria are indeed more comprehensive and were preferred by research associates. CTC v. 2.0 represents an improvement in the evaluation and grading of acute toxicity for all modalities.

Pharmacokinetic monitoring and dose modification of etanidazole in the RTOG 85-27 phase III head and neck trial.

PURPOSE: To prospectively evaluate the pharmacokinetic monitoring and drug dose adjustment of Etanidazole (Eta) in patients treated on the RTOG randomized trial for Stage III and IV head and neck cancer. METHODS AND MATERIALS: From June, 1986 to October, 1991, 521 patients were randomized to conventional RT alone or RT plus Eta. The primary goal was to determine whether the addition of Eta to conventional radiation therapy improves local-regional control and tumor-free survival. Of the 264 patients who received Eta, 233 had their drug exposure calculated and the Eta dose and schedule adjusted accordingly to prevent the occurrence of serious peripheral neuropathy. Drug exposure was assessed using the area under the curve (AUC) for a single treatment that was calculated by the integral over time of the serum concentration of Eta. The total drug exposure (total-AUC) was estimated by multiplying the AUC by the number of drug administrations. RESULTS: Eighteen percent of patients developed Grade I and 6% developed Grade II peripheral neuropathy. There was no Grade 3 or 4 peripheral neuropathy. There is a trend for an increased risk of neuropathy by single dose AUC. The minimal difference in incidence of neuropathy by single-dose AUC was due to the use of dose and schedule modification for patients with the higher values. CONCLUSIONS: The pharmacokinetics investigated in this study confirm previous work that monitoring Eta levels, with dose adjustment, allows it to be used safely in the clinic. In a subset analysis there was a statistically significant improvement in local-regional control and survival rates for patients with N0 and N1 disease, that will require confirmation (14). However, the clinical efficacy of Eta in this trial proved to be of little overall benefit.

Lung reduction surgery in severe COPD decreases central drive and ventilatory response to CO2.

BACKGROUND AND OBJECTIVES: Lung volume reduction surgery (LVRS) improves ventilatory function in selected patients with severe COPD. The reasons for the observed benefits include the following: increased elastic recoil, improved airflow, and lesser dynamic hyperinflation and decreased lung volumes. We reasoned that these changes could also alter respiratory drive. METHODS: Respiratory central drive was prospectively assessed using the mouth occlusion pressure (P0.1), and the P0.1 response to increasing CO2 (P0.1/PETCO2 [end-tidal CO2 pressure]), in eight sequential patients before and 3 to 5 months after LVRS. Results were compared with those from 13 control subjects. RESULTS: LVRS decreased total lung capacity from 7.44+/-1.8 L to 5.92+/-1.3 L (p<0.05) and residual volume from 4.97+/-1.5 L to 3.56+/-1.1 L (p<0.05). It also significantly improved FEV1 from 0.85+/-0.26 L to 0.99+/-0.26 L (p<0.05). Baseline P0.1 (3.4+/-1.8 vs 1.4+/-0.4 cm H2O, p<0.01) and P0.1/PETCO2 (0.24+/-0.07 vs 0.11+/-0.04 cm H2O/mm Hg, p<0.05) were higher in patients than in control subjects. After LVRS, P0.1 decreased from 3.4+/-1.8 to 1.3+/-0.75 cm H2O (p<0.01) and P0.1/PETCO2 from 0.24+/-0.07 to 0.16+/-0.06 cm H2O/mm Hg (p<0.05). These postoperative values were similar to those of control subjects. There were no correlations between changes in the factors known to influence central drive (PaO2, PaCO2, age, weight, height, FVC, and FEV1) and changes in P0.1. CONCLUSIONS: We conclude that decreased ventilatory drive should be added to the list of benefits of LVRS, and may help explain the symptomatic improvement reported by many patients after this surgery.

Lung-volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function.

Lung-volume reduction surgery (LVRS) improves static lung elastic recoil in selected patients with severe chronic obstructive pulmonary disease (COPD). This explains the increase in FEV1 in many COPD patients who undergo LVRS, but fails to explain clinical improvement in those without changes in FEV1. We prospectively evaluated 17 patients after pulmonary rehabilitation but prior to and again at least 3 mo after bilateral LVRS done via median sternotomy. In addition to pulmonary function, lung elastic recoil, walking distance, and exercise capacity, we evaluated static and dynamic respiratory muscle (RM) function, and dyspnea. In 12 patients we also quantified dynamic hyperinflation (end-expiratory and end-inspiratory lung volume [EELV and EILV, respectively]). After LVRS, FEV1 rose from 26.7 +/- 1.8 to 39.0 +/- 3.7% predicted (p < 0.004), whereas TLC dropped from 134.7 +/- 4.8 to 118.3 +/- 4.4% predicted (p < 0.0002), and RV from 239.6 +/- 14.8 to 180.3 +/- 8.7% predicted (p < 0.0002). Isowork dyspnea decreased as assessed with a visual analogue scale (VAS) (79.6 +/- 5.2 versus 49.3 +/- 7.5 mm, p < 0.005) and the Borg scale (7.1 +/- 0.6 versus 3.5 +/- 0.6, p = 0.002). Walking distance improved significantly and, in the 12 patients in whom they were measured, EELV and EILV decreased at rest and at isowork. Maximal transdiaphragmatic pressure rose from 67.1 +/- 8.3 to 92.0 +/- 7.5 cm H2O (p < 0.03). Resting RM function changed little, but at isowork improved significantly after LVRS. Excluding one outlier, there was a strong linear correlation between the change in Borg-scale score at equivalent work loads before and after LVRS and the change in EELV (% predicted TLC, r = 0.75, p < 0.001), as well as between the change in Borg-scale score and the absolute decrease in end-expiratory pleural pressure (Ppl(e)) (r = 0.78, p = 0.004). Successful LVRS improves not only lung recoil, but also respiratory muscle function, and reduces dynamic hyperinflation. These changes help explain the decreased dyspnea and improved exercise capacity seen after LVRS, and add to current understanding of the mechanisms by which this procedure may help selected patients with severe emphysema.

Fast-neutron therapy in advanced head and neck cancer: a collaborative international randomized trial.

PURPOSE: To compare the efficacy of fast-neutron radiotherapy with that of conventionally fractionated photon therapy in the management of patients with locally advanced squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Patients with Stage III or IV disease were randomized to receive either 20.4 Gy/12 fractions/4 weeks of neutrons or 70 Gy/35 fractions/7 weeks of photons (control). Between April 1986 and March 1991, 178 patients were entered, 169 of whom were eligible for analysis. The treatment arms were balanced for age, stage, and performance status, but not for primary site of origin. RESULTS: Complete response occurred in 70 and 52% with neutrons and photons, respectively (p = 0.006). Local regional failure at 3 years for all patients was 63% for neutrons and 68% for photons. Actuarial overall survival curves were virtually identical in both study arms, falling to 27% at 3 years. Acute toxicity was similar in the two arms, but late grade 3-5 toxicity was 40% with neutrons compared to 18% with photons (p = 0.008). CONCLUSION: Although the initial response rate was higher with neutrons, permanent local control and survival were not improved, and the incidence of late normal tissue toxicity was increased. As a result, fast-neutron therapy for advanced squamous cell carcinoma of the head and neck can only be recommended for patients in whom the logistic benefit of treatment in 12 sessions over 4 weeks outweighs the increased risk of late toxicity.

Late injury of cancer therapy on the female reproductive tract.

The purpose of this article is to review the late effects of cancer therapy on the female reproductive tract. The anatomic sites detailed are the vulva, vagina, cervix, uterus, fallopian tubes, and ovaries. The available pathophysiology is discussed. Clinical syndromes are presented. Tolerance doses of irradiation for late effects are rarely presented in the literature and are reviewed where available. Management strategies for surgical, radiotherapeutic, and chemotherapeutic late effects are discussed. Endpoints for evaluation of therapeutic late effects have been formulated utilizing the symptoms, objective, management, and analytic (SOMA) format. Late effects on the female reproductive tract from cancer therapy should be recognized and managed appropriately. A grading system for these effects is presented. Endpoints for late effects and tolls for the evaluation need to be further developed.

Radiation Therapy Oncology Group quality of life assessment: design, analysis, and data management issues.

The Radiation Therapy Oncology Group (RTOG) has embarked on seven phase II or phase III multicentre clinical trials involving a quality of life component. Each quality of life trial used questionnaires or examinations that have been tested for reliability and validity by independent investigators. Each trial includes questionnaires that examine the patient's physical, functional, social, and emotional status, and that measure a specific quality of life issue pertinent to the patient's diagnosis or treatment. Two trial designs have been implemented for studies with quality of life endpoints. One design involves companion trials to the primary treatment study pertaining solely to the quality of life endpoint. The second design integrates the quality of life component into the primary trial design. The RTOG has found a need for education of individuals and institutions expected to administer and obtain the quality of life data. Once the data have been collected several methods for the analysis of the quality of life data are available. However, there is no one best method for analysing quality of life data, thus more than one method should be used in order to provide insight into the data.

Smooth muscle cell outgrowth from human atherosclerotic plaque: implications for the assessment of lesion biology.

OBJECTIVES: The purpose of this study was to determine whether the kinetics of smooth muscle cell outgrowth from in vitro explants of human atherosclerotic tissue is dependent on the nature of the atherosclerotic lesion in vivo. BACKGROUND: The use of techniques for percutaneous in vivo extraction of atherosclerotic plaque has provided the opportunity to study human atheroma-derived smooth muscle cells in culture. However, because of cell selection and changes in phenotype, in vitro findings may not always reflect the biologic properties of the vessel wall, particularly if cells are in culture for prolonged periods. In contrast, studies with nonhuman cells have suggested that the rate at which cells grow out of tissue explants is closely related to the status of the cells in vivo. METHODS: Atherosclerotic tissue from 41 lesions, including primary plaques (from peripheral arteries and venous bypass conduits) and restenotic lesions (from peripheral arteries and venous conduits) were divided into a total of 1,596 fragments and placed in culture on fibronectin-coated wells. Explant outgrowth was scored over the ensuing 1 month to determine the prevalence and time course of smooth muscle cell outgrowth and the total cellular accumulation. RESULTS: Explant fragments from 40 (98%) of the 41 lesions yielded an outgrowth of smooth muscle cells, confirmed by immunocytochemistry. The mean proportion of adherent explant fragments yielding outgrowth, per lesion, was 69 +/- 4% and was higher in restenotic tissue (81 +/- 3%) than in primary tissue (56 +/- 6%, p < 0.001). For primary lesions, initiation of outgrowth was half-maximal by 8.7 +/- 0.4 days; for restenotic explants, initiation of outgrowth was considerably faster (half-maximal by 5.9 +/- 0.6 days, p < 0.001). Similarly, accumulation of smooth muscle cells around an explant was significantly greater for restenotic lesions (2,791 +/- 631 cells/explant) than for primary lesions (653 +/- 144 cells/explant, p < 0.01). Labeling of first-passage cells with [3H]-thymidine indicated that cells from restenotic lesions had a 1.3-fold greater incorporation rate than did cells from primary lesions (p < 0.05). CONCLUSIONS: Smooth muscle cells may be reliably cultivated by explant outgrowth from a variety of human atherosclerotic plaque types obtained intraoperatively or percutaneously. The kinetics of outgrowth from restenotic tissue is distinctly different from that of outgrowth from primary tissue, suggesting a relation between the in vitro outgrowth behavior and the biology of the lesion in vivo. Assessment of smooth muscle cell outgrowth from human atherosclerotic plaque may thus represent a practical and reliable means to investigate the biologic behavior, including growth characteristics, of individual atherosclerotic lesions from human subjects. This technique may also offer a suitable assay system for evaluating therapies designed to inhibit lesion proliferation.

Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03.

This is a report of a 10-year median follow-up of a randomized, prospective study investigating the optimal sequencing of radiation therapy (RT) in relation to surgery for operable advanced head and neck cancer. In May 1973, the Radiation Therapy Oncology Group (RTOG) began a Phase III study of preoperative radiation therapy (50.0 Gy) versus postoperative radiation therapy (60.0 Gy) for supraglottic larynx and hypopharynx primaries. Of 277 evaluable patients, duration of follow-up is 9-15 years, with 7.6% patients lost to follow-up before 7 years. Loco-regional control was significantly better for 141 postoperative radiation therapy patients than for 136 preoperative radiation therapy patients (p = 0.04), but absolute survival was not affected (p = 0.15). When the analysis was restricted to supraglottic larynx primaries (60 postoperative radiation therapy patients versus 58 preoperative radiation therapy patients), the difference for loco-regional control was highly significant (p = .007), but not for survival (p = 0.18). In considering only supraglottic larynx, 78% of loco-regional failures occurred in the first 2 years. Thirty-one percent (18/58) of preoperative patients failed locally within 2 years versus 18% (11/60) of postoperative patients. After 2 years, distant metastases and second primaries became the predominant failure pattern, especially in postoperative radiation therapy patients. This shift in the late failure pattern along with the increased number of unrelated deaths negated any advantage in absolute survival for postoperative radiation therapy patients. The rates of severe surgical and radiation therapy complications were similar between the two arms. Because of an increased incidence of late distant metastases and secondary primaries, additional therapeutic intervention is required beyond surgery and postoperative irradiation to impact significantly upon survival.

Clinical trials with etanidazole (SR-2508) by the Radiation Therapy Oncology Group (RTOG).

Following the completion of a phase I study of etanidazole (SR 2508), a new hypoxic cell sensitizer, the RTOG, began a phase II/III trial. The objectives of the study were to determine the toxicity and efficacy of SR 2508, combined with conventional radiotherapy for the management of unresectable stage III and IV head and neck squamous carcinomas. During the first step (or the Phase II portion) of the study, 33 patients received radiotherapy plus SR 2508 (RT + SR 2508). The incidence of drug toxicities was modest; including 24% grade I peripheral neuropathy (PN), 6% grade II PN, 27% grade I or II nausea and vomiting, 9% allergy and 15% reversible neutropenia. Because observed toxicities were deemed acceptable, the second step (or phase III portion) was then activated. Patients were randomized to receive either RT or RT + SR 2508. As of November 20, 1989, a total of 242 patients have been entered onto the Phase III portion of the study. One hundred twenty-two patients were randomized to the RT + SR 2508 arm and 120 patients were randomized to the RT alone arm. The analyses presented in this report are based on data available. The incidence of drug toxicities has been low, with 18% grade I or II PN, 26% nausea and vomiting (including one grade III), 14% allergy (including one grade III) and 13% reversible neutropenia.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and hemodynamic performance of the Ionescu-Shiley valve in the small aortic root. Results in 117 patients with 17 and 19 mm valves.

The Ionescu-Shiley pericardial valve was our bioprosthetic valve of choice between 1981 and 1985 for patients in whom the aortic anulus could not accept a valve larger than 19 mm in outer diameter or in whom the avoidance of warfarin sodium (Coumadin) was important. A series of 117 consecutive patients who received 17 or 19 mm valves for isolated aortic valve replacement or aortic valve replacement combined with coronary artery bypass grafting or other valvular procedures was analyzed. Overall, 74% of the patients were female, with a mean age of 70.9 years and a body surface area of 1.67 +/- 0.19 m2; 92.3% were in New York Heart Association class III-IV, and the operation was urgent or emergent in 46%. The operative mortality rate was 7.7%, with no deaths in patients undergoing isolated elective first-time aortic valve replacement. Mean follow-up for survivors was 2.5 years (10 to 62 months). There were 20 late deaths, of which three were valve related, three were due to sudden death or arrhythmias, and two were due to persistent heart failure. The actuarial survival rate at 5 years was 68%. Clinical follow-up revealed a low incidence of valve-related complications, and 96.4% of survivors were in class I-II. Postoperative echocardiography before hospital discharge revealed a maximum instantaneous gradient of 18.4 +/- 3.0 mm Hg in five patients having a 17 mm valve and 31.3 +/- 12.7 mm Hg in 20 patients having a 19 mm valve. Doppler echocardiography was performed in 22 patients at a mean follow-up of 39.3 +/- 11.7 months. The maximum instantaneous gradient was 25 +/- 17.2 mm Hg for 17 mm and 17.41 +/- 5.4 mm Hg for 19 mm valves at late follow-up. The effective orifice area was 0.85 +/- 0.1 cm2 for 17 mm and 1.21 +/- 0.21 cm2 for 19 mm valves. This study defines the normal range of Doppler echocardiographic transprosthetic gradients for the Ionescu-Shiley valve and confirms that low operative mortality and excellent clinical improvement can result from the use of small Ionescu-Shiley valves in elderly patients despite moderate postoperative transvalvular gradients.

Chemotherapy following surgery for head and neck cancer. A Radiation Therapy Oncology Group Study.

The feasibility of chemotherapy of three courses of cis-platin and 120-h 5-fluorouracil (5-FU) infusion after definitive surgery, followed by standard radiotherapy, in patients with resectable locally advanced head and neck cancer was carried out in Radiation Therapy Oncology Group (RTOG). Seventy-nine percent of the patients had stage IV cancer, 65% of the tumors were moderately differentiated, and primary sites were 38% oropharynx and 28% larynx. Toxicity to chemotherapy was acceptable, with no life-threatening side effects. Nausea and vomiting were the most common side effects (78%) and were severe in 26%; 30% of patients experienced had leukopenia, 22% had anemia, 13% had thrombocytopenia, and 9% had renal impairment--all of which were mild and reversible. In six patients, chemotherapy was not given for medical conditions or because of patient refusal. Of 23 patients started on cis-platin and 5-FU postsurgery, 18 (78%) completed all three courses. Ninety-six percent of the patients finished adequate radiotherapy according to the protocol. With minimum follow-up of 24 months, 62% of the patients were alive. Of the expired patients, 5 died from other causes, without evidence of recurrence at the time of their death. It is our conclusion that chemotherapy with cis-platin and 5-FU infusion following definitive surgery is feasible on the group level, and a Phase III trial comparing this combined modality therapy to standard treatment of surgery and post-operative radiotherapy is underway by the Head and Neck Cancer Intergroup.