Structural model for the beta-amyloid fibril based on interstrand alignment of an antiparallel-sheet comprising a C-terminal peptide.

Amyloids are a class of noncrystalline, yet ordered, protein aggregates. A new approach was used to provide the initial structural data on an amyloid fibril--comprising a peptide (beta 34-42) from the C-terminus of the beta-amyloid protein--based on measurement of intramolecular 13C-13C distances and 13C chemical shifts by solid-state 13C NMR and individual amide absorption frequencies by isotope-edited infrared spectroscopy. Intermolecular orientation and alignment within the amyloid sheet was determined by fitting models to observed intermolecular 13C-13C couplings. Although the structural model we present is defined to relatively low resolution, it nevertheless shows a pleated antiparallel beta-sheet characterized by a specific intermolecular alignment.

Factors influencing cosmetic results after conservation therapy for breast cancer.

PURPOSE: Host, tumor, and treatment-related factors influencing cosmetic outcome are analyzed for patients receiving breast conservation treatment. METHODS AND MATERIALS: Four-hundred and fifty-eight patients with evaluable records for cosmesis evaluation, a subset of 701 patients treated for invasive breast cancer with conservation technique between 1969 and 1990, were prospectively analyzed. In 243 patients, cosmetic evaluation was not adequately recorded. Cosmesis evaluation was carried out from 3.7 months to 22.3 years, median of 4.4 years. By pathologic stage, tumors were 62% T1N0, 14% T1N1, 15%, T2N0, and 9% T2N1. The majority of patients were treated with 4-6 MV photons. Cosmetic evaluation was rated by both patient and physician every 4-6 months. A logistic regression analysis was completed using a stepwise logistic regression. P-values of 0.05 or less were considered significant. Excellent cosmetic scores were used in all statistical analyses unless otherwise specified. RESULTS: At most recent follow-up, 87% of patients and 81% of physicians scored their cosmetic outcome as excellent or good. Eighty-two percent of physician and patient evaluations agreed with excellent-good vs. fair-poor rating categories. Analysis demonstrated a lower proportion of excellent cosmetic scores when related to patient age > 60 years (p = 0.001), postmenopausal status (p = 0.02), black race (p = 0.0034), and T2 tumor size (p = 0.05). Surgical factors of importance were: volume of resection > 100 cm3 (p = 0.0001), scar orientation compliance with the National Surgical Adjuvant Breast Project (NSABP) guidelines (p = 0.0034), and > 20 cm2 skin resected (p = 0.0452). Extent of axillary surgery did not significantly affect breast cosmesis. Radiation factors affecting cosmesis included treatment volume (tangential breast fields only vs. three or more fields) (p = 0.034), whole breast dose in excess of 50 Gy (p = 0.0243), and total dose to tumor site > 65 Gy (p = 0.06), as well as optimum dose distribution with compensating filters (p = 0.002). Daily fraction size of 1.8 Gy vs. 2.0 Gy, boost vs. no boost, type of boost (brachytherapy vs. electrons), total radiation dose, and use of bolus were not significant factors. Use of concomitant chemotherapy with irradiation impaired excellent cosmetic outcome (p = 0.02). Use of sequential chemotherapy or adjuvant tamoxifen did not appear to diminish excellent cosmetic outcomes (p = 0.31). Logistic regression for excellent cosmetic outcome analysis was completed for age, tumor size, menopausal status, race, type of surgery, volume of breast tissue resected, scar orientations, whole breast radiation dose, total radiation dose, number of radiation fields treated, and use of adjuvant chemotherapy. Significant independent factors for excellent cosmetic outcome were: volume of tissue resected (p = 0.0001), type of surgery (p = 0.0001), breast radiation dose (p = 0.005), race (p = 0.002), and age (p = 0.007). CONCLUSIONS: Satisfactory cosmesis was recorded in 81% of patients. Impaired cosmetic results are more likely with improper orientation of tylectomy and axillary incisions, larger volume of breast resection, radiation dose to the entire breast in excess of 50.0 Gy, and concurrent administration of chemotherapy. Careful selection of treatment procedures for specific patients/tumors and refinement in surgical/irradiation techniques will enhance the cosmetic results in breast conservation therapy.

Management of the axilla in patients with breast cancers one centimeter or smaller.

Very small breast cancers are being diagnosed with increased frequency, and, until recently, little information regarding the incidence of axillary lymph node metastases in these most favorable tumors was available. Moreover, scarce data exist regarding axillary failure in this cohort as a function of initial treatment, be it surgery, radiation, or simply observation. In the present study, limited to women with invasive cancers measuring no more than 10 mm, the incidence of pathologically positive axillary nodes was 12.3%. The incidence of nodal metastases was influenced by tumor size (albeit not quite significantly, p = .08); not one patient with a tumor < or = 5 mm had axillary node metastases, compared to 14.7% in those with cancers 6 to 10 mm. The histologic grade and tumor location were also important in predicting nodal positivity. The incidence of positive nodes was 38% in those with poorly differentiated cancers, compared to 8% and 7% in women with well and moderately differentiated cancers, respectively, p = .03. Axillary nodal positivity was seen in 17% of outer quadrant vs 3% of central and inner quadrant primaries, p < .01. The axilla was managed with surgery alone (76%), radiation alone (6%), surgery and radiation (6%), or simply observation (10%). With a median follow-up of 55 months, not one patient has suffered a nodal recurrence, and in our experience, survival free of distant relapse was not adversely affected by the omission of axillary surgery.

Survival following breast-conserving surgery and irradiation or modified radical mastectomy in patients with invasive breast cancers with a maximum diameter of 1 cm.

The reported relapse-free survival for women with invasive breast cancers measuring no more than 10 mm in dimension ranges from 75% to 95%, with axillary status an important prognostic factor in most series. Further study of prognostic variables in this most favorable subset is notably limited. We retrospectively reviewed the records of 168 women with invasive breast cancers < or = 10 mm treated with either breast conserving surgery+axillary dissection (AXD) and radiation therapy, or mastectomy+AXD. The actuarial survival and survival free of distant metastases (DMFS) at 7 years was 95% and 97%, respectively. Location and size of the primary tumor were most important in predicting outcome, although statistical significance was not achieved. The 5-year distant metastases-free survival (DMFS) was 100% for central and inner quadrant tumors, compared to 97% in those with outer quadrant tumors, p = 0.18. The 5-year DMFS was 100%, 95%, and 98% for patients with cancers 2-5 mm, 6-9 mm, and 10 mm, respectively, p = 0.15. Status of the axillary lymph nodes, type of breast surgery, clinical tumor status (palpable vs. nonpalpable), age, menopausal status, histologic grade, systemic therapy, or histologic type were not found to have a significant impact on prognosis.

Age as a prognostic factor for breast and regional nodal recurrence following breast conserving surgery and irradiation in stage I and II breast cancer.

PURPOSE: To evaluate the association between age and breast/regional nodal relapse following breast conserving surgery and irradiation. METHODS AND MATERIALS: The results of treatment in 511 patients with 519 Stage I and II breast cancers treated at Mallinkrodt Institute of Radiology and affiliated hospitals between 1958 and 1988 were reviewed. RESULTS: Seventy women, of whom 96% had axillary dissections, were 39 years of age or younger. These young patients were more likely to have chemotherapy (p < 0.0001), and tumor bed reexcision (p < 0.01), and less likely to have an undissected axilla (p < 0.01), or estrogen receptor positive tumor (p = 0.02) than the older women (> 40 years). Although breast recurrence tended to appear earlier in the younger patients (12% at 5 years for those < 40 years vs. 6% at 5 years for those older), by 7 years the breast failure rate for the two groups was the same (12%), p = 0.13. In the 37 women 35 years of age or younger, the actuarial rate of breast recurrence was 9% at 7 years. Compared to other series in the literature, in which cancers were grossly excised without regard to the microscopic margins of resection, and reexcision was not routinely performed, young women treated with breast conserving surgery and irradiation at our institution frequently underwent reexcision of the tumor bed (57%), and had negative pathologic margins of resection (75%). Regional nodal relapse was in general uncommon, and not seen with increased frequency in the youngest cohort. CONCLUSION: Our experience suggests that young age is not a contraindication to breast conserving surgery and irradiation. Although breast cancers in this cohort may have certain features rendering them prone to local failure, we believe this risk can be mitigated by appropriate patient selection and optimal surgical resection.

Radiation therapy alone for stage I non-small cell lung cancer.

PURPOSE: This paper is a retrospective analysis of patients with clinical Stage I non-small cell carcinoma of the lung treated with definitive radiation therapy alone. The results of therapy, patterns of failure and the relationship of technical aspects of the delivery of radiotherapy to outcome are presented. MATERIALS AND METHODS: From 1980 through 1990, 53 patients with Stage I non-small cell lung cancer were treated with definitive radiation therapy alone at the Radiation Oncology Center of the Mallinckrodt Institute of Radiology and its affiliated hospitals. All patients had a pathologic diagnosis of non-small cell lung cancer and were not candidates for surgical resection because of either patient refusal (10 patients), poor performance status (5 patients), or premorbid medical problems (38 patients). The median age was 73 years. Histologic cell type included squamous (32), adenocarcinoma (11), large cell (4), and unclassified non-small cell (6). Initial tumor size was < or = 3 cm in 23 patients, between 3 and 5 cm in 13 patients and > or = 5 cm in 17 patients. Diagnostic staging varied during the study period. All patients had chest X-rays and computed tomography scans of the chest. A majority had liver and bone scans, but only four underwent mediastinoscopy. The radiation therapy was of megavoltage energy in all patients, with a median primary prescription tumor dose of 63.2 Gy. Survival was measured from the date radiation therapy was initiated. RESULTS: The actuarial overall survival rate for the entire group was 19% at 3 years and 6% at 5 years, with a median survival time of 20.9 months. Of the 49 deaths, 35 died of lung cancer; 13 died of intercurrent illness, and one died of pancreatic cancer, which made the actuarial cause-specific survival 33% at 3 years and 13% at 5 years. The actuarial 3-year disease-free survival was 33%. Local primary tumor progression occurred in 22 patients, resulting in a 51% 3-year actuarial freedom from local progression. An additional four patients failed in regional lymph nodes that were included in the original treatment portals. Multivariate analysis found only T stage to be associated with overall survival (p = .02). However multivariate analysis showed age as a prognostic factor to be approaching statistical significance (p = .07). Patients under 70 years of age showed an increased survival rate compared to patients over 70 years. Radiation therapy doses > or = 65 Gy appeared to result in a decreased proportion of patients dying of lung cancer with no apparent increase in either acute or long-term complication rates. CONCLUSION: Results of definitive radiation therapy for inoperable Stage I non-small cell lung remain inferior to surgical therapy. Potential methods to improve local control with radiotherapy are discussed.

Regional nodal management and patterns of failure following conservative surgery and radiation therapy for stage I and II breast cancer.

PURPOSE: To determine the incidence, pattern of regional nodal failure, and treatment sequelae as determined by the extent of lymphatic irradiation. METHODS AND MATERIALS: The records of 511 patients with 519 Stage I and II breast cancers treated with breast conserving surgery with or without axillary dissection and irradiation were reviewed. The extent of nodal irradiation was at the discretion of the attending radiation oncologist and varied considerably over the years. Management of the axilla consisted of axillary dissection alone in 351, axillary dissection and supplemental irradiation in 74, irradiation alone in 75, and simply observation in 21 patients. RESULTS: Overall, axillary recurrence was uncommon (1.2%), but was slightly more frequent after irradiation alone (2.7%) than after surgery alone (0.3%), p = 0.14. There was no benefit for supplemental axillary irradiation after an axillary dissection yielding negative or 1 to 3 positive nodes. In the 21 patients in whom the axilla was observed, axillary recurrence was not observed. Supraclavicular failures were rare in women with negative or 1 to 3 positive axillary lymph nodes (0.5%), and not significantly affected by elective irradiation. Internal mammary node recurrence was seen in only one patient, and was not significantly influenced by elective internal mammary irradiation. Both arm and breast edema were significantly more common in women having breast and nodal irradiation than after breast irradiation alone. These sequelae were not influenced significantly by the number of lymph nodes obtained in the axillary dissection specimen. Radiation pneumonitis was seen with increased frequency with more extensive nodal radiotherapy. Pneumonitis was not found to be affected by the administration or sequencing of chemotherapy. CONCLUSION: There is little justification for axillary or supraclavicular irradiation following an axillary dissection which yields negative or minimally involved (1 to 3 positive) lymph nodes. There were too few patients with extensive axillary node metastases (> or = 4 positive) in our series to draw conclusions about the optimal extent of nodal irradiation in this subset. Elective internal mammary lymph node irradiation increases technical complexity, does not appear to be advantageous, and when combined with supraclavicular irradiation places the patient at highest risk for pneumonitis.

On-line image verification in radiation therapy: an early USA experience.

The intense effort in the past 5 to 10 years to develop on-line image verification (OLIV) systems is made partly in anticipation of the increased verification demands of complex 3-dimensional (3D) conformal radiation therapy, and partly to improve on the current practice of weekly treatment verification. These systems allow convenient acquisition of daily portal images or many images during one treatment session. Systems based on fluoroscopic and scanning approaches can now be purchased from various vendors and are being evaluated at several radiation therapy centers. The performances of these systems vary, but all appear to be adequate for clinical use. At the Mallinckrodt Institute of Radiology, we have been conducting clinical on-line imaging for the past 3 years using a fiber-optic fluoroscopic system. Daily operation of the system requires coordinated participation of the physics and radiation therapy technology staff. The major consideration is in the management and evaluation of the large amount of verification images about each individual patient. At present, it is not clear whether the technology would be cost-effective in the clinical setting. However, it is clear that OLIV provides a powerful tool in enhancing our knowledge of treatment variation. The information will be invaluable in the development of improved treatment techniques. It is also likely that these systems will play a important part in the verification of 3D conformal radiation therapy.

Locoregional recurrence of breast cancer: a retrospective comparison of irradiation alone versus irradiation and systemic therapy.

The role of systemic therapy in addition to irradiation for locoregional recurrence of breast cancer is controversial. In the absence of prospective randomized trials, treatment decisions must be based on retrospective studies. We retrospectively analyzed 230 patients treated for locoregionally recurrent breast cancer between 1964 and 1986. Forty-seven were premenopausal, 173 were postmenopausal, and the menopausal status was unknown in 10 patients. Each patient treated with radiotherapy (RT) and chemotherapy or with RT and hormonal therapy was matched with a control patient treated with RT alone. The addition of hormonal therapy to radiation therapy significantly improved the 5-year overall survival (50 versus 28%), disease-free survival (37 versus 26%), and distant metastases-free survival (45 versus 29%). No improvement in locoregional control was observed. In contrast, chemotherapy did not confer such survival benefits, but there was a trend towards improvement in 5-year locoregional control (68 versus 50%), p = 0.08. Our data support the use of hormonal therapy along with RT at the time of locoregional recurrence of breast cancer. Although our data suggest that chemotherapy is not routinely indicated, controlled clinical trials are needed to define which subsets of patients, if any, benefit from systemic therapy.

Breast conservation therapy. The St. Luke's Hospital experience.

Between 1979 and 1987, 170 patient with stages 0, I and II breast cancer were treated with breast conservation therapy. Twenty-eight women (16%) had intraductal carcinomas, 110 (65%) stage I disease and 32 (19%) had stage II breast cancers. Seventy-five percent of the patients received no adjuvant systemic treatment, whereas 20% received adjuvant chemotherapy and 5% were given Tamoxifen. All patients received radiation therapy to the breast after lumpectomy and, when appropriate, axillary dissection. Twelve patients (7%) recurred within the treated breast, whereas two patients (1%) recurred in regional lymph nodes. Fourteen women (8%) developed distant metastases and seven women (4%) developed contralateral breast cancer. The actuarial 5 year disease-free survival was 92% for the patients with intraductal carcinoma, 90% for T1 and 65% for T2 patients. Overall actuarial survival was 100%, 96% and 87%, respectively. The St. Luke's Hospital results are comparable to those reported in the literature. We conclude that breast conservation therapy, including irradiation, is an alternative to modified radical mastectomy and that this option should be thoroughly discussed with the patient.

Survival following locoregional recurrence of breast cancer: univariate and multivariate analysis.

Although prognostic variables for locoregional recurrence of breast cancer have been evaluated by univariate analysis, multifactorial analysis has not been previously performed. In the present study, survival following chest wall and/or regional lymphatic recurrence was determined in 230 patients with locoregionally recurrent breast cancer without evidence of distant metastases treated at the Radiation Oncology Center, Mallinckrodt Institute of Radiology and affiliated hospitals. Multifactorial analysis demonstrated that the site of recurrences correlated most strongly with overall survival (p = 0.001). The 5-year actuarial overall survival was 44-49% for patients with isolated chest wall, axillary, and internal mammary lymph node recurrence. Patients with either supraclavicular, multiple lymphatic, or concomitant chest wall and lymphatic recurrence had an 21-24% 5-year overall survival. The 5-year disease-free survival was 28-37% for patients with chest wall, axillary, or internal mammary recurrences compared to 4-13% for those with supraclavicular, chest wall and lymphatic, or those with multiple sites of lymphatic recurrence. Disease-free interval from mastectomy to recurrence was also found to be a significant prognostic factor for overall survival (p = 0.005). Fifty percent of patients with a disease-free interval of at least 2 years survived 5 years following locoregional relapse, compared to 35% for those with disease-free interval of less than 2 years. In the subset of patients with small chest wall recurrences (excised or less than 3 cm) and a disease-free interval of at least 2 years, the 5-year overall and disease-free survivals were 67% and 54%, respectively. These results suggest that subsets of patients with locoregional recurrence of breast cancer can survive for long periods of time. The conventional wisdom that chest wall and/or regional nodal recurrence following mastectomy uniformly confers a dismal prognosis is not necessarily true.

An unusual peptide conformation may precipitate amyloid formation in Alzheimer's disease: application of solid-state NMR to the determination of protein secondary structure.

The formation of insoluble proteinaceous deposits is characteristic of many diseases which are collectively known as amyloidosis. There is very little molecular-level structural information available regarding the amyloid deposits due to the fact that the constituent proteins are insoluble and noncrystalline. Therefore, traditional protein structure determination methods such as solution NMR and X-ray crystallography are not applicable. We report herein the application of the solid-state NMR technique rotational resonance (R2) to the accurate measurement of carbon-to-carbon distances in the amyloid formed from a synthetic fragment (H2N-LeuMetValGlyGlyValValIleAla-CO2H) of the amyloid-forming protein of Alzheimer's disease (AD). This sequence has been implicated in the initiation of amyloid formation. Two distances measured by R2 indicate that an unusual structure, probably involving a cis amide bond, is present in the aggregated peptide amyloid. This structure is incompatible with the accepted models of fibril structure. A relationship between this structure and the stability of the amyloid is proposed.

Study of treatment variation in the radiotherapy of head and neck tumors using a fiber-optic on-line radiotherapy imaging system.

On-line radiotherapy imaging systems allow convenient daily acquisition of portal images for treatment verification. The information can also be used to study treatment variability. Using a prototype fiber-optic imaging system, we have measured the treatment variation of 17 head and neck patients. Daily digital portal images were acquired for the on-cord left and right lateral fields. Treatment variations were quantified using the Cumulative Verification Image Analysis (CVIA) method developed at our institute. In the CVIA method, daily portal images were aligned according to three anatomical points predefined on a digitized simulation, or prescription, image. After each image alignment, the block position was cumulated in a bit-map and superimposed on the prescription image to give a cumulative verification summary image. Iso-frequency distributions, or contours, of the block overlap were calculated and examined with respect to the prescription treatment area. The range of the treatment variation was large for the 17 patients. On average, separation of the 0% to 100% block overlap contours was about 10 mm, and the 20% to 80%, 5 mm. The block overlap contours were also used to calculate the frequency with which the prescription area as defined on the simulation film had been treated. The fraction of the prescription area treated depended on the accuracy of the treatment setup and patient repositioning, as expected. At best, approximately 95% of the prescribed area was irradiated 100% of the time during the entire course of radiotherapy. At worst, approximately 70% of the prescribed area was irradiated 100% of the time. These results demonstrate that despite immobilization, large setup variation can still occur. Presenting treatment variation data as population averages does not reflect on the large variation that may be observed in the individual patient.

Isolated local-regional recurrence of breast cancer following mastectomy: radiotherapeutic management.

Two hundred twenty-four patients with their first, isolated local-regional recurrence of breast cancer were irradiated with curative intent. Patients who had previous chest wall or regional lymphatic irradiation were not included in the study. With a median follow-up of 46 months (range 24 to 241 months), the 5- and 10-year survival for the entire group were 43% and 26%, respectively. Overall, 57% of the patients were projected to be loco-regionally controlled at 5 years. The 5-year local-regional tumor control was best for patients with isolated chest wall recurrences (63%), intermediate for nodal recurrences (45%), and poor for concomitant chest wall and nodal recurrences (27%). In patients with solitary chest wall recurrences, large field radiotherapy encompassing the entire chest wall resulted in a 5- and 10-year freedom from chest wall re-recurrence of 75% and 63% in contrast to 36% and 18% with small field irradiation (p = 0.0001). For the group with recurrences completely excised, tumor control was adequate at all doses ranging from 4500 to 7000 cGy. For the recurrences less than 3 cm, 100% were controlled at doses greater than or equal to 6000 cGy versus 76% at lower doses. No dose response could be demonstrated for the larger lesions. The supraclavicular failure rate was 16% without elective radiotherapy versus 6% with elective radiotherapy (p = 0.0489). Prophylactic irradiation of the uninvolved chest wall decreased the subsequent re-recurrence rate (17% versus 27%), but the difference is not statistically significant (p = .32). The incidence of chest wall re-recurrence was 12% with doses greater than or equal to 5000 cGy compared to 27% with no elective radiotherapy, but again was not statistically significant (p = .20). Axillary and internal mammary failures were infrequent, regardless of prophylactic treatment. Although the majority of patients with local and/or regional recurrence of breast cancer will eventually develop distant metastases and succumb to their disease, a significant percentage will live 5 years. Therefore, aggressive radiotherapy should be used to provide optimal local-regional control.(ABSTRACT TRUNCATED AT 400 WORDS)

Juvenile nasopharyngeal angiofibroma: efficacy of radiation therapy.

From 1962 to 1984, 13 patients with juvenile nasopharyngeal angiofibroma (JNA) were treated with megavoltage radiation therapy. Follow-up ranged from 40 to 255 months (median, 136 months). Two patients received radiation therapy as the initial treatment; the other 11 patients had undergone unsuccessful previous surgical treatment (median, three resections). Gross tumor was evident at the start of radiation therapy in seven patients, and orbital, sphenoid sinus, or intracranial extension was noted in eight of 13 (62%). Doses ranged from 3,600 to 5,200 cGy (median, 4,800 cGy in daily fractions of 180-200 cGy). Tumor was controlled in 11 patients (85%) after irradiation. Two patients were treated with embolization for residual mass; both remained asymptomatic and without evidence of tumor 134 and 83 months after embolization, respectively. With the exception of xerostomia and caries, no significant chronic morbidity was seen. This review and other studies demonstrate that megavoltage radiation therapy is an effective and appropriate treatment for advanced and recurrent JNA; its routine use for early tumors remains controversial.