Changes in local pulmonary injury up to 48 months after irradiation for lymphoma and breast cancer.

PURPOSE: To assess the recovery from early local pulmonary injury after irradiation and to determine whether regional differences exist. METHODS: For 110 patients treated for breast cancer or malignant lymphoma, single photon emission computed tomography (SPECT) perfusion and ventilation scans and CT scans were made before, 3, 18, and 48 months after radiotherapy. Dose-effect relations for changes in local perfusion, ventilation, and density were determined for each individual patient using spatially correlated SPECT and CT data sets, for each follow-up period. Average dose-effect relations for both subgroups were determined, as well as dose-effect relations for different regions. RESULTS: In general, partial improvement of local pulmonary injury was observed between 3 and 18 months for each of the three endpoints. After 18 months, no further improvement was seen. Patients with breast cancer and malignant lymphoma showed a similar improvement (except for the perfusion parameter), which was attributed to a recovery from the early radiation response and could not be explained by contraction effects of fibrosis of lung parenchyma. No regional differences in radiosensitivity 18 months after treatment were observed, except for the dorsal versus ventral region. This difference was attributed to a gravity-related effect in the measuring procedure. CONCLUSION: For all patients, a partial recovery from early local perfusion, ventilation, and density changes, was seen between 3 and 18 months after radiotherapy. After 18 months, local lung function did not further improve (lymphoma patients).

Effect of radiotherapy and chemotherapy on pulmonary function after treatment for breast cancer and lymphoma: A follow-up study.

PURPOSE: To determine the changes in pulmonary function tests (PFTs) 0 to 48 months after treatment for breast cancer and lymphoma. PATIENTS AND METHODS: The alveolar volume (V(A)), vital capacity, forced expiratory volume in 1 second, and corrected transfer factor of carbon monoxide (T(L,COc)) were measured in 69 breast cancer and 41 lymphoma patients before treatment and 3, 18, and 48 months after treatment with radiotherapy alone or radiotherapy in combination with chemotherapy (mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine; cyclophosphamide, epidoxorubicin, fluorouracil; cyclophosphamide, thiotepa, carboplatin; cyclophosphamide, methotrexate, fluorouracil). The three-dimensional dose distribution in the lung of each patient was converted to the mean lung dose. Statistical analysis was used to evaluate the changes in PFT values over time in relation to age, sex, smoking, chemotherapy, and the mean lung dose. RESULTS: After an initial reduction in PFT values at 3 months, significant recovery was seen at 18 months for all patients. Thereafter, no further improvement could be demonstrated. Reductions in spirometry values and V(A) were related to the mean lung dose only (0.9% per Gy at 3 months and 0.4% per Gy mean dose at 18 months). T(L,COc) decreased 1. 1% per Gy mean dose and additionally decreased 6% when chemotherapy was given after radiotherapy. Chemotherapy administered before radiotherapy reduced baseline T(L,COc) values by 8% to 21%. All patients showed an improvement of 5% at 18 months. CONCLUSION: On the basis of the mean lung dose and the chemotherapy regimen, the changes in PFT values can be estimated before treatment within 10% of the values actually observed in 72% to 85% of our patients with healthy lungs.

Dose-effect relations for early local pulmonary injury after irradiation for malignant lymphoma and breast cancer.

PURPOSE: To quantify the influence of treatment- and patient-related factors on the severity of early local pulmonary injury and to establish whether regional differences are present for local dose-effect relations for early radiation-induced pulmonary injury. METHODS: Forty-two patients with malignant lymphoma and 40 breast cancer patients were examined prior to and 3 months after radiotherapy. The lymphoma patients were irradiated with mantle fields to an average dose of 38 Gy and the breast cancer patients were irradiated with internal mammary node fields with or without tangential breast fields to an average dose of 50 Gy. Dose-effect relations for local perfusion, ventilation and density changes were determined using correlated single photon emission computed tomography (SPECT) and CT data. A multivariate analysis was performed to study the influence of irradiated volume, chemotherapy (CMF and MOPP/ABV), smoking, age and gender. In addition, dose-effect relations for different regions in the lung were determined. RESULTS: A similar and almost linear increase of early functional changes as a function of radiation dose was observed for perfusion and ventilation, whereas the shape of the dose-effect relation and the magnitude of early structural changes were different for density. For the three end-points studied, regional differences in radiosensitivity could not be demonstrated. For the posterior lung region compared to the anterior lung region, however, a difference was observed, which could be attributed to a gravity-related effect in the measuring procedure. Local structural changes (density) were significantly smaller for smokers (P = 0.002) and young patients (P = 0.007), whereas the CMF chemotherapy regimen given after radiotherapy (P = 0.017) significantly increased the amount of functional changes (perfusion). The magnitude of local pulmonary changes was independent of the irradiated volume, the MOPP/ABV chemotherapy regimen and gender. CONCLUSION: The dose-effect relations for early radiation-induced local pulmonary changes were independent of the irradiated volume, MOPP/ABV, gender and lung region. CMF, smoking and age influenced the magnitude of early pulmonary changes and should be taken into account in dose-escalation protocols.

Evaluation of two dose-volume histogram reduction models for the prediction of radiation pneumonitis.

PURPOSE: To evaluate the similarities between the mean lung dose and two dose-volume histogram (DVH) reduction techniques of 3D dose distributions of the lung. PATIENTS AND METHODS: DVHs of the lungs were calculated from 3D dose distributions of patients treated for malignant lymphoma (44), breast cancer (42) and lung cancer (20). With a DVH reduction technique, a DVH is summarized by the equivalent uniform dose (EUD), a quantity which is directly related to the normal tissue complication probability (NTCP). Two DVH reduction techniques were used. The first was based on an empirical model proposed by Kutcher et al. (Kutcher, G.J., Burman, C., Brewster, M.S., Goitein, M. and Mohan, R. Histogram reduction method for calculating complication probabilities for three-dimensional treatment planning evaluations. Int. J. Radiat. Oncol. Biol. Phys. 21: 137-146, 1991), which needs a volume exponent n. Several values for n were tested. The second technique was based on a radiobiological model, the parallel functional subunit model developed by Niemierko et al. (Niemierko, A. and Goitein, M. Modeling of normal tissue response to radiation: the critical volume model. Int. J. Radiat. Oncol. Biol. Phys. 25: 135-145, 1993) and Jackson et al. (Jackson, A., Kutcher, G.J. and Yorke, E.D. Probability of radiation-induced complications for normal tissues with parallel architecture subject to non-uniform irradiation. Med. Phys. 20: 613-625, 1993), for which a local dose-effect relation needed to be specified. This relation was obtained from an analysis of perfusion and ventilation SPECT data. RESULTS: It can be shown analytically that the two DVH reduction techniques are identical, if the local dose-effect relation obeys a power-law relationship in the clinical dose range. Local dose-effect relations based on perfusion and ventilation SPECT data can indeed be fitted with a power-law relationship in the range 0-80 Gy, from which values of n = 0.8-0.9 were deduced. These correspond to the commonly used value of n = 0.87 for lung tissue and yielded EUDn=0.87 values which were almost identical to the mean lung doses. For other n values, for which no experimental data are present, differences exist between EUD and mean dose values. Six patients with malignant lymphoma (6/44) and none of the breast cancer patients (0/42) developed radiation pneumonitis. These cases occurred only at high values for the mean lung dose. CONCLUSION: The two DVH reduction techniques are identical for lung and are very similar to mean dose calculations. The two techniques are also relatively similar for other model parameter values.

Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients.

PURPOSE: To determine the relation between the incidence of radiation pneumonitis and the three-dimensional dose distribution in the lung. METHODS AND MATERIALS: In five institutions, the incidence of radiation pneumonitis was evaluated in 540 patients. The patients were divided into two groups: a Lung group, consisting of 399 patients with lung cancer and 1 esophagus cancer patient and a Lymph./Breast group with 78 patients treated for malignant lymphoma, 59 for breast cancer, and 3 for other tumor types. The dose per fraction varied between 1.0 and 2.7 Gy and the prescribed total dose between 20 and 92 Gy. Three-dimensional dose calculations were performed with tissue density inhomogeneity correction. The physical dose distribution was converted into the biologically equivalent dose distribution given in fractions of 2 Gy, the normalized total dose (NTD) distribution, by using the linear quadratic model with an alpha/beta ratio of 2.5 and 3.0 Gy. Dose-volume histograms (DVHs) were calculated considering both lungs as one organ and from these DVHs the mean (biological) lung dose, NTDmean, was obtained. Radiation pneumonitis was scored as a complication when the pneumonitis grade was grade 2 (steroids needed for medical treatment) or higher. For statistical analysis the conventional normal tissue complication probability (NTCP) model of Lyman (with n=1) was applied along with an institutional-dependent offset parameter to account for systematic differences in scoring patients at different institutions. RESULTS: The mean lung dose, NTDmean, ranged from 0 to 34 Gy and 73 of the 540 patients experienced pneumonitis, grade 2 or higher. In all centers, an increasing pneumonitis rate was observed with increasing NTDmean. The data were fitted to the Lyman model with NTD50=31.8 Gy and m=0.43, assuming that for all patients the same parameter values could be used. However, in the low dose range at an NTDmean between 4 and 16 Gy, the observed pneumonitis incidence in the Lung group (10%) was significantly (p=0.02) higher than in the Lymph./Breast group (1.4%). Moreover, between the Lung groups of different institutions, also significant (p=0.04) differences were present: for centers 2, 3, and 4, the pneumonitis incidence was about 13%, whereas for center 5 only 3%. Explicitly accounting for these differences by adding center-dependent offset values for the Lung group, improved the data fit significantly (p < 10(-5)) with NTD50=30.5+/-1.4 Gy and m=0.30+/-0.02 (+/-1 SE) for all patients, and an offset of 0-11% for the Lung group, depending on the center. CONCLUSIONS: The mean lung dose, NTDmean, is relatively easy to calculate, and is a useful predictor of the risk of radiation pneumonitis. The observed dose-effect relation between the NTDmean and the incidence of radiation pneumonitis, based on a large clinical data set, might be of value in dose-escalating studies for lung cancer. The validity of the obtained dose-effect relation will have to be tested in future studies, regarding the influence of confounding factors and dose distributions different from the ones in this study.

Automatic three-dimensional matching of CT-SPECT and CT-CT to localize lung damage after radiotherapy.

UNLABELLED: The aim of this study was to develop a fast and clinically robust automatic method to register SPECT and CT scans of the lungs. METHODS: CT and SPECT scans were acquired in the supine position from 20 patients with healthy lungs. After partial irradiation of the lungs by radiotherapy, the scans were repeated. Two matching methods were compared: a conventional method with external skin markers and a new method using chamfer matching of the lung contours. In the latter method, a unique value for the SPECT threshold, needed for segmentation of the SPECT lungs, was determined by iteratively applying the chamfer matching algorithm. RESULTS: The new technique for CT-SPECT matching could be implemented in a fully automatic manner and required less than 2 min. No large systematic shifts or rotations were present between the matches obtained with the marker method and the lung contour method for healthy or partially irradiated lungs. For healthy lungs, the number of ventilation SPECT counts outside the CT-defined lung was taken as a measure for a good match. This number of outside counts was slightly lower for the new method than for the conventional method, which indicates that the accuracy of the new method is at least comparable to the conventional method. For ventilation, a systematic difference between the results of the matching methods, a small translation in the anterior --> posterior direction, could be attributed to an inconsistency of the marker positions (2 mm). For perfusion, a somewhat larger anterior --> posterior shift was found, which was attributed to the gravity force. CT-CT correlation on the lung contours using chamfer matching was tested with the same dataset. For accurate matching, the CT slices encompassing the diaphragm had to be deleted. CONCLUSION: The new method based on lung contour matching is a fast, automatic procedure and allows accurate clinical follow-up.

Prediction of overall pulmonary function loss in relation to the 3-D dose distribution for patients with breast cancer and malignant lymphoma.

PURPOSE: To predict the changes in pulmonary function tests (PFTs) 3-4 months after radiotherapy based on the three-dimensional (3-D) dose distribution and taking into account patient- and treatment-related factors. METHODS: For 81 patients with malignant lymphoma and breast cancer, PFTs (VA, VC, FEV1 and TL,COc) were performed prior to and 3-4 months after irradiation and dose-effect relations for early changes in local perfusion, ventilation and air-filled fraction were determined using correlated CT and SPECT data. The 3-D dose distribution of each patient was converted into four different dose-volume parameters, i.e. the mean dose in the lung and three overall response parameters (ORPs, which represent the average local injury over the complete lung). ORPs were determined using the dose-effect relations for early changes in local perfusion, ventilation and air-filled fraction. Correlation coefficients were calculated between these dose-volume parameters and the changes in PFTs. In addition, the impact of the variables chemotherapy (MOPP/ABV and CMF), tamoxifen, smoking, age and gender on the relation between the mean lung dose and the relative changes in PFTs following radiotherapy was studied using multiple regression analysis. RESULTS: The mean lung dose proved to be the easiest parameter to predict the reduction in PFTs 3-4 months following radiotherapy. For all patients the relation between the mean lung dose and the changes in PFTs could be described with one regression line through the origin and a slope of 1% reduction in PFT for each increase of 1 Gy in mean lung dose. Smoking and CMF chemotherapy influenced the reduction in PFTs significantly for VA and TL,COc, respectively. Patients treated with MOPP/ABV prior to radiotherapy had lower pre-radiotherapy PFTs than other patient groups, but did not show further deterioration after radiotherapy (at 3-4 months). CONCLUSIONS: The relative reduction in VA, VC, FEV1 and TL,COc 3-4 months after radiotherapy for breast cancer and malignant lymphoma can be estimated before radiotherapy based on the mean lung dose of each individual patient and taking into account the use of chemotherapy and smoking habits of the patient.

A multimer model for P680, the primary electron donor of photosystem II.

We consider a model of the photosystem II (PS II) reaction center in which its spectral properties result from weak (approximately 100 cm-1) excitonic interactions between the majority of reaction center chlorins. Such a model is consistent with a structure similar to that of the reaction center of purple bacteria but with a reduced coupling of the chlorophyll special pair. We find that this model is consistent with many experimental studies of PS II. The similarity in magnitude of the exciton coupling and energetic disorder in PS II results in the exciton states being structurally highly heterogeneous. This model suggests that P680, the primary electron donor of PS II, should not be considered a dimer but a multimer of several weakly coupled pigments, including the pheophytin electron acceptor. We thus conclude that even if the reaction center of PS II is structurally similar to that of purple bacteria, its spectroscopy and primary photochemistry may be very different.

Polarized fluorescence and absorption of macroscopically aligned Light Harvesting Complex II.

Polarized absorption and fluorescence measurements have been performed at 77 K on isotropic and anisotropic preparations of trimeric Light Harvesting Complex II (LHC-II) from spinach. The results enable a decomposition of the absorption spectrum into components parallel and perpendicular to the trimeric plane. For the first time, it is shown quantitatively that the strong absorption band around 676 nm is polarized essentially parallel to the plane of the trimer, i.e., the average angle between the corresponding transition dipole moments and this plane is at most 12 degrees. The different absorption bands for LHC-II should not be considered as corresponding to individual pigments but to collective excitations of different pigments. Nevertheless, the average angle between the Qy transition dipole moments of all chlorophyll a pigments in LHC-II and the trimeric plane could be determined and was found to be 17.5 degrees +/- 2.5 degrees. For the chlorophyll b pigments, this angle is significantly larger (close to 35 degrees). At 77 K, most of the fluorescence stems from a weak band above 676 nm and the corresponding transition dipole moments are oriented further out of plane than the dipole moments corresponding to the 676-nm band. The results are shown to be of crucial significance for understanding the relation between the LHC-II structure and its spectroscopy.

Low-temperature energy transfer in LHC-II trimers from the Chl a/b light-harvesting antenna of photosystem II.

Temperature dependence in electronic energy transfer steps within light-harvesting antenna trimers from photosystem II was investigated by studying Chl a pump-probe anisotropy decays at several wavelengths from 675 to 682 nm. The anisotropy lifetime is markedly sensitive to temperature at the longest wavelengths (680-682 nm), increasing by factors of 5 to 6 as the trimers are cooled from room temperature to 13 K. The temperature dependence is muted at 677 and 675 nm. This behavior is modeled using simulations of temperature-broadened Chl a absorption and fluorescence spectra in spectral overlap calculations of Förster energy transfer rates. In this model, the 680 nm anisotropy decays are dominated by uphill energy transfers from 680 nm Chl a pigments at the red edge of the LHC-II spectrum; the 675 nm anisotropy decays reflect a statistical average of uphill and downhill energy transfers from 676-nm pigments. The measured temperature dependence is consistent with essentially uncorrelated inhomogeneous broadening of donor and acceptor Chl a pigments.

Steady-state polarized light spectroscopy of isolated Photosystem I complexes.

Monomeric and trimeric Photosystem I core complexes from the cyanobacterium Synechocystis PCC 6803 and LHC-I containing Photosystem I (PS I-200) complexes from spinach have been characterized by steady-state, polarized light spectroscopy at 77 K. The absorption spectra of the monomeric and trimeric core complexes from Synechocystis were remarkably similar, except for the amplitude of a spectral component at long wavelength, which was about twice as large in the trimeric complexes. This spectral component did not contribute significantly to the CD-spectrum. The (77 K) steady-state emission spectra showed prominent peaks at 724 nm (for the Synechocystis core complexes) and at 735 nm (for PS I-200). A comparison of the excitation spectra of the main emission band and the absorption spectra suggested that a significant part of the excitations do not pass the red pigments before being trapped by P-700. Polarized fluorescence excitation spectra of the monomeric and trimeric core complexes revealed a remarkably high anisotropy (∼0.3) above 705 nm. This suggested one or more of the following possibilities: 1) there is one red-most pigment to which all excitations are directed, 2) there are more red-most pigments but with (almost) parallel orientations, 3) there are more red-most pigments, but they are not connected by energy transfer. The high anisotropy above 705 nm of the trimeric complexes indicated that the long-wavelength pigments on different monomers are not connected by energy transfer. In contrary to the Synechocystis core complexes, the anisotropy spectrum of the LHC I containing complexes from spinach was not constant in the region of the long-wavelength pigments, and decreased significantly below 720 nm, the wavelength where the long-wavelength pigments on the core complexes start to absorb. These results suggested that in spinach the long-wavelength pigments on core and LHC-I are connected by energy transfer and have a non-parallel average Qy(0-0) transitions.

Complex between single-stranded DNA and gene 5 protein of bacteriophage M13 studied with linear dichroism and ultraviolet absorption.

We have studied complexes between the gene 5 protein (gp5) of bacteriophage M13 and various polynucleotides, including single-stranded DNA, using ultraviolet absorption and linear dichroism. Upon complex formation the absorption spectra of both the protein and the polynucleotides change. The protein absorption changes indicate that for at least two of the five tyrosine residues per protein monomer the environment becomes less polar upon binding to the polynucleotides but also to the oligonucleotide p(dT)8. All gp5-polynucleotide complexes give rise to intense linear dichroism spectra. These spectra are dominated by negative contributions from the bases, but also a small positive dichroism of the protein can be discerned. The spectra can be explained by polynucleotide structures, which are the same in all complexes. The base orientations are characterized by a substantial inclination and propellor twist. The number of possible combinations of inclination and propeller twist values, which are in agreement with the linear dichroism results, is rather limited. The base orientations with respect to the complex axis are essentially different from those in the complex with the single-stranded DNA-binding protein gp32 of bacteriophage T4.

Evaluation of intermittent long-term negative-pressure ventilation in patients with severe chronic obstructive pulmonary disease.

We tested the hypothesis that intermittent ventilatory assistance in patients with severe chronic obstructive pulmonary disease (COPD) improves pulmonary function and exercise capacity. Twenty stable patients with severe COPD were recruited from outpatient pulmonary clinics and were randomized to use a poncho wrap, negative-pressure ventilator or to receive standard care. After 6 months, the patients receiving standard care were switched over to the ventilator and vice versa, and follow-up was continued for an additional 6 months. After 3 to 6 months of ventilator use, we observed no clinically significant improvements in FEV1, FVC, blood gas determinations, maximal inspiratory and expiratory pressures, and exercise duration. However, 11 of our patients dropped out of the study because of an inability to tolerate the ventilator, and all but one of the nine who completed the study expressed dissatisfaction with it, using it for less time (4.1 h/day) than we recommended. Musculoskeletal pain and inconvenience were the most frequently voiced complaints. Because we did not document that ventilator use actually rested the respiratory muscles in our patients and because duration of ventilator use may have been too brief, we cannot conclude that intermittent rest of respiratory muscles in patients with severe COPD fails to bring about improvement. On the other hand, our results demonstrate that the poncho wrap ventilator is poorly tolerated by patients with severe COPD in a typical outpatient setting. We suggest that future trials seek to utilize better tolerated ventilatory assist devices.

The association between parental occupation and childhood malignancy.

A case control study was conducted to test Fabia and Thuy's observation that there was an excess of fathers in hydrocarbon-related occupations among children who died of childhood cancer compared to their controls. The study comprised 692 children who were born and died in Massachusetts for the years 1947-1957, and 1963-1967 and a control group of 1,384. No significant association was found between the four major groups of childhood cancer and the three hydrocarbon-related occupations: (1) mechanics and gas station attendants; (2) machinists; and (3) painters, cleaners, and dyers. However, there were two significant associations: (a) paternal employment as a paper or pulp mill worker was associated with tumors of the brain and other parts of the nervous system (relative odds of 2.8); and (b) paternal employment as a mechanic or machinist was associated with tumors of the urinary tract (relative odds of 2.5). Without strong supporting evidence from other studies, the authors are reluctant to conclude that these associations are causal. A weak association between childhood leukemia-lymphoma are parents' ages was observed.