Dose escalation for non-small cell lung cancer using conformal radiation therapy.

PURPOSE: Improved local control of non-small cell lung cancer (NSCLC) may be possible with an increased dose of radiation. Three-dimensional radiation treatment planning (3D RTP) was used to design a radiation therapy (RT) dose escalation trial, where the dose was determined by (a) the effective volume of normal lung irradiated, and (b) the estimated risk of a complication. Preliminary results of this trial were reviewed. METHODS AND MATERIALS: A graph of the iso-normal tissue complication probability (NTCP) levels associated with a dose and effective volume (V(eff)) was derived, using normal tissue parameters derived from the literature. This led to a dose escalation schema, where patients were sorted into 1 of 5 treatment bins, determined by the V(eff) of the best possible treatment plan. The starting doses ranged from 63 to 84 Gy. Each treatment bin was then escalated separately, as in Phase I dose escalation fashion, with Grade > or = 3 radiation pneumonitis defined as dose limiting. To allow for dose escalation, we required patient follow-up to be > or = 6 months for at least three patients. 3D treatment planning was used to irradiate only the radiographically abnormal areas, with 2.1 Gy (corrected for lung inhomogeneity)/day. Clinically uninvolved lymph nodes were not treated prophylactically. RESULTS: A total of 48 NSCLC patients have been treated (Stage I/II: 18 patients; Stage III: 28 patients; mediastinal recurrence postsurgery: 2 patients). No radiation pneumonitis has been observed in the 30 patients currently evaluable beyond the 6-month time point. All treatment bins have been escalated at least once. Current doses in the five treatment bins are 69.3, 69.3, 75.6, 84, and 92.4 Gy. None of the 15 evaluable patients in any bin with > or = 30% NTCP experienced clinical radiation pneumonitis, implying that the actual risk is < 20% (beta error rate 5%). Despite the observation of the clinically negative lymph nodes at high risk, there has been no failure in the untreated mediastinum as the sole site of first failure. Three of 10 patients receiving > or = 84 Gy have had biopsy proven residual or locally recurrent disease. CONCLUSION: Successful dose escalation in a volume-dependent organ can be performed using this technique. By incorporating the effective volume of irradiated tissue, some patients have been treated to a total dose of radiation over 50% higher than traditional doses. The literature-derived parameters appear to overestimate pneumonitis risk with higher volumes. There has been no obvious negative effect due to exclusion of elective lymph node radiation. When completed, this trial will have determined the maximum tolerable dose of RT as a single agent for NSCLC and the appropriate dose for Phase II investigation.

"Anatometabolic" tumor imaging: fusion of FDG PET with CT or MRI to localize foci of increased activity.

Positron emission tomographic (PET) images of visceral cancers are commonly visualized as "hot spots" of increased activity with relatively little normal anatomy discernable, when 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) is used as the tracer. We describe a method by which computed tomography or magnetic resonance anatomic images can be digitally fused in three dimensions, using a rigid rotate-translate scale model with PET "metabolic" images, to simultaneously display registered anatomic and metabolic information. Such "anatometabolic" fusion images were produced in 10 patients with a variety of visceral cancers. External fiducial markers placed during both the anatomic and the metabolic study, as well as internal anatomic fiducials defined from landmarks observed on reconstructed transmission images, were used to achieve image fusion. The mean error magnitude +/- s.e.m. of fiducial registration in the nine patients with successful realignments was 5.0 +/- 0.8 mm. The mean accuracy in realignment between known anatomic structures seen on both the anatomic study and on the emission PET scan (but not used in realignment) was 6.3 +/- 0.8 mm. Localization of foci of increased FDG uptake to specific anatomic structures was achieved by this method, which represented an enhancement over the rudimentary anatomy available from the emission images alone. Anatometabolic fusion images made using this reasonably simple method should prove useful in the management of patients with cancer and other diseases.

Retrograde cerebral perfusion during hypothermic circulatory arrest reduces neurologic morbidity.

Hypothermic circulatory arrest has become an accepted technique for a variety of cardiac and complex aortic operations. However, prolonged periods (> 45 min) of hypothermic circulatory arrest in older patients is associated with marginal cerebral protection and an increased incidence of adverse neurologic events. In an effort to minimize such morbidity, we used a technique of retrograde cerebral perfusion with continuous monitoring of cerebral hemoglobin oxygen saturation during hypothermic circulatory arrest in 35 patients who underwent thoracic aortic operations or resection of intracardiac tumor. There were 27 men and 8 women (mean age 60 years, range 21 to 83 years). Sixteen patients had acute dissection, 6 had contained rupture of a thoracic aortic aneurysm, 10 had either a chronic dissection or aneurysm, and 3 had hypernephromas extending into the heart. Six patients underwent root replacement by means of an open technique for their distal anastomosis, 7 underwent root and partial arch replacement, 12 had root and total arch replacement, 7 had total arch replacement, and 3 had resection of tumor in the heart and retrohepatic vena cava. Seven patients had simultaneous coronary artery bypass grafting, 3 had replacement of one of the arch vessels, and 2 patients had a cesarean section. Sixteen cases were emergency, 6 urgent, and 13 elective. Nine (26%) were reoperations. Thirty-four patients underwent the procedure via a median sternotomy and one patient through a posterolateral thoracotomy. The mean retrograde cerebral perfusion time was 63 minutes (range 35 to 128 minutes), with 30 (86%) patients having more than 45 minutes, 12 (34%) having more than 65 minutes, and 4 (11%) having more than 90 minutes. There was 1 operative death caused by a preoperative myocardial infarction from an aortic dissection, and there were 2 late deaths (multiple organ failure and ruptured total aortic aneurysm). One patient had a stroke with a residual right hemiplegia and a pronounced aphasia. There were no other significant neurologic events or reoperations for bleeding. The average length of stay for patients having elective operations was 11 days and for those having emergency operations, 27 days. At a mean follow-up of 6 months all surviving patients (91%) are well. Hypothermic circulatory arrest is a relatively simple technique that provides a bloodless field and good visualization without the need for aortic crossclamps. Moreover, retrograde cerebral perfusion with continuous monitoring of cerebral oxygen saturation extends the "safe" time for hypothermic circulatory arrest, allowing ample opportunity to perform complicated cardiac and aortic operations with reduced risk of adverse neurologic events.

Generating a normalized geometric liver model using warping.

RATIONALE AND OBJECTIVES: Automated liver surface determination in abdominal computed tomography scans, currently difficult to achieve, is of interest to determine liver location and size for various medical applications, including radiation therapy treatment planning, surgical planning, and oncologic monitoring. The authors propose to facilitate automation by the addition of a priori shape information in the form of a liver model. METHODS: The normalized geometric liver model is generated by averaging outlines from a set of normal liver studies previously registered using thin-plate spline warping. The model consists of an averaged liver surface, a set of anatomic landmarks, and a deformation function. RESULTS: A liver model is presented and its ability to represent normal liver shapes is demonstrated. CONCLUSIONS: Liver surface warping provides a means of data normalization for model construction and a means of model deformation for representation of liver organ shapes.

Actuarial analysis of variables associated with rupture of small abdominal aortic aneurysms.

This study identified risk factors associated with rupture of small abdominal aortic aneurysms in patients initially selected for nonoperative management. Sixty-seven patients, 53 men and 14 women, 50 to 91 years of age (mean 72 years) were followed 3 to 99 months (mean 36 months). All patients underwent serial aortic ultrasonography. The annual rate of aneurysm rupture was 6%, with an annual mortality rate caused by rupture of 5% and an annual mortality rate caused by coexistent disease of 6%. Thirty potential risk factors, including blood pressure, aneurysm size measured by ultrasonography, rate of aneurysm expansion, smoking, serum cholesterol levels, and cardiac, pulmonary, and renal risks, were analyzed by Cox proportional hazards regression to identify variables related to rupture. Aneurysm anteroposterior expansion rates varied from 0 to 1.5 cm/year but were not different in aneurysms that ruptured. Only diastolic blood pressure, initial aneurysm anteroposterior diameter, and degree of obstructive pulmonary disease were independently predictive of rupture (p less than 0.05, Wald test). With these data, actuarial rupture rates were predicted for patients with selected values of these three covariates. Predicted 5-year rupture rates varied from 2% when these risk factors were absent to 100% when all three risk factors were significant. Obstructive pulmonary disease, initial aneurysm size, and diastolic hypertension must be evaluated prospectively to assess their accuracy in predicting small aneurysm rupture.

Cross-sectional imaging anatomy of the anal sphincters.

BACKGROUND: To describe the cross-sectional anatomy of the anal sphincter mechanism relevant to magnetic resonance imaging (MRI) and ultrasound cross-sectional images. METHOD: Axial, sagittal, and coronal 5-mm sections of female pelves were reviewed from six cadaver specimens (ages 24-72 years). Fetal anatomy was studied in plastinated histologic sections from 19 and 26 weeks' gestation. Images of the anal sphincter were obtained by MRI in six and by ultrasound using an exoanal technique in 12 nulliparous volunteers. EXPERIENCE: The internal anal sphincter is clearly visible in anatomic sections central to the external sphincter and is visible in MRI and ultrasound images. The external anal sphincter can be subdivided into a subcutaneous and a deep portion. On anatomic sections and on MRI, the subcutaneous part shows as two parallel muscle strips in the axial plane; the deep portion presents with a characteristic teardrop form in the section perpendicular to the axis of the anal canal. The puborectalis muscle and the external anal sphincter form a "double bump" in the sagittal section. The longitudinal muscle can be identified by its fiber orientation in anatomic sections but is not clearly visible in imaging studies. CONCLUSION: This information should make it possible to identify accurately anal sphincter anatomy in two-dimensional sectional images of the anal sphincter.

Magnetic resonance imaging anatomy of the female urethra: a direct histologic comparison.

OBJECTIVE: To define the urethral structures visible on magnetic resonance imaging (MRI) relevant to stress urinary incontinence. METHODS: The urethra and surrounding tissues were harvested from 13 female cadavers (ages 21-81) and fixed in 10% buffered formalin. High-resolution T1- and T2-weighted images were obtained at 1.5 tesla. Mallory trichrome-stained histologic sections were prepared in corresponding planes from the cadaveric specimens. Immunohistologic stains for smooth muscle (actin) and vascular endothelium (CD-34 and factor VIII) were obtained on two specimens. Histology and MRI were compared using side-by-side correlation of projected images and by superimposing projected images. Comparison was also made to a non-cadaveric urethral MRI of a 29-year-old woman and to the MRI of another specimen imaged pre- and post-fixation. RESULTS: Distinct layers of the cadaveric urethra were seen best on proton density and T2-weighted images. From the center to the periphery, a series of concentric rings were visible: an inner bright ring, the mucosa; a dark ring, the submucosa; an outer bright ring, the smooth muscle of the urethra in a loose connective tissue matrix; and a peripheral dark ring, the striated urogenital sphincter muscle of the urethra in dense connective tissue. No significant alterations were caused by fixation. These cadaveric images matched the non-cadaveric MRI of the 29-year-old woman. CONCLUSION: The internal urethral anatomy visible on high-resolution MRI can be identified and confirmed histologically, and these findings may form the basis for future anatomic investigation of stress urinary incontinence and other urethral abnormalities.

Risk analysis for aortic surgery using hypothermic circulatory arrest with retrograde cerebral perfusion.

BACKGROUND: Retrospective analysis of 144 patients undergoing aortic arch reconstruction using hypothermic circulatory arrest (HCA) with retrograde cerebral perfusion (RCP) for cerebral protection was performed. METHODS: The diagnosis, procedure, and anatomic site of the arch anastomosis were analyzed to see if they were independent predictors of mortality or morbidity. In addition age, gender, HCA-RCP times, preoperative malperfusion (both treated and untreated), surgical status, and redo surgery status were also examined to determine their influence on the incidence of death and complications. Both multivariate and univariate analysis were performed using linear regression and cross-tabulation with either chi2 or Fisher's exact test where appropriate. RESULTS: Preoperative surgical status (emergent) and the presence of untreated preoperative malperfusion were the only variables that were significant independent predictors for mortality (p <0.05). No variable was significant for the prediction of stroke or other complications. The severity of surgery had no bearing on the patient outcome. CONCLUSIONS: Complex aortic surgery using HCA-RCP can be performed with acceptable risk to the patients.

Helical computed tomography for the evaluation of tracheal stenosis.

BACKGROUND: Helical computed tomography with multiplanar reconstruction (CT/MPR) was used to study proximal airway stenosis. METHODS: Twenty-eight helical CT/MPR studies were obtained in 25 patients with known or suspected stenosis of the trachea or main bronchi. Computed tomographic results were compared with planar tomograms and bronchoscopic evaluation of the airway. RESULTS: CT/MPR accurately demonstrated the site and degree of tracheal and main bronchial stenoses with a sensitivity of 93%, a specificity of 100%, and an accuracy of 94%. There was one false negative study in a patient with tracheomalacia. In a second patient, a tracheal web was only apparent on nonstandard viewing windows. CONCLUSIONS: CT/MPR provides good anatomic detail and is an increasingly available technique. Potential drawbacks include the need for a longer breath-hold (15 to 45 seconds) and increased complexity of data compared with conventional tomograms. Helical CT/MPR is useful in the preoperative evaluation of these patients and, as experience accumulates, may replace the use of conventional tomograms.

Surgical delay for acute type A dissection with malperfusion.

BACKGROUND: An acute type A aortic dissection is considered a surgical emergency. Review of the risk factors for a type A dissection showed that preoperative malperfusion was associated with a 22% (2/9) intraoperative mortality and an 89% (8/9) hospital mortality. Intraoperative deaths were secondary to pulmonary failure resulting from capillary leak; the remaining patients died of multiorgan failure resulting from reperfusion injury. METHODS: The surgical delay approach was adopted for malperfused patients, and treatment in these patients included percutaneous reperfusion, with aortic fenestration and branch stenting where appropriate. Twenty patients had a type A dissection and malperfusion shown by pulsed-wave Doppler echocardiography, transesophageal echocardiography, or spiral computed tomographic scanning. Malperfusion was documented by angiography. After reperfusion, all patients' conditions were stabilized in the intensive care unit; intravenous beta-blockers were administered to decrease the maximum rate of increase of left ventricular pressure. Once patients completely recovered from the consequences of malperfusion, surgical repair was performed. Statistical comparison of the non-delay and delay groups was performed using Fisher's exact test and Student's t test. Multiple logistic regression analysis was used to establish independent predictors for mortality. RESULTS: The mean delay to repair was 20 days (2 to 67 days). Four (31%) patients were discharged home and readmitted for operation. Three patients (15%) died preoperatively, 1 of retrograde dissection and rupture and 2 of reperfusion injury. Seventeen underwent surgical repair, with two deaths (12%); 15 (75%) were discharged, with an average follow-up of 16.8 months (p < 0.003). Delay was the only independent predictor of outcome. CONCLUSIONS: Patients with an acute type A dissection and malperfusion should undergo percutaneous reperfusion, and surgical repair should be delayed until the reperfusion injury resolves.

Distribution of distant metastases from newly diagnosed non-small cell lung cancer.

BACKGROUND: The purpose of our study was to determine the incidence and locations of M1 disease at presentation in patients with non-small cell lung cancer to help design appropriate preoperative imaging algorithms. METHODS: All patients with non-small cell lung cancer seen between 1991 and 1993 were identified, and records were reviewed. For patients with M1 disease, the sites of distant metastases and the methods of diagnosis were recorded. RESULTS: Of 348 patients identified, 276 (79%) had M0 disease and 72 (21%) had M1 disease. In 40 of 72 patients (56%), M1 disease was detected via chest or abdominal computed tomography (CT). Brain, bone, liver, and adrenal glands were the most common sites of metastatic disease, in decreasing order. Brain metastases often occurred as an isolated finding, although isolated liver metastases were uncommon. CONCLUSIONS: M1 disease was common at presentation, and was often detectable via chest CT. The incremental yield of abdominal CT over chest CT was very small, and therefore abdominal CT is not an effective method of screening for metastases if chest CT has been performed.

Simultaneous usage of homologous points, lines, and planes for optimal, 3-D, linear registration of multimodality imaging data.

The authors have extended point-based registration to include simultaneous registration of points, lines, and planes, to permit accurate and easily implemented three-dimensional (3-D) registration of multimodal data sets for fusion of clinical anatomic and functional imaging modalities. Constructive geometry is used to define user-identified features where each feature's role in the reconstruction is weighted based on its relative statistical quality, i.e., variance. The algorithm employs singular value decomposition (SVD) and optimization techniques to find the minimum weighted least mean square error (LMSE) affine solution. The new method is generally more accurate due to the availability of more features to register. Notably the error surface contains only one minimum. Different subclasses of affine solutions can be obtained based on appropriateness and sufficiency of the number and type of input features. Preliminary results indicate that this method is useful in multimodal diagnostic image fusion.

Enhancing mediastinal mass at MR: Castleman disease.

We report a case of an enhancing middle mediastinal mass imaged by MR and CT. Repeated nondiagnostic biopsies in this 25-yr-old male patient had resulted in profuse hemorrhage. Final pathological diagnosis after thoracotomy and debulking was Castleman disease. This is a rare, benign lymphoproliferative disorder of uncertain etiology. Histological varieties include the hyaline vascular type (80-90%) and the plasma cell type (10-20%). Cure is generally accomplished via surgical excision. This entity should be included in the differential diagnosis of enhancing mediastinal lesions, prompting awareness of the potential for bleeding complications following biopsy.

Evaluation of competence in the interpretation of chest radiographs.

RATIONALE AND OBJECTIVES: The purpose of this study was to determine relative rates of missed diagnoses for radiologists as a measure of competence in interpreting chest radiographs. MATERIALS AND METHODS: Cases involving differing interpretations of chest radiographs were collected from January 1994 through December 1999 by faculty (chest and nonchest radiology specialists) in an academic radiology department. A quarterly peer-review process designated cases months after the fact, and anonymously, as no miss or as class I (nondiagnosable), class II (very difficult diagnosis), class III (should be diagnosed most of time), or class IV (should almost always be diagnosed) missed diagnoses. The rates and classes of missed diagnoses were compared among chest faculty and for the nonchest radiology specialists as a group. RESULTS: Chest radiologists read 184,977 studies, and nonchest radiologists read 300,684 studies. Of these, 243 missed diagnoses were classified (classes I and II, 184 cases; class III, 50; and class IV, nine). No difference was detected in the rate of class III and IV misses among chest faculty, but nonchest faculty had significantly more class III (P = .022) and class IV misses (P = .016). CONCLUSION: Random sampling of differing interpretations can yield a relative rate of missed diagnoses for radiologists. No difference was detected in clinically important misses (ie, classes III and IV) among chest radiologists, but a statistically significantly higher rate of seemingly obvious misdiagnoses was found for nonchest specialty radiologists. Potential biases may have influenced this analysis, including disease prevalence, sampling, clinical factors, observer variability, and truth-in-diagnosis.

Radiologic staging of lung cancer.

Preoperative tumor staging in patients with known or suspected non-small cell lung cancer is generally performed using contrast enhanced chest computed tomography (CT) (including the adrenal glands). Abdominal CT is generally unnecessary, given the low frequency of isolated liver metastases. The role of MRI is limited, and it is used mainly as a problem solving tool in certain specific situations. A CT showing no mediastinal lymph node enlargement usually oviates preoperative mediastinal lymph node sampling, with certain exceptions. If enlarged mediastinal lymph nodes are demonstrated at CT, then CT may be used to direct preoperative lymph node sampling via transbronchoscopic Wang needle biopsy, mediastinoscopy, mediastinotomy, or video assisted thoracoscopy.

Diaphragmatic shape change after lung volume reduction surgery.

Diaphragmatic shape in normal patients was significantly different from shape in emphysema patients. Postoperative diaphragmatic shape in patients with good clinical outcome differed from preoperative shape and was similar to shape in normal patients. In patients with poor clinical outcome, surgery appeared to have little effect on diaphragm shape.

Three dimensional CT of central lung tumors.

Three-dimensional computed tomography (CT) reconstructions and conventional CT were compared with surgical/pathological findings in seven patients with central lung tumors, in order to assess accuracy in predicting the lobectomy/pneumonectomy decision. Although conventional CT surpassed 3D CT in diagnosing bronchial tumor invasion, 3D CT appeared to be better for central arterial invasion. Despite problems due to motion effects, partial volume averaging and the time consuming nature of the reconstruction process, 3D CT is probably useful in this setting and promises to have similar applications throughout the body.

Multidisciplinary approach to thoracic tissue sampling.

When choosing the best method to undertake a biopsy of a lesion in the lung or mediastinum, it is important to consider the entire range of possible options, such as surgical, bronchoscopic/endoscopic, and radiologic techniques. Features to be considered include the anatomic location of the lesion, the amount of tissue needed, cost, availability of specific techniques, safety and risks, and expected diagnostic yield/accuracy.

Aortic growth rates in chronic aortic dissection.

AIM: To determine and compare rates of descending aortic enlargement and complications in chronic aortic dissection with and without a proximal aortic graft. METHODS AND MATERIALS: Fifty-two patients with dissection involving the descending aorta and who had undergone at least two computed tomography (CT) examinations at our institution between November, 1993 and February, 2004 were identified, including 24 non-operated patients (four type A, 20 type B) and 28 operated patients (type A). CT examinations per patient ranged from two to 10, and follow-up ranged from 1-123 months (mean 49 months, median 38.5 months). On each CT image, the aortic short axis (SA), false lumen (FL), and true lumen (TL) diameters were measured at the longitudinal midpoint of the dissection and at the point of maximum aortic diameter. Complications were tabulated, including aortic rupture and aortic enlargement requiring surgery. RESULTS: For non-operated patients, the midpoint and maximum point SA, TL, and FL diameters increased significantly over time. For operated patients, the midpoint and maximum point SA and FL diameters increased significantly over time. In both groups, aortic enlargement was predominantly due to FL expansion. Diameter increases in non-operated patients were significantly larger than those in operated patients. The rate of change in aortic diameter was constant, regardless of aortic size. Four non-operated and six operated patients developed aortic complications. CONCLUSIONS: In patients with a dissection involving the descending thoracic aorta, the FL increased in diameter over time, at a constant rate, and to a greater degree in non-operated patients (mostly type B) compared with operated patients (all type A).