Outcomes after intensity-modulated compared with 3-dimensional conformal radiotherapy with chemotherapy for squamous cell carcinoma of the anal canal.

Purpose: We report our institution's treatment techniques, disease outcomes, and complication rates after radiotherapy for the management of anal canal carcinoma with intensity-modulated radiotherapy (imrt) and concurrent chemotherapy relative to prior cases managed with 3-dimensional conformal radiotherapy (3D-crt). Methods: In a retrospective review of the medical records of 21 patients diagnosed with biopsy-proven stage i (23%), stage ii (27%), or stage iii (50%) squamous-cell carcinoma of the anal canal treated with curative chemotherapy and imrt between July 2009 and December 2014, patient outcomes were determined. Results for patients treated with 3D-crt by the same group were previously reported. The median initial radiation dose to the pelvic and inguinal nodes at risk was 45 Gy (range: 36-50.4 Gy), and the median total dose, including local anal canal primary tumour boost, was 59.4 Gy (range: 41.4-61.2 Gy). Patients received those doses over a median of 32 fractions (range: 23-34 fractions). Chemotherapy consisted of 2 cycles of concurrent fluorouracil-cisplatin (45%) or fluorouracil-mitomycin C (55%). Results: Median follow-up was 3.1 years (range: 0.38-6.4 years). The mean includes a patient who died of septic shock at 38 days. The 3-year rates of overall survival, metastasis-free survival, locoregional control, and colostomy-free survival were 95%, 100%, 100%, and 100% respectively. No patients underwent abdominoperitoneal resection after chemoradiotherapy or required diverting colostomy during or after treatment. Those outcomes compare favourably with the previously published series that used 3D-crt with or without brachytherapy in treating anal canal cancers. Of the 21 patients in the present series, 10 (48%) experienced acute grade 3, 4, or 5 toxicities related to treatment. Conclusions: The recommended use of imrt with concurrent chemotherapy as an improvement over 3D-crt for management of anal canal carcinoma achieves a high probability of local control and colostomy-free survival without excessive risk for acute or late treatment-related toxicities.

Effect of angiotensin II induced hypertension on tumor blood flow and interstitial fluid pressure.

The effect of angiotensin II-induced hypertension on tumor interstitial fluid pressure (TIFP) and tumor blood flow (TBF) was investigated to examine blood flow and pressure regulation in solid tumors. TIFP measurements were made before and after administration of angiotensin II using the wick-in-needle method in s.c. tumor implants. Relative TBF was continuously monitored by laser doppler velocimetry. The effect of host strain on TIFP was evaluated in MCA-IV mammary carcinoma, transplanted in C3H and SCID mice, and showed no significant difference. The effects of tumor types were evaluated by comparing two murine tumors, MCA-IV mammary carcinoma and FSaII fibrosarcoma, and a human tumor xenograft, LS174T adenocarcinoma, transplanted in SCID mice. Baseline TIFP was elevated in all three tumor lines to significantly different pressures. AII-induced hypertension (approximately 150 mm Hg) had a variable but tumor line-specific effect on TIFP and TBF. The increase in TIFP was correlated with the baseline TIFP (r2 = 0.853) (increasing from 6.9 to 8.7 mm Hg, 10.5 to 15.8 mm Hg, and 21.7 to 29.4 mm Hg in FSaII, MCA-IV, and LS174T, respectively). These data suggest that in addition to blood flow redistribution due to the steal phenomenon, arterial control of TBF and TIFP exists within these solid tumors; however, the extent of control is tumor line dependent and less than that in normal tissues. Moreover, parallel increases in TIFP and TBF do not support the hypothesis that elevated TIFP causes vascular collapse and thus decreases TBF.

Conservative treatment of rectal adenocarcinoma with endocavitary irradiation or wide local excision and postoperative irradiation.

PURPOSE: To evaluate the role of endocavitary irradiation and wide local excision followed by irradiation in the treatment of early-stage rectal adenocarcinoma. MATERIALS AND METHODS: Sixty-five patients with early-stage adenocarcinoma of the rectum were treated with endocavitary irradiation (n = 20) or wide local excision followed by external-beam irradiation (n = 45) between 1974 and 1994 at the University of Florida. All patients were monitored for a minimum of 2 years or until death. RESULTS: The rates of local-regional control at 5 years were 80% after endocavitary irradiation and 86% after wide local excision and radiotherapy. The ultimate 5-year local-regional control rates were 85% and 92%, respectively. Multivariate analysis of local-regional control with sphincter preservation showed that tumor configuration (exophytic v ulcerative) significantly influenced this end point; local-regional control was decreased in patients with ulcerated cancers. Five-year cause-specific survival rates were 84% after endocavitary irradiation and 88% after wide local excision and radiotherapy. Multivariate analysis revealed that tumor configuration significantly influenced cause-specific survival; patients with ulcerated tumors had a worse prognosis. CONCLUSION: Endocavitary irradiation is a highly effective treatment for properly selected patients with early-stage rectal adenocarcinoma. Patients with less favorable lesions that appear to be limited to the muscularis propria have a high chance of cure with sphincter preservation after wide local excision and external-beam irradiation.

Radiotherapy for local control of aggressive fibromatosis.

PURPOSE: To evaluate local control rates in patients treated with radiotherapy for aggressive fibromatosis. METHODS AND MATERIALS: Fifty-three patients with histologically confirmed aggressive fibromatosis were treated with radiotherapy at the University of Florida between march 1975 and June 1992. The minimum length of follow-up was 2 years; 81% of the patients had follow-up for at least 5 years. The lesions arose in an extremity or limb girdle (39 patients), the trunk (10 patients), or the head and neck area (4 patients). Twenty-four patients were treated for gross disease and 29 for presumed microscopic residual disease after one or more operations. Patients were treated with total doses between 35 and 70 Gy; 83% of patients received 50 to 60 Gy. RESULTS: Local control was achieved in 23 of 29 patients (79%) treated postoperatively for microscopic residual disease and in 21 of 24 patients (88%) treated for gross disease; gross disease was controlled in all 8 patients with previously untreated lesions and in 13 of 16 patients treated postoperatively for gross residual or recurrent disease. Overall, aggressive fibromatosis was locally controlled in 83% of treated patients. All nine treatment failures occurred in patients with extremity lesions 4 to 68 months after initiation of treatment. Three recurrences were in the irradiated field, two were out of the field, and four were at the field margin. Eight patients were salvaged with surgery alone or combined with postoperative radiotherapy. A functional limb was maintained in 38 of 39 patients with extremity or limb girdle lesions. Pathologic fracture occurred in three patients; two patients required rod fixation for treatment. CONCLUSIONS: Radiotherapy is a valuable adjunct to surgery in the management of aggressive fibromatosis and can be used alone in patients with unresectable or inoperable disease.

Squamous cell carcinoma of the anal canal.

PURPOSE: To report the results of primary radiotherapy for treatment of anal canal carcinoma from the University of Florida series and review issues related to treatment of this disease. METHODS AND MATERIALS: Forty-nine patients were treated with primary radiation therapy (RT) for cure. Patients had a minimum 2-year follow-up (median, 9.8 years). After 1990, patients with lesions of at least 3 cm also received chemotherapy with fluorouracil (1000 mg/m(2)) plus cisplatin (100 mg/m(2)) or mitomycin (10-15 mg/m(2)) if medically fit (n = 26). RT was delivered with a 4-field box technique to deliver 45 Gy in 25 fractions. The inguinal nodes were treated daily using electrons to supplement the dose in that region to a total dose of 45 Gy if clinically negative or about 60 Gy if involved. There were no planned breaks. A 10- to 15-Gy boost was delivered using interstitial iridium 192 implant (n = 32), en face (60)Co field (n = 5), or external-beam photon fields (n = 11). RESULTS: Local control rates at 5 years were 100% for T1N0, 92% for T2N0 or N1, 75% for T3N0, 67% for T4N0, 88% for T4N(pos) or T(any)N2-3, and 85% overall. With surgical salvage, ultimate local control rates were 100%, 100%, 81%, 100%, and 88%, respectively, with 92% overall. Cause-specific survival rates at 5 years were 100% for Stage I, 88% for Stage II, 100% for Stage IIIA, and 70% for Stage IIIB. Absolute survival rates at 5 years were 62%, 68%, 100%, and 70%. Sphincter preservation rates were 83%, 79%, 75%, and 100% by stage and 81% overall. There was an improvement in local control with the addition of chemotherapy in more advanced disease, but it was not significant. There was an increase in acute toxicity with the addition of chemotherapy (12% > or = Grade 4) but not long-term toxicity. Late toxicity requiring colostomy occurred in 6% of patients and consisted of soft tissue necrosis. CONCLUSIONS: The majority of patients with anal canal carcinoma can be treated with curative intent using a sphincter-sparing approach of radiation with or without chemotherapy even with advanced disease. With the addition of chemotherapy to radiation, there is an increased risk of acute toxicity and about 1-2% incidence of toxic death. Smaller tumors (T1 and early T2) probably do not require the addition of chemotherapy.

Potential clinical efficacy of intensity-modulated conformal therapy.

PURPOSE: The purpose of this study was to examine the potential benefit of using intensity-modulated conformal therapy for a variety of lesions currently treated with stereotactic radiosurgery or conventional radiotherapy. METHODS AND MATERIALS: Intensity-modulated conformal treatment plans were generated for small intracranial lesions, as well as head and neck, lung, breast, and prostate cases, using the Peacock Plan treatment-planning system (Nomos Corporation). For small intracranial lesions, intensity-modulated conformal treatment plans were compared with stereotactic radiosurgery treatment plans generated for patient treatment at the University of Florida Shands Cancer Center. For other sites (head and neck, lung, breast, and prostate), plans generated using the Peacock Plan were compared with conventional treatment plans, as well as beam's-eye-view conformal treatment plans. Plan comparisons were accomplished through conventional qualitative review of two-dimensional (2D) dose distributions in conjunction with quantitative techniques, such as dose-volume histograms, dosimetric statistics, normal tissue complication probabilities, tumor control probabilities, and objective numerical scoring. RESULTS: For small intracranial lesions, there is little difference between intensity-modulated conformal treatment planning and radiosurgery treatment planning in the conformation of high isodose lines with the target volume. However, stereotactic treatment planning provides a steeper dose gradient outside the target volume and, hence, a lower normal tissue toxicity index. For extracranial sites, objective numerical scores for beam's-eye-view and intensity-modulated conformal planning techniques are superior to scores for conventional treatment plans. The beam's-eye-view planning technique prevents geographic target misses and better excludes healthy tissues from the treatment portal. Compared with scores for the beam's-eye-view planning technique, scores for intensity-modulated conformal plans using the Peacock Plan were significantly better for the lung and head and neck cases studied, equivalent for prostate cases, and inferior for breast cases. CONCLUSION: Using the entire 3D data set to construct radiotherapy plans through virtual simulation is always advantageous, whether done for stereotactic radiosurgery, beam's-eye-view conformal therapy, or intensity-modulated conformal treatment. Intensity modulation of the photon beam further enhances treatment planning under specific conditions. In general, the intensity-modulated technique is advantageous for large, irregular targets with critical structures in close proximity. Intensity-modulated treatment planning does not appear advantageous for stereotactic radiosurgery or treatment of the intact breast.

Megavoltage radiotherapy for aneurysmal bone cysts.

PURPOSE: An aneurysmal bone cyst (ABC) is a rapidly expansile and destructive benign tumor of bone that is usually treated by curettage and bone graft, with or without adjuvant treatment. For recurrent tumors, or tumors for which surgery would result in significant functional morbidity, does radiotherapy (RT) provide a safe and effective alternative for local control? PATIENTS AND METHODS: Nine patients with histologically diagnosed aneurysmal bone cysts without other associated benign or malignant tumors were treated at the University of Florida with megavoltage RT between February 1964 and June 1992. The patients received local radiotherapy doses between 20 and 60 Gy, with 6 patients receiving 26--30 Gy. In 6 patients the diagnosis was made by biopsy alone; 3 underwent intralesional curettage before RT. Minimum follow-up was 20 months; 7 of 9 patients (77%) had follow-up greater than 11 years. RESULTS: No patient experienced a local recurrence (median follow-up, 17 years). One patient required stabilization of the cervical spine 10 months after RT because of dorsal kyphosis from vertebral body collapse. No other significant side effects were experienced, and no patients developed secondary malignancies. Four patients were lost to follow-up: at 20 months, 11.5 years, 17 years, and 20 years after the initiation of treatment, none with any evidence of local recurrence. All of the patients who had significant pain before RT had relief of their symptoms within 2 weeks of completion of therapy. CONCLUSIONS: Using modern-day RT, patients with recurrent or inoperable aneurysmal bone cysts can be treated effectively (with minimal toxicity) using a prescribed tumor dose of 26--30 Gy.

Use of PSA nadir to predict subsequent biochemical outcome following external beam radiation therapy for T1-2 adenocarcinoma of the prostate.

PURPOSE: This study assessed the ability of nadir prostate-specific antigen (PSA) to act as an early surrogate for subsequent freedom from biochemical failure following radiation therapy for T1-2 prostatic adenocarcinoma. METHODS AND MATERIALS: A retrospective analysis was performed on the biochemical outcome of 314 consecutive men with T1-2 disease treated by conventional external beam radiation at the Massachusetts General Hospital. Minimum follow up was 2 years, and failure was defined as three successive rises in serum PSA of greater than 10%. Kaplan-Meier actuarial analysis of outcome was employed. RESULTS: The overall 5-year freedom from biochemical progression was 63%. For those who achieved a PSA nadir of < or = 0.5 ng/ml (n = 123) it was 90%, for 0.6-1.0 ng/ml (n = 103) it was 55%, and for > 1.0 ng/ml (n = 88) it was 34%. Multivariate analysis showed an undetectable PSA nadir to be independent of Gleason grade and initial PSA in predicting subsequent outcome (P < 0.05). The likelihood of achieving an undetectable PSA nadir correlated strongly with the pretreatment value: 74% if this was below 4 ng/ml; 42% for those between 4.1 and 10 ng/ml; and 32% for those above 10 ng/ml. CONCLUSION: A PSA nadir of < or = 0.5 ng/ml represents an early endpoint strongly predictive of a favorable outcome following radiation therapy which may be used for the rapid assessment of new radiation strategies.

External-beam radiation therapy for improved dialysis access patency: feasibility and early safety.

Rectenwald, J. E., Pretus, H. A., Seeger, J. M., Huber, T. S., Mendenhall, N. P., Zlotecki, R. A., Palta, J. R., Li, Z. F., Hook, S. Y., Sarac, T. P., Welborn, M. B., Klingman, N. V., Abouhamze, Z. S. and Ozaki, C. K. External-Beam Radiation Therapy for Improved Dialysis Access Patency: Feasibility and Early Safety. Radiat. Res. 156, 53-60 (2001).Prosthetic dialysis access grafts fail secondary to neointimal hyperplasia at the venous anastomosis. We hypothesized that postoperative single-fraction external-beam radiation therapy to the venous anastomosis of hemodialysis grafts can be used safely in an effort to improve access patency. Dogs (n = 8) underwent placement of expanded polytetrafluoroethylene grafts from the right carotid artery to the left jugular vein. Five dogs received single-fraction external-beam photon irradiation (8 Gy) to the venous anastomosis after surgery. Controls were not irradiated. Shunt angiograms were completed 3 and 6 months postoperatively. Anastomoses, mid-graft, and the surrounding tissues were analyzed. Immunohistochemistry for smooth muscle cell alpha-actin, proliferating cellular nuclear antigen (PCNA), and apoptosis was performed. Incisions healed well, though all animals developed wound seromas. One control suffered graft thrombosis 4 months postoperatively. Angiography/histology confirmed severe neointimal hyperplasia at the venous anastomosis. The remaining seven dogs developed similar amounts of neointimal hyperplasia. PCNA studies showed no accelerated fibroproliferative response at irradiated anastomoses compared to controls. Skin incisions and soft tissues over irradiated anastomoses revealed no radiation-induced changes or increase in apoptosis. Thus we conclude that postoperative single-fraction external-beam irradiation of the venous anastomosis of a prosthetic arteriovenous graft that mimics the situation in humans is feasible and safe with regard to early wound healing.

Conservative treatment of rectal adenocarcinoma.

Endocavitary radiotherapy and transrectal excision are highly effective treatments for properly selected patients with favorable early-stage rectal adenocarcinoma. The likelihood of local control and survival after treatment with either modality is similar, and differences among various series probably reflect selection. The parameter most predictive of local control and survival in the authors' series was tumor configuration. As has been previously observed, "selection is the silent partner of success." Suitable candidates for endocavitary radiotherapy or wide local excision are patients whose tumors are 3 cm or less in diameter, well-to-moderately differentiated, exophytic, mobile, limited to the submucosa on transrectal ultrasound, and within 10 cm of the anal verge. The advantages of endocavitary irradiation are (1) it is an outpatient procedure, (2) it does not require anesthesia, and (3) it is less expensive than transrectal excision. The advantages of transrectal excision are (1) it may be performed during one brief hospitalization (as opposed to four outpatient visits), and (2) a small subset of patients will have pathologic findings predicting an increased risk of regional lymph node involvement, revealing the need to treat the nodes with external-beam radiotherapy. A disadvantage of wide local excision is that some patients who would be suitable for a local procedure alone must be subjected to a course of external-beam radiotherapy when they are found to have equivocal or positive margins. Patients who are treated with transrectal excision and external-beam radiotherapy have less favorable lesions and are not comparable with patients who are treated with endocavitary radiotherapy or wide local excision alone. They are best compared with patients who have undergone major surgery consisting of abdominoperineal resection or low anterior resection. Because the risk of positive nodes is significantly increased with adverse pathologic findings such as poor differentiation, invasion of the muscularis propria, and endothelial-lined space invasion, a subset of these patients treated with wide local excision would have positive nodes. This subset of patients is not comparable with patients with stage pT1N0 and pT2N0 tumors treated with major surgery. The latter group of patients undergo complete surgical staging, whereas the pathologic staging for patients who undergo wide local excision and radiotherapy is limited to the extent of the primary tumor. With this caveat in mind, wide local excision and radiotherapy seem to result in locoregional control and survival rates similar to the rates obtained with major surgery for patients with pT1 and pT2 cancers (Table 5). Patients who should receive postoperative irradiation have tumors that exhibit one or more of the following characteristics: size greater than 3 cm in diameter, poorly differentiated, invasion of the muscularis propria, endothelial-lined space invasion, fragmented resection, equivocal or positive margins, or perineural invasion. Patients with gross residual disease are not suitable candidates for radiotherapy and require further surgery. The authors' policy is to treat these patients with chemoradiation followed by resection. Patients thought to have transmural invasion before treatment are probably best treated with preoperative chemoradiation combined with major surgery, although a subset of patients can be downstaged and rendered suitable for a wide local excision.

The role of radiotherapy and limb-conserving surgery in the management of soft-tissue sarcomas in adults.

The treatment of soft-tissue sarcomas has undergone significant changes over the past several decades. Previously, patients were often treated with surgery alone, which frequently necessitated amputation of the affected extremity. Less extensive, limb-sparing operations combined with adjuvant irradiation are now feasible for most patients without compromising the likelihood of cure.

Squamous cell carcinoma of the anal margin treated with radiotherapy.

Squamous cell carcinoma of the anal margin is relatively rare. We present a series of patients treated with radiotherapy alone or combined with concomitant chemotherapy at our institution and review the pertinent literature. Ten patients with AJCC T2N0 and T3N0 squamous cell carcinoma of the anal margin were treated with radiotherapy alone or radiotherapy plus chemotherapy at the University of Florida between 1979 and 1993. All patients had a follow-up for at least 2 years, and no patient was lost to follow-up. All ten patients have remained continuously disease free after treatment. Three patients died of intercurrent disease at 29, 37 and 113 months after treatment. The remaining seven patients were alive and disease-free from 24 to 143 months after radiotherapy. No patient experienced a major complication and all retained a functional anal sphincter. Based on our experience and a review of the literature, superficial, well to moderately differentiated, T1 and T2 cancers may be successfully treated with radiotherapy alone or a local excision. More advanced lesions are best treated with combined radiotherapy and concomitant chemotherapy. Abdominoperineal resection should be reserved for those presenting with faecal incontinence and those with locally recurrent disease after previous radiotherapy.

Squamous cell carcinoma of the anal margin.

Based on our experience and a review of the literature, we conclude that superficial, well- to moderately differentiated T1 cancers of the anal margin may be successfully treated with radiotherapy alone or local excision. Stage T2 lesions have a significant risk of inguinal lymph node metastases and should be treated with radiotherapy to the primary tumor in conjunction with elective inguinal lymph node irradiation. The best treatment for T3 and T4 lesions is radiotherapy to the primary lesion and regional nodes (inguinal and pelvic) combined with concomitant chemotherapy. Abdominoperineal resection (APR) should be reserved for patients who have fecal incontinence at presentation or locally recurrent disease after previous radiotherapy.

External-beam radiotherapy in the management of carcinoma of the prostate.

BACKGROUND: External-beam radiotherapy (EBRT) has been used in the treatment of adenocarcinoma of the prostate gland for more than 30 years. Well-documented clinical series have demonstrated the effectiveness of EBRT in achieving both cause-specific survival and freedom from biochemical (prostate-specific antigen [PSA]) progression. METHODS: The indications and expected treatment results for treatment by EBRT in the management of adenocarcinoma of the prostate gland are reviewed. The treatment of early-stage disease definitively by EBRT alone or as complement to radioactive seed implant is emphasized. In the management of locally advanced disease, the use of EBRT with combined androgen ablation is discussed as definitive therapy and also as indicated in the postoperative adjuvant management of surgically identified pathologic stage T3 disease. RESULTS: The relative clinical benefit of EBRT compared with the mostly predictable and well-defined moderate side effects, which are manageable in most instances by conservative measures treatment, is well established. Advances in defining radiation-beam parameters have led to more effective and safer treatment for prostate cancer. CONCLUSIONS: EBRT has historically been a mainstay in the management of prostate cancer. It remains a useful and indicated treatment modality in patients with early-stage, locally advanced, and metastatic disease.

Decreased metastasis and improved survival with early thoracic radiotherapy and prophylactic cranial irradiation in combined-modality treatment of limited-stage small cell lung cancer.

In an attempt to verify the relative efficacy of early concurrent vs. sequential timing of thoracic radiotherapy (TRT) and platinum/etoposide chemotherapy, 48 patients with limited-stage small cell lung cancer treated with either early-concurrent (29 patients) or sequential (19 patients) TRT and platinum/etoposide chemotherapy were evaluated. Disease-specific prognostic variables and the role of prophylactic cranial irradiation (PCI) were also analyzed. Thirty-four patients (71%) received TRT to a dose of 45 Gy in 25 fractions (range, 30-55 Gy). Most patients (75%) received 4-6 cycles of chemotherapy. Twenty-one of 27 patients achieving a complete response after completion of TRT and chemotherapy received PCI. Median follow-up was 29.3 months (range, 12-98 months). Variables of potential prognostic significance were evaluated by both univariate and multivariate analysis. The absolute and relapse-free survival rates for all patients were 42% and 35% at 2 years and 32% and 31% at 5 years, respectively. Thirty-six sites of failure were observed in 27 patients. Thoracic recurrence occurred in nine patients, and the central nervous system (CNS) was the most common site of distant failure (15 patients). Multivariate analysis demonstrated that (a) early concurrent TRT and chemotherapy vs. chemotherapy followed by sequential TRT and (b) disease volume [less than or greater than one-third of the thoracic width] were significantly predictive for survival (P=0.036 and P=0.05, respectively). Rates of control of thoracic disease were 79% for patients with a disease volume less than one-third of the thoracic width vs. 36% for disease volumes greater than one-third of the thoracic width (P=0.0009). Early concurrent TRT and chemotherapy resulted in a significantly lower incidence of distant metastasis (26% for concurrent vs. 63% for sequential; P=0.008). In patients who received PCI, the CNS control rate was 86% vs. 56% in patients not treated with PCI. Our findings suggest that (a) treatment with early concurrent TRT and platinum/etoposide chemotherapy may improve survival when compared with sequential treatment and (b) PCI for patients with complete systemic responses is effective in preventing CNS recurrence. We also conclude that thoracic disease volume is a significant prognostic factor for both local control and overall survival.

Visualization of tumor vascularity in a rabbit VX2 carcinoma by Doppler flow mapping.

Using an ultrasonic dynamic flow imager that displays both soft tissues and color-coded flow in the same two-dimensional slice, we were able to display neovascularity in a rabbit VX2 carcinoma. Intravenous infusion of epinephrine altered the flow dynamics in two arteries, one within the tumor and one at the periphery. Further, we were also able to visualize areas of multidirectional flow presumably due to complex arterial patterns and arteriovenous shunts. It is concluded that the color-coded Doppler instrument may overcome some of the methodological problems associated with tumor diagnosis via flow characteristics in the human breast. The literature indicates that the vascular response to the vasoactive drugs or thermal stress may increase differentiation of malignant breast lesions. This experiment suggests that Doppler images and measurements may be made efficiently with color-coded Doppler images, particularly with the addition of more quantitative features to the imager.

Pharmacologic modification of tumor blood flow and interstitial fluid pressure in a human tumor xenograft: network analysis and mechanistic interpretation.

Various vasoactive agents have been used to modify tumor blood flow with the ultimate goal of improving cancer detection and treatment, with widely disparate results. Furthermore, the lack of mechanistic interpretations has hindered understanding of how these agents affect the different physiological parameters involved in perfusion. Thus, there is a need to develop a unified framework for understanding the interrelated physiological effects of pharmacological and physical agents. The goals of this study were (1) to develop a mathematical model which helps determine the location and magnitude of changes in the vascular resistance of tumor and normal tissues and (2) to test the model with our experimental studies and by comparison with results from the literature. The systemic and interstitial pressures and relative tumor blood flow were measured before and after administration of angiotensin II, epinephrine, norepinephrine, nitroglycerin, and hydralazine in SCID mice bearing LS174T human colon adenocarcinoma xenografts. A mathematical model was developed in analogy to electrical circuits which examined the pressure, flow, and resistance relationships for arterial and venous segments of the vasculature of a tumor and surrounding normal tissue. Vasoconstrictor-induced increases in the mean arterial blood pressure led to increases in tumor blood flow and interstitial pressure with the magnitude of change dependent on the agent (percentage change in blood flow: angiotensin > epinephrine > norepinephrine). The vasodilating agents induced decreases in tumor blood flow in parallel to the induced decreases in the systemic pressure, but only the long-acting arterial vasodilator hydralazine was capable of effecting a decrease in tumor interstitial pressure. The model was also found to be consistent with other data available in the literature on norepinephrine, pentoxifylline, nicotinamide, and hemodilution, and was useful in providing input as to the location and degree of the physiological effects of these agents. The results of the data and model show that the steal phenomenon is the dominant mechanism for redistribution of host blood flow to the tumor. However, some degree of arterial control was found to be present in the tumors. Moreover, the parallel increases in tumor interstitial pressure and blood flow contradict any hypothesis suggesting that elevated interstitial fluid pressure precipitates chronic vascular collapse, thus decreasing blood flow.

Specific and sensitive assays for digoxin in plasma, urine and heart tissue.

A combined internal standard and marker was added directly to urine, then after mixing, an aliquot was injected directly onto a C18 mu-Bondapak HPLC column. The 4.5 ml digoxin fraction was collected over 1.5 min starting 1 min after the appearance of the marker peak (UV detection), and the digoxin determined in the fraction by radioimmunoassay using 3H-digoxin. Digoxin was extracted from alkalinized plasma into dichloromethane. After evaporating the extract and addition of internal standard the remainder of the assay was as described above for urine. Multiple samples of urine and plasma collected in a single dose bioavailability trial in normal human volunteers were assayed by one of these specific methods as well as by the usual direct nonspecific RIA method. There were no significant differences in results by the specific and nonspecific methods. Heart tissue was homogenized with internal standard and phosphate buffer than the mixture was centrifuged. The supernatant was extracted with dichloromethane, the solvent evaporated from the extract, the residue redissolved in mobile phase and the remainder of the assay carried out as for urine and plasma.

Carcinoma of the extrahepatic biliary tract: surgery and radiotherapy for curative and palliative intent.

Forty-seven patients were treated for carcinoma of the extrahepatic biliary tract between 1962 and 1993: 17 by surgery alone, 20 by surgery and postoperative radiotherapy, and 10 with radiotherapy alone. Initial operations included gross total resection (17 patients), simple cholecystectomy (6 patients), subtotal resection (11 patients), biopsy (3 patients), and percutaneous decompression (10 patients). External-beam radiotherapy (30-60 Gy) was administered to 30 patients: 10 after gross total resection or simple cholecystectomy, 10 after subtotal resection or surgical biopsy, and 10 after percutaneous decompression. Overall survival was 26% at 3 years and 15% at 5 years. The 5-year survival rate was 15% for 17 patients treated by surgery alone and 14% for 30 patients treated with radiotherapy alone or following surgery. After gross total resection, median survival time was 26.1 months for 9 patients treated by surgery alone vs. 43.4 months for 8 patients who received postoperative radiotherapy. After gross total resection or cholecystectomy, 5-year survival rates were 19% for surgery alone and 35% for surgery and postoperative radiotherapy (P=.07). Median survival for 10 patients treated by radiation therapy alone after percutaneous decompression was 6.4 months. Postoperative adjuvant radiotherapy was well tolerated and may improve local-regional control after gross total resection.

Local excision and postoperative radiation therapy for rectal adenocarcinoma.

Sixty-seven patients with early-stage adenocarcinoma of the rectum who had lesions thought to be unsuitable for either local excision alone or endocavitary irradiation were treated with local excision followed by postoperative radiation therapy. The purpose of this study was to evaluate the effectiveness of local excision followed by radiation therapy for treatment of rectal adenocarcinoma. The patients were treated between 1974 and 1999; follow-up time was 6 to 273 months (median, 65 months). All living patients had follow-up for at least 2 years. The indications for postoperative irradiation included equivocal or positive margins, invasion of the muscularis propria, endothelial-lined space invasion, poorly differentiated histology, and perineural invasion. Cox proportional hazards regression analysis was performed using six explanatory variables including tumor size, configuration (exophytic vs. ulcerative), histologic differentiation, pathologic T stage, endothelial-lined space invasion, and margin status. The time interval between treatment and development of recurrent disease was in the range of 11 to 48 months. The 5-year results were as follows: local-regional control, 86%; ultimate local-regional control, 93%; distant metastasis-free survival, 93%; absolute survival, 80%; and cause-specific survival, 90%. When the Cox proportional hazards regression analysis was performed for these endpoints, margin status influenced absolute survival (P = 0.0074), cause-specific survival (P = 0.0405), and ultimate local-regional control (P = 0.0439). Tumor configuration marginally influenced cause-specific survival (P = 0.0577). None of the variables had an influence on the endpoints' local-regional control, ultimate local-regional control with sphincter preservation, or distant metastasis. Five patients (7%) had severe complications; no complication was fatal. Local excision and postoperative radiation therapy results in a high probability of local-regional control and survival for selected patients with relatively early-stage rectal adenocarcinoma. Patients with ulcerative tumors may have a lower likelihood of cause-specific survival.