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Though bioaccumulation of pharmaceuticals by aquatic organisms continues to receive scientific attention, the internal disposition of these contaminants among different tissue compartments of fish species has been infrequently investigated, particularly among fish at different trophic positions. We tested a human to fish biological read-across hypothesis for contaminant disposition by examining tissue-specific accumulation in three understudied species, longnose gar (Lepisosteus osseus; piscivore), gizzard shad (Dorosoma cepedianum; planktivore/detritivore), and smallmouth buffalo (Ictiobus bubalus; benthivore), from a river influenced by municipal effluent discharge. In addition to surface water, fish plasma, and brain, gill, gonad, liver, and lateral muscle fillet tissues were analyzed via isotope dilution liquid chromatography tandem mass spectrometry. Caffeine and sucralose, two common effluent tracers, were quantitated at low micrograms per liter levels in surface water, while an anticonvulsant, carbamazepine, was observed at levels up to 37 ng/L. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline and primary metabolites were detected in at least one tissue of all three species at low micrograms per kilogram concentrations. Within each species, brain and liver of select fish contained the highest levels of SSRIs compared to plasma and other tissues, which is generally consistent with human tissue disposition patterns. However, we observed differential accumulation among specific tissue types and species. For example, mean levels of sertraline in brain and liver tissues were 13.4 µg/kg and 1.5 µg/kg in gizzard shad and 1.3 µg/kg and 7.3 µg/kg in longnose gar, respectively. In contrast, smallmouth buffalo did not consistently accumulate SSRIs to detectable levels. Tissue-specific eco-exposome efforts are necessary to understand mechanisms associated with such marked bioaccumulation and internal dispositional differences among freshwater fish species occupying different trophic positions. Environ Toxicol Chem 2024;43:1894-1902. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Nano-titanium dioxide (TiO 2 ) is the most widely used form of nanoparticles in commercial industry and comes in 2 main configurations: rutile and anatase. Rutile TiO 2 is used in ultraviolet (UV) screening applications, whereas anatase TiO 2 crystals have a surface defect that makes them photoreactive. There are numerous reports in the literature of photo-induced toxicity to aquatic organisms following coexposure to anatase nano-TiO 2 and UV. All natural freshwater contains varying amounts of natural organic matter (NOM), which can drive UV attenuation and quench reactive oxygen species (ROS) in aquatic ecosystems. The present research examined how NOM alters the photo-induced toxicity of anatase nano-TiO 2 . Daphnia magna neonates were coexposed to NOM and photoexcited anatase nano-TiO 2 for 48 h. Natural organic matter concentrations as low as 4 mg/L reduced anatase nano-TiO 2 toxicity by nearly 100%. These concentrations of NOM attenuated UV by <10% in the exposure system. However, ROS production measured using a fluorescence assay was significantly reduced in a NOM concentration--dependent manner. Taken together, these data suggest that NOM reduces anatase nano-TiO 2 toxicity via an ROS quenching mechanism and not by attenuation of UV. Environ Toxicol Chem 2017;36:1661-1666. © 2016 SETAC., (© 2016 SETAC.)

Titanium dioxide nanoparticles (TiO2 NP) are one of the most abundantly utilized nanoparticles in the world. Studies have demonstrated the ability of the anatase crystal of TiO2 NP to produce reactive oxygen species (ROS) in the presence of ultraviolet radiation (UVR), a co-exposure likely to occur in aquatic ecosystems. The goal of this study was to examine the photo-induced toxicity of anatase TiO2 NP under natural sunlight to Daphnia magna. D. magna were exposed to a range of UVR intensities and anatase TiO2 concentrations in an outdoor exposure system using the sun as the source of UVR. Different UVR intensities were achieved using UVR opaque and transparent plastics. AnataseTiO2-NP demonstrated the reciprocal relationship seen in other phototoxic compounds such as polycyclic aromatic hydrocarbons (PAHs) at higher UVR treatments. The calculated 8h LC50 of anatase TiO2 NP was 139 ppb under full intensity ambient natural sunlight, 778 ppb under 50% natural sunlight, and >500 ppm under 10% natural sunlight. Mortality was also compared between animals allowed to accumulate a body burden of anatase TiO2 for 1h and organisms whose first exposure to anatase TiO2 aqueous suspensions occurred under UVR. A significantly greater toxic effect was observed in aqueous, low body burden suspensions than that of TiO2 1h body burdens, which is dissimilar from the model presented in PAHs. Anatase TiO2 presents a unique photo-induced toxic model that is different than that of established phototoxic compounds., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Anesthetic preconditioning (APC) is a protective mechanism, whereby exposure to a volatile anesthetic renders a tissue resistant to a subsequent ischemic insult. We hypothesized that APC of the rat spinal cord with sevoflurane would reduce neurologic deficit after an ischemic-reperfusion injury. Rats were randomly assigned to 1 of 5 groups. The ischemic preconditioning (IPC) group (n = 14) had 3 min of IPC, 30 min of reperfusion, and 12 min of ischemia. The chronic APC (cSEVO) group (n = 14) had 1 h of APC with 3.5% sevoflurane on each of 2 days before ischemia. The acute APC (aSEVO) group (n = 14) had 1 h of APC with 3.5% sevoflurane followed by a 1-h washout period before the induction of ischemia. The controls (n = 14) underwent no preconditioning before ischemia. IPC attenuated the ischemia-reperfusion injury, whereas aSEVO and cSEVO groups were no better than control animals. Histologic evaluation of the spinal cord showed severe neurologic damage in all groups except for the IPC group and sham-operated rats. APC with sevoflurane did not reduce neurologic injury in a rat model of spinal cord ischemia. Traditional ischemic preconditioning had a strong protective benefit on neurologic outcome.

Recent evidence has identified the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) as a regulator of cardiac energy metabolism and mitochondrial biogenesis. We describe the development of a transgenic system that permits inducible, cardiac-specific overexpression of PGC-1alpha. Expression of the PGC-1alpha transgene in this system (tet-on PGC-1alpha) is cardiac-specific in the presence of doxycycline (dox) and is not leaky in the absence of dox. Overexpression of PGC-1alpha in tet-on PGC-1alpha mice during the neonatal stages leads to a dramatic increase in cardiac mitochondrial number and size coincident with upregulation of gene markers associated with mitochondrial biogenesis. In contrast, overexpression of PGC-1alpha in the hearts of adult mice leads to a modest increase in mitochondrial number, derangements of mitochondrial ultrastructure, and development of cardiomyopathy. The cardiomyopathy in adult tet-on PGC-1alpha mice is characterized by an increase in ventricular mass and chamber dilatation. Surprisingly, removal of dox and cessation of PGC-1alpha overexpression in adult mice results in complete reversal of cardiac dysfunction within 4 weeks. These results indicate that PGC-1alpha drives mitochondrial biogenesis in a developmental stage-dependent manner permissive during the neonatal period. This unique murine model should prove useful for the study of the molecular regulatory programs governing mitochondrial biogenesis and characterization of the relationship between mitochondrial dysfunction and cardiomyopathy and as a general model of inducible, reversible cardiomyopathy.

Purpose: Positive surgical margins adversely influence local tumor control in breast conservation therapy (BCT). However, reports have conflicted regarding whether an increased radiation dose can overcome this poor prognostic factor. In this study, we evaluated the influence of an increased radiation dose on tumor control in women with positive surgical margins undergoing BCT., Methods and Materials: Between 1978 and 1994, 733 women with pathologic Stage I-II breast cancer and known surgical margin status were treated at Thomas Jefferson University Hospital with BCT. Of these 733 patients, 641 women had a minimal tumor bed dose of 60 Gy and had documentation of their margin status; 509 had negative surgical margins, and 132 had positive surgical margins before definitive radiotherapy. Complete gross excision of the tumor and axillary lymph node sampling was obtained in all patients. The median radiation dose to the primary site was 65.0 Gy (range 60-76). Of the women with positive margins (n = 132), the influence of higher doses of radiotherapy was evaluated. The median follow-up time was 52 months., Results: The local tumor control rate for patients with negative margins at 5 and 10 years was 94% and 88%, respectively, compared with 85% and 67%, respectively, for those women with positive margins (p = 0.001). The disease-free survival rate for the negative margin group at 5 and 10 years was 91% and 82%, respectively, compared with 76% and 71%, respectively, for the positive margin group (p = 0.001). The overall survival rate of women with negative margins at 5 and 10 years was 95% and 90%, respectively. By comparison, for women with positive surgical margins, the overall survival rate at 5 and 10 years was 86% and 79%, respectively (p = 0.008). A comparison of the positive and negative margin groups revealed that an increased radiation dose (whether entered as a dichotomous or a continuous variable) >65.0 Gy did not improve local tumor control (p = 0.776). On Cox multivariate analysis, margin status and menopausal status had prognostic significance for local tumor control and DFS., Conclusion: Patients with positive surgical margins have a higher risk of local tumor recurrence and worse survival when undergoing BCT. Higher doses of radiation are unable to provide an adequate level of local control in patients with positive margins.

Purpose: Intensity-modulated arc therapy (IMAT) is a method for delivering intensity-modulated radiation therapy (IMRT) using rotational beams. During delivery, the field shape, formed by a multileaf collimator (MLC), changes constantly. The objectives of this study were to (1) clinically implement the IMAT technique, and (2) evaluate the dosimetry in comparison with conventional three-dimensional (3D) conformal techniques., Methods and Materials: Forward planning with a commercial system (RenderPlan 3D, Precision Therapy International, Inc., Norcross, GA) was used for IMAT planning. Arcs were approximated as multiple shaped fields spaced every 5-10 degrees around the patient. The number and ranges of the arcs were chosen manually. Multiple coplanar, superimposing arcs or noncoplanar arcs with or without a wedge were allowed. For comparison, conventional 3D conformal treatment plans were generated with the same commercial forward planning system as for IMAT. Intensity-modulated treatment plans were also created with a commercial inverse planning system (CORVUS, Nomos Corporation). A leaf-sequencing program was developed to generate the dynamic MLC prescriptions. IMAT treatment delivery was accomplished by programming the linear accelerator (linac) to deliver an arc and the MLC to step through a sequence of fields. Both gantry rotation and leaf motion were enslaved to the delivered MUs. Dosimetric accuracy of the entire process was verified with phantoms before IMAT was used clinically. For each IMAT treatment, a dry run was performed to assess the geometric and dosimetric accuracy. Both the central axis dose and dose distributions were measured and compared with predictions by the planning system., Results: By the end of May 2001, 50 patients had completed their treatments with the IMAT technique. Two to five arcs were needed to achieve highly conformal dose distributions. The IMAT plans provided better dose uniformity in the target and lower doses to normal structures than 3D conformal plans. The results varied when the comparison was made with fixed gantry IMRT. In general, IMAT plans provided more uniform dose distributions in the target, whereas the inverse-planned fixed gantry treatments had greater flexibility in controlling dose to the critical structures. Because the field sizes and shapes used in the IMAT were similar to those used in conventional treatments, the dosimetric uncertainty was very small. Of the first 32 patients treated, the average difference between the measured and predicted doses was -0.54 +/- 1.72% at isocenter. The 80%-95% isodose contours measured with film dosimetry matched those predicted by the planning system to within 2 mm. The planning time for IMAT was slightly longer than for generating conventional 3D conformal plans. However, because of the need to create phantom plans for the dry run, the overall planning time was doubled. The average time a patient spent on the table for IMAT treatment was similar to conventional treatments., Conclusion: Initial results demonstrated the feasibility and accuracy of IMAT for achieving highly conformal dose distributions for different sites. If treatment plans can be optimized for IMAT cone beam delivery, we expect IMAT to achieve dose distributions that rival both slice-based and fixed-field IMRT techniques. The efficient delivery with existing linac and MLC makes IMAT a practical choice.

Clonogenic survival and early cell death during treatment of human colon carcinoma cells were investigated following X-irradiation (IR) alone, IR followed by 5-FU for 24 h, and Taxol administered 24 h before IR and 5F-U. The investigated cell lines were: HCT116, 40-16 clonally derived from HCT116, and two HCT116 variants: N6CHR3 expressing hMLH1, and TP53 null cells denoted HCT116 p53-/-. The objective was to determine efficacy of the combined treatment and to correlate response with constitutive levels of TP53, WAF1, and hMLH1 proteins, as well as with mRNA levels of the apoptosis-related genes survivin, BNIP3, and MYC. At the end of treatment with 5-FU, the proportion of viable cells was between 0.65 and 0.70 for all cell lines. Additional cell loss occurred in 40-16 and HCT116 p53-/- cells following administration of Taxol before IR and 5-FU. Radiation sensitivity was unaffected by combined treatments, except for Taxol, irradiation, and 5-FU sequence in the HCT116 p53-/- and 40-16 cell lines, where radiation sensitivity determined by clonogenic survival curve slopes was doubled or quadrupled, respectively. Under our present experimental conditions, treatment response did not correlate with TP53 or hMLH1 status, but was associated with apoptosis-related genes, most notably BNIP3. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 175-185 (2000)., (Copyright 2000 Wiley-Liss, Inc.)

Background: The aim of this study was to compare the outcomes of bilateral breast carcinoma (BBC) patients with those of patients who had unilateral disease., Methods: From 1960 to 1995, 1465 Stage 0-III patients with primary breast carcinoma were treated with either mastectomy or breast conservation therapy at the Kimmel Cancer Center of Jefferson Medical College and Thomas Jefferson University Hospital. There were 1315 (89.9%) unilateral, 103 (7.1%) metachronous, and 47 (3.0%) synchronous breast carcinoma patients. Patients with synchronous breast carcinoma were defined as having a contralateral cancer diagnosed within 1 year of initial diagnosis. The percentage of patients with Stage 0-I disease at initial diagnosis was 49.4%, whereas 68% had Stage 0-I disease at subsequent diagnosis. For patients with metachronous breast carcinomas, the median interval between the first and second diagnosis was 44 months (range, 13-287 months). The median follow-up time was 58 months (range, 12-229 months) for patients with synchronous cancers and 87 months (range, 0.25-414 months) for those with metachronous cancers. Rates of overall survival and survival with no evidence of disease (NED survival), local control, and distant metastasis from the time of the second diagnosis were calculated for patients with synchronous and metachronous disease. These figures were then compared with each other and also with those for unilateral breast carcinoma patients., Results: Patients with synchronous and metachronous breast carcinoma had worse 5- and 8-year NED survival rates compared with unilateral breast carcinoma patients, as well as an increased risk of distant metastasis. In multivariate analysis, differences in local control and overall survival were not statistically significant for patients who had bilateral disease compared with those who had unilateral disease. There was no difference when patients with metachronous and unilateral breast carcinoma were compared with respect to local control and overall survival., Conclusions: Patients with bilateral breast carcinoma who present with synchronous disease are at greater risk for distant metastasis than women with unilateral or metachronous breast tumors. There was a trend toward decreased overall survival and local control for patients with synchronous bilateral breast carcinoma compared with patients who had either metachronous or unilateral disease., (Copyright 2000 American Cancer Society.)

Background: There are conflicting reports regarding whether focally positive surgical margins influence tumor control in breast-conservation therapy. The authors have evaluated the relation between positive surgical margins on tumor control and whether the number of positive margins affects tumor control in patients undergoing reexcision lumpectomy., Methods: From 1978 to 1994, 453 American Joint Committee on Cancer Stage I/II breast carcinoma patients were treated at Thomas Jefferson University Hospital with breast conservation therapy. Patients underwent excisional biopsy and margin sampling with shaved biopsies of the tumor cavity. The entire breast received 45 grays (Gy) with a 20-Gy iridium-192 implant or an electron boost. Eighty-six patients had microscopically positive margins (19%), and the remainder had confirmed negative margins. The median follow-up time was 45 months., Results: Local tumor control rates for patients with negative margins at 5 and 10 years were 94% and 87%, respectively, compared with 86% and 69%, respectively, for those patients with positive margins (P=0.005). The disease free survival rates for the negative margin group at 5 and 10 years were 91% and 82%, respectively, compared with 76% and 71%, respectively, for the positive margin group (P=0.001). Overall survival rates for patients with negative margins at 5 and 10 years were 95% and 84%, respectively, compared with 87% and 78%, respectively, for those with positive margins (P=0.047). When comparing the negative margin group with the one positive margin group, there was no significant difference in local tumor control (P=0.12). However, women with two or more positive margins had an inferior local tumor control compared with those women with negative margins (P=0.002)., Conclusions: Patients with positive margins have a higher risk for local failure and worse survival when undergoing breast conservation therapy. Inferior local tumor control was noted in those patients with two or more positive margins.

Purpose: 192Ir interstitial breast implants performed at the time of lumpectomy present a unique problem because they cannot be preplanned, and yet they are expected to produce a treatment dose rate (TDR) from 0.3 to 0.5 Gy/h using sources already procured. The purpose of this work is to describe a system of dosimetry that works within these constraints and has been used to perform more than 600 such implants., Methods and Materials: The underlying principle is to fix the ribbon spacing, the interplaner separation, and the linear activity (1 mCi/cm) so that the TDR will depend only on the area (L x W) implanted. The ribbons are spaced 1.5 cm and 2.0 cm apart in single plane and double implants, respectively. Idealized implants were used to study the TDR as a function of the implant dimensions, and to study the effects of varying the ribbon spacing and interplanar separation. Volume-dose histograms were generated to study the homogeneity of dose., Results: The TDRs of single plane implants range from 0.3 Gy/h for small 4 x 4 cm2 implants to 0.4 Gy/h for large 10 x 10 cm2 implants. The TDRs for double plane implants are similar for the same range of dimensions., Conclusions: Implants with a TDR between 0.3 and 0.5 Gy/h can be performed for a wide range of geometries without preplanning using fixed ribbons spacings of 1.5 and 2.0 cm for single and double plane implants, respectively, and a linear activity of 1 mCi/cm.

DNA index (ploidy) and S-phase fraction (SPF) were measured by flow cytometry in 131 invasive stage I and II breast carcinomas. Ploidy showed a strong correlation with SPF (p = 0.0001), with aneuploid tumors having a high SPF. Both cytometric parameters correlated with tumor size and hormonal receptor status. Smaller tumors tended to be diploid and have low SPF. Nodal status did not demonstrate an association with cytometric findings. There was a highly significant connection between tumor grade, especially nuclear grade, and SPF (p = 0.0001). The study demonstrates the relationship between conventional prognostic factors, DNA content, and proliferative activity of breast tumors.

Background: One thousand seventy patients treated conservatively for Stages I and II breast cancer between the years 1982 and 1994 were reviewed. The median follow-up was 40 months with a maximum follow-up of 152 months., Methods: All patients had a wide local excision and lower lymph axillary node dissection followed by radiation therapy. The entire breast received an external beam dose of 4500 cGy at 180 cGy/5 days/week. An additional boost dose of 2000 cGy to the tumor bed was given at the time of lumpectomy (perioperative) with an Ir-192 implant or with electron beam therapy after the external beam therapy., Results: The 5- and 10-year disease specific survival results were 97 and 90%, respectively for Stage I and 87 and 69% for patients with Stage II disease. The 5- and 10-year local control rates were 93 and 85% for Stage I and 92 and 87% for Stage II, respectively. The risk factors for local failure were premenopausal status and estrogen receptor-negative status at the univariate level but at the multivariate level the premenopausal and margins status were significant., Conclusion: These 10-year results were at least equivalent to reported series of similarly staged patients treated by mastectomy. This should encourage more surgeons to offer conservative treatment as an alternative to mastectomy to patients with Stage I and II breast cancer.

Extensive recurrences on the chest wall of advanced carcinoma of the breast in 20 patients were treated with multiple field patchwork hyperthermia combined with radiation therapy between 1987-1991. The objective of the study was to evaluate the feasibility, tumour response and complications of treating extensive lesions with multiple, overlapping fields of hyperthermia. All lesions were diffuse encompassing up to 2900 cm2 in area with or without multiple nodules < or = 3 cm deep. All lesions had failed previous therapy with all but three failing previous radiotherapy. Hyperthermia consisted of 282 hyperthermia applicator fields and 357 hyperthermia treatments with external 915 MHz microwaves using commercially available applicators. Hyperthermia applicator fields were defined by the surface 50% SAR distribution of a particular applicator, and hyperthermia fields were abutted to cover the entire tumour bearing area. Radiation therapy consisted of 81 fields to a mean dose of 40 +/- 1 Gy (SE), 88% of fields received between 30 and 50 Gy. The equivalent dose was 42 +/- 1 Gy, based on the linear-quadratic model and alpha/beta = 25 (Fowler 1989). Overlapping hyperthermia fields were separated by an interval of at least three days. Up to four heat sessions per week were required to cover the entire tumour in a rotating fashion. The hyperthermia treatment time was 60 min. Hyperthermia treatments were continued for the duration of radiation therapy. Each hyperthermia applicator field was heated at least once. Patients were exposed to a mean of 14 +/- 3 hyperthermia applicator fields (range of 3-46 fields) and a mean of 18 +/- 3 hyperthermia treatments (range of 6-61) delivered over a mean of 7.5 +/- 0.9 weeks (range of 3-17 weeks). Each field was heated an average of 1.3 times. The tumour complete response rate was 95% with a recurrence rate of 5%. Nevertheless, the mean survival of patients with a complete response was only 10.8 +/- 1.7 months (range of 2-28 months) because of the systemic tumour burden existing outside of the treated fields in these patients. Neither complete response, local control nor survival after thermoradiotherapy correlated with the disease free interval between initial mastectomy and recurrence. There was no evidence of increased thermal damage to skin nor evidence of tumour recurrence at junctions of hyperthermia field overlap. It is concluded that recurrent advanced carcinoma of the breast presenting as extensive, diffuse lesions on the chest wall can be treated as effectively with multiple field patchwork thermoradiotherapy as can nodular lesions treated with single hyperthermia fields.

Purpose: To assess the efficacy of perioperative implantation of iridium-192 for stage I and II breast cancer., Materials and Methods: The authors retrospectively reviewed findings from 655 patients with stage I and II cancer treated with conservative surgery and Ir-192 implantation between 1982 and 1992. Hollow plastic tubes were placed in the tumor bed as a single- or double-plane implant at lumpectomy. Ribbons with Ir-192 seeds were inserted into the tubes 4-6 hours later. The Ir-192 was left in place for approximately 50 hours. External-beam irradiation was given to the whole breast 10-14 days later., Results: Follow-up ranged from 2 to 146 months. The local control at 10 years for stage I and II disease was 93% and 87%, respectively. The 10-year actuarial survival rate was 92% +/- 1 for stage I disease and 72% +/- 4 for stage II disease. The rate of survival with no evidence of disease for stage I and II disease combined was 82% +/- 1 at 5 years and 75% +/- 3 at 10 years., Conclusion: Perioperative implantation produced excellent local control equal to that with electron-beam therapy.

Objective: To determine if low-dose involved field radiation after complete remission induction with chemotherapy is effective in preventing relapse and improving survival in patients with stage III or IV Hodgkin disease., Design: A randomized controlled trial with a median follow-up time of 8.1 years., Setting: A Southwest Oncology Group multi-institutional study. Patients were entered from university- and community-based practices., Patients: 278 adults with clinical or pathologic stage III or IV Hodgkin disease, who achieved complete responses after 6 cycles of MOP-BAP (nitrogen mustard, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine) and who agreed to be randomly assigned to either radiation or no further treatment., Intervention: Patients were assigned to either no further treatment or low-dose radiation to all initially involved sites (radiation dose, 2000 cGy to lymph node areas and 1000 to 1500 cGy to other involved organ sites)., Measurements: Differences in remission duration, relapse-free survival, and survival., Results: Remission duration, relapse-free survival, and overall survival were similar for the two groups (P = 0.09, P > 0.2, and P = 0.14, respectively). Factors that predicted shorter remission duration in a multivariate analysis were nodular sclerosis histology, bulky disease, and receipt of less than 85% of planned chemotherapy. Low-dose radiation improved remission duration in the subgroups of patients with nodular sclerosis and bulky disease. For the 169 patients with nodular sclerosis, the 5-year remission-duration estimate was 82% for the low-dose radiation group and 60% for the no further treatment group (P = 0.002). For all patients with bulky disease, the 5-year remission-duration estimate was 75% for the low-dose radiation group and 57% for the no further treatment group (P = 0.05). No difference in overall survival was noted between low-dose radiation and no further treatment in all patients or major subgroups. The 5-year survival was 86% for all patients who had a complete response as well as for patients in the nodular sclerosis subgroup., Conclusions: Low-dose involved field radiation after MOP-BAP chemotherapy in patients with stage III or IV Hodgkin disease did not prolong remission duration or overall survival in randomized patients. However, remission duration was prolonged in several subgroups of patients, most prominently in those with nodular sclerosis histology.

Background: Few women with locally advanced breast cancer remain disease-free, even for 2 years. Response to induction chemotherapy may be associated with longer disease-free and overall survival rates. The role of breast conservation in selected patients with response to induction chemotherapy was evaluated., Methods: Since 1979, patients with Stages IIB and III breast cancer have undergone induction chemotherapy; patients with response continued chemotherapy until a plateau of regression was achieved. Before 1983, all patients having a response to chemotherapy underwent mastectomy; since 1983, selected patients have undergone breast conservation. Outcomes were tallied comparing these two groups of patients., Results: The study group included 189 women, who were followed up for 12-159 months (median, 46 months) after diagnosis. Of the patients, 85% had a response to induction chemotherapy. Patients with no response were excluded from additional consideration in this study. One hundred three (64%) women underwent mastectomy; 55 (36%) were treated with breast conservation. The disease-free 5-year survival rate was 61% for all patients with a response to chemotherapy; 56% for those having mastectomy and 77% for those having breast conservation. The overall 5-year survival rate was 69% for all patients with a response to chemotherapy, 67% for those undergoing mastectomy and 80% for those having breast conservation., Conclusions: Induction chemotherapy achieves significant tumor regression in most women with locally advanced breast cancer, permitting subsequent breast conservation or mastectomy with a greater expectation of long-term success. Breast conservation is used more frequently with the same expectation of success as mastectomy, presuming careful selection based on response to chemotherapy.

Between 1982 and 1993, 620 of 938 patients with pathologically staged I-II breast cancer were treated at the time of reexcision (perioperatively), with an iridium-192 (Ir-192) implant to the tumor bed to give 2000 cGy to the 30 to 40 cGy/ph isodose line. This was followed by 4500 cGy to the entire breast at 180 cGy/d for 25 fractions. The local control for the 620 patients at 5 and 10 years was 93 and 89%, respectively. The actuarial survival at 5 and 10 years was 92 and 81%. The cosmetic results were good to excellent for 87% of the patients. Chemotherapy had no impact on local control in this study. Ir-192 implant is especially useful for deep tumors, making possible more flexibility in the techniques used to boost the tumor volume. Perioperative implantation has increased the accuracy of placing the boost dose, shortened the overall treatment time, and, for some patients, eliminated the need for rehospitalization and anesthesia.

Chest wall lesions of advanced breast carcinoma in 23 patients were treated with thermoradiotherapy with clinical intent between January 1987 and March 1992. Treatment consisted of external 915 MHz microwave hyperthermia with commercially available applicators and radiation therapy to doses between 32-58 Gy. Twenty-three large, diffuse lesions were treated with multiple field patchwork hyperthermia. All lesions were diffuse with or without multiple nodules < or = 3 cm depth. All lesions had failed previous therapy. The mean number of hyperthermia fields per patient was 3.2 +/- 0.4 (range of 2-7). The complete response rate was 91% in this group of extensive, diffuse lesions treated by the patchwork technique. Mean total radiation dose administered concurrently with multiple field patchwork hyperthermia was 42 +/- 1 Gy. The recurrence rate was 5%. The mean survival in patients who had a complete response was 9.0 +/- 1.3 months. The reduced survival among patchwork treated patients was due to the extensive tumor burden existing outside of the treated fields in these patients. The skin reactions were minor, causing minimal discomfort. There was no evidence of increased thermal damage to skin, or of tumor recurrence at junctions of hyperthermia field overlap. It is concluded that extensive, diffuse lesions of chest wall recurrence of advanced carcinoma of the breast can be treated effectively with multiple field patchwork thermotherapy.

Background: Between 1980-1990, 126 patients were treated with radiation therapy (RT) and hyperthermia using 915-MHz external microwave applicators. All but 11 patients had failed to respond to previous therapy., Methods: The mean tumor volume was 73 +/- 13 cm3, and the mean radiation dose delivered was 45 +/- 1 Gy. Hyperthermia was administered biweekly in 83% of the fields in 5.5 +/- 0.2 sessions. Lesions were stratified by depth. The predictive influence of pretreatment or treatment parameters was analyzed for the probability of response by logistic regression and for the duration of local control by proportional hazards., Results: In tumors considered potentially heatable (i.e., < or = 3-cm deep), the complete response (CR) rate was 70%, whereas the CR rate for patients with tumors deeper than 3 cm was 18% (P < 0.0001). Among superficial lesions of less than or equal to 3-cm depth that exhibited a CR, 14 recurred (26%, 8.7 +/- 1.6 months), while 39 lesions were recurrence-free at last follow-up of 17.8 +/- 1.4 months. The 50% tumor-effective dose was 44 Gy. For superficial lesions that received between 30-60 Gy, the CR rate was 55% when the fraction size was less than 3 Gy, whereas it was 77% when the fraction size was 3-4 Gy (P = 0.05). Multivariate logistic regression analysis indicated that the model best correlating with CR included concurrent radiation dose (P = 0.006) and tumor volume (P = 0.02; model P = 0.0001). Multivariate proportional hazard analysis indicated that the model best correlating with duration of local control included tumor histology (P = 0.004; model P = 0.0007). The overall survival rate of patients with lesions of less than or equal to 3-cm depth who were treated with thermoradiation therapy was 16.1 +/- 1.2 months. For patients with lesions more than 3-cm deep, survival was 8.7 +/- 1.1 months (P < 0.001). Forty-two fields were treated without any skin reactions (33%), 59 exhibited erythema (47%), and 25 experienced thermal blistering (20%)., Conclusions: Treatment of superficial malignant tumors can benefit from the adjuvant use of hyperthermia delivered with external 915-MHz applicators provided tumors are less than 3 cm from the surface and the lateral margins are within the 50% specific absorption rate (SAR) on the surface.

Two hundred forty-five women (250 breasts) with early-stage breast cancer were treated between June 1982 and June 1990 with lumpectomy, immediate (boost) interstitial iridium-192 to 15-20 Gy, and external-beam irradiation to the entire breast to 45-50 Gy. There were 123 stage I cancers (T1N0M0), 123 stage II cancers (36 T1N1, 50 T2N0, 33 T2N1, four T3N0), and four stage III cancers (two T2N2, two T3N1). At a median follow-up of 69 months (range, 26-122 months), there were 14 recurrences in the treated breasts. Four were at the site of primary disease, eight were in other quadrants, and two were in both. With immediate interstitial boost, the 11-year actuarial recurrence rate in the breast is 7.7% and the recurrence rate at the site of primary disease is 3.2%.

It is important that physicians be aware of the current theories on the etiology of breast cancer. This article reviews some of the more probable etiologic factors of breast cancer.

Irradiation has been used to treat cancer of the breast since 1895. Over the period between 1895 to the present, the therapeutic use of irradiation has evolved from a cauterizing agent to a sophisticated use of theory and practice to cause tumor cell death while at the same time producing maximum normal tissue sparing. The use of radiation has made it possible for the surgeon to use conservative breast sparing surgery to obtain excellent cosmetic results, while at the same time producing a local control equal to that of mastectomy. For the patient, conservative surgery becomes a better option than mastectomy because it not only produces local control equal to that of mastectomy, but gives the wonderful added benefit of a more superior and pleasing cosmetic result.

Treatment planning of the electron boost in breast irradiation at this institution is performed by using information from CT scanning and from surgical clips used to define the tumor bed. A refinement of this technique, taking into account the surgical axis of approach, using computer-CT planning is now implemented. The location of the scar and the clips are digitized using a computer to define the tumor bed dimensions. With 3-D computer software a line, simulating the surgical axis and the central ray of the electron beam, is drawn between the deepest clip and the surgical scar. This beam's eye view along the surgical axis is projected onto a screen as a starting point. Appropriate gantry angle, treatment table position, beam energy, and precise shaping of the electron field borders with a 2 cm margin around the clips and the scar are determined. Simulation films comparing clinically set-up fields and computer-CT planned fields were reviewed. In only 5 of 17 patients did the clinically set-up field have adequate inclusion of the tumor bed within the treatment volume. Computer-CT planned fields ensured adequate inclusion of the tumor bed in all, including the remaining 12. In 7 patients obvious increased sparing of normal breast tissue was seen with computer-CT planned fields. This technique enables accurate placement of a shaped electron field and further refinement of electron boost treatment planning. This is especially true in situations in which the tumor bed is located at a site distant from the lumpectomy scar rather than directly beneath it and in cases where the tumor bed lies deep within the breast.

The authors reviewed the records of 139 patients who had laparotomy plus computed tomography (CT) and/or lymphangiograms (LAG) as part of a their staging workup for Hodgkin's disease, in accordance with Southwest Oncology Group (SWOG) protocol 7808. They evaluated the relative ability of CT and LAG to detect disease in the abdomen. Two regions of the abdomen were designated, the upper and the lower, to further examine the capabilities of CT and LAG in the lower abdomen and CT in the upper abdomen. A LAG was more sensitive (P less than 0.05) than CT in detecting positive lower abdominal nodes. In the upper abdomen, CT scan had low sensitivity for detecting positive nodes, liver, or spleen. This study suggests that LAG of the lower abdomen provided more information than CT, and therefore should not be abandoned as a valid method for detecting nodal disease.

Patients with early breast cancer (T1-2 N0-1) can be treated by lumpectomy and irradiation with a local control and survival equal to more radical surgery. Between 1982 and 1988, 323 patients with early breast cancer were treated, when possible, with Ir-192 implants at the time of lumpectomy to a local dose of 2000 cGy in 40-50 hours. Ten to 14 days later, the whole breast was treated to 4500 cGy at 180 per fraction in 5 weeks. The 6-year actuarial survival for stages I and II disease was 98% and 91%, respectively, and the recurrence-free survival was 96% and 98%, respectively. When these 323 patients were evaluated by T status, a local control of 97% was the same for T1 and T2 lesions. The cosmetic results were good to excellent in 95% of the patients. This approach has improved our ability to accurately place the boost dose in the breast.

The preponderance of evidence indicates that lumpectomy plus radiation therapy produces the same survival as modified radical mastectomy in patients with early breast cancer and further suggests that the local failure rate may be lower in the patients who undergo irradiation. In this series, patients were treated with immediate implantation of the tumor bed with iridium Ir 192. There have been two recurrences in the breast from 110 breast cancers (44% had a clinical stage greater than T1, and 41% had axillary-node involvement) in 107 patients followed up for four to 52 months (25.8 +/- 13.3 months [mean +/- SD]). These preliminary data suggest that local treatment failure can be minimized by aggressive, immediate intraoperative implantation of the tumor bed with iridium Ir 192.

Several new electron-affinic compounds have been shown to possess radiosensitizing ability in hypoxic mammalian cells. The correlation between chemical structure and biological activity can aid in the design and synthesis of new agents with potentially greater hypoxic cell radiosensitizing ability.

Dihydroxyanthraquinone (DHAQ; NSC 279836) is a recently synthesized compound that is structurally similar to Adriamycin and produces greater antitumor effects in murine model systems. We compared DHAQ to Adriamycin in rats, with and without irradiation of the chest at various intervals after drug treatment. A single injection of Adriamycin (1 mg/kg i.p.) had little effect on animal survival, even if combined with radiation (12 Gy 25 MV X-rays), greater than 90% being alive at 1 year. A single injection of DHAQ (3 mg/kg i.p.) was equally uneffective up to 200 days after treatment (survival, greater than 90%). However, between 200 and 370 days after treatment, all animals died, producing a median survival time of 280 days. Further, when DHAQ was combined with radiation, there was an increase in animal deaths between Days 300 and 200. For animals irradiated on Days 0, 43, and 93 after DHAQ treatment, only 50, 75, and 80%, respectively, survived to Day 200. All animals that survived past Day 200 subsequently died by 1 year, displaying the same kinetics of lethality as those animals that had received DHAQ only. A repeat experiment using DHAQ at 1 mg/kg produced similar results. Based on these findings, we conclude that DHAQ produces a long-term (greater than 200 days) toxicity in rats that is not detectable by short-duration toxicity screening. In addition, radiation enhances short-term (less than 200 days) lethality, with the degree of enhancement decreasing as the interval between drug and radiation is increased.

Conservation of the breast in early breast cancer with limited resection and radiation is proving to be as effective as modified radical mastectomy in survival and in loco-regional control. Management at the University of Kansas Medical Center consists of an interstitial implant at the time of lumpectomy to facilitate perioperative irradiation with Iridium-192 to the tumor bed. An axillary node dissection is also performed at that time. Two to 3 weeks later external beam irradiation is delivered to the entire breast. One hundred and twenty-three breasts in 120 patients have been treated between June 1982 and June 1986. There were 49 pathological Stage I, 63 Stage II, 8 Stage III carcinomas, and 3 carcinomas in situ, consisting of 72 T1, 43 T2, 5 T3, and 3 TIS lesions. Patients have been followed for a median of 30 months. One patient had a "true" recurrence in the breast. Another patient developed recurrence in a different quadrant. Ninety percent of the patients had good to excellent cosmetic results, 7% were considered fair, and 3% had poor results. Seven patients developed mild arm edema, 4 were found to have moderate edema, and 1 had severe arm edema. Our preliminary results indicate that interstitial irradiation immediately after excision results in excellent local control, with very satisfactory cosmesis and no morbidity due to the simultaneous excision and irradiation.

Limited resection of the breast combined with radiation has proved to be as effective as more radical surgery in treating early breast cancer. At the University of Kansas Medical Center, the radiotherapy consists of an interstitial implant at the time of lumpectomy to deliver an interstitial boost dose to the tumor bed with iridium-192 immediately following the surgical procedure. An axillary node dissection is also performed at the time of lumpectomy. A dose of 2,000 cGy is delivered to the tumor bed between 40 and 60 h. Two to three weeks later, 4,500-5,000 cGy is delivered to the entire breast with external beam radiation over 5-5.5 weeks. One hundred breasts in 98 patients were so treated between June 1982 and February 1986, with 2 carcinomas in situ, 40 stage I, 51 stage II, and 7 stage III cancers, consisting of 2 TIS, 54 T1, 39 T2, and 5 T3 lesions. Locoregional control with a median follow-up of 31 months was 98%. One recurrence was in a different quadrant, and the other revealed predominantly the in situ component. Immediate implant did not compromise wound healing or cosmesis. The cosmetic result was graded as good to excellent in 88% of the breasts. Our preliminary results appear to suggest a better local control with immediate interstitial irradiation.

The value of radiotherapy to the chest (RC) in disseminated small cell lung carcinoma (SCLC) has been questioned. Two protocols for disseminated SCLC from the Southwest Oncology Group (SWOG) have been compared. They were developed four years apart. The first one included radiotherapy (RT), 3000 rad in two weeks, to the primary tumor, mediastinum and supraclavicular areas, while the second one deleted any RC. Multidrug chemotherapy (CT) and brain RT were used in both protocols. Nonresponders to CT were removed from the study. Our main findings are as follows: (1) Initial chest relapses (patients with no initial extrathoracic relapse) have increased from 24-55% when RC is not given (P = 0.0001). Overall chest relapse (adding those patients that relapsed simultaneously in the chest plus other sites) in the second protocol was 73%. (2) Amount of response to CT does not influence the chances for relapse. Even complete responders to CT have a high chance for chest relapse. (3) Sites of relapse without RC are mainly in the primary tumor, ipsilateral hilus and mediastinum. (4) With RC, relapses shift to the chest periphery, mostly to the lung outside the radiotherapy field and to the pleura. (5) The two very different CT regimens have produced similar percentages and duration of response. (6) CT schema with periodic reinductions prolongs duration of response and survival over schema with continuous maintenance. Hence, interruption of CT to allow RC does not seem to adversely influence CT efficacy. From our results and the review of the literature we conclude that: (1) patients with disseminated SCLC that respond to CT should be given RC to decrease chest relapses. (2) A dose of 3000 rad in two weeks seems to be enough to produce a low percentage of chest relapse in disseminated SCLC, as survival of these patients is short and many will die prior to developing chest relapse. However, according to the literature, 4000-4800 rad is probably a more effective dose. (3) More studies and guidelines are needed to outline proper boundaries of radiotherapy fields, to decrease chances of peripheral chest relapses. (4) Median survival might not be a good parameter to evaluate the impact of RC in disseminated SCLC. The study of long-term survivors seems to be more important.

Intraoperative interstitial implantation of iridium 192 during a lumpectomy for carcinoma of the breast has been well tolerated by the patient. This procedure has decreased the need for anesthesia and repeat hospitalization.

There is growing evidence in the world literature that radiation therapy plus lumpectomy produces survival rates equal to those of mastectomy for stage I and stage II breast cancer. The technique of using an interstitial implant at the time of lumpectomy could improve local control by increasing the accuracy of the interstitial implantation. It will certainly decrease hospital stay, anesthesia, and cost to the patient.

Preliminary results indicate that film dosimetry is a simple and precise method of determining volume dose distributions. Calculated dose distributions using computers or estimations of surface dose using TLD dosimeters are within 5% of the measured dose. Initial attempts to find suitable alternate techniques tailored to each clinical situation are encouraging.

A retrospective review of 17 patients with a diagnosis of chemodectomas of glomus jugulare is presented. The patients' age ranged from 32 to 63 years, with a female to make ratio of 4:1, with 14 females and 3 males. In the majority of the patients (15/17), the primary treatment was surgery, with 10/15 (70%) incidents of recurrence. Radiation therapy was used in 11 patients, in 7 for recurrence, in 2 as postoperative and in 2 as a primary therapy. The radiation dose ranged from 2200 to 5600 rad. The follow-up period ranged from 2 to 22 years. Sixteen patients were living with disease controlled at the last follow-up.

Twenty-two patients with malignant uterine tumors were examined with computed tomography (CT) for treatment planning after insertion of an afterloading Fletcher applicator. The CT findings maximized the individualization of treatment planning, including the number, dosage, and loading arrangement of radioactive sources. Artifacts were produced by the metal; but in most cases the scans accurately portrayed the three-dimensional anatomic relationship of the applicator, uterus, and neighboring vital structures. The CT information made it possible to calculate dose distribution more rapidly and accurately for both intracavitary therapy and combined intracavitary and external therapy. Unsuspected uterine perforation was detected by CT in one case.

The effect of combined modalities (radiotherapy-chemotherapy) on the development of long-term normal tissue damage was investigated in rats. Animals received single I.P. injections of Hank's balanced saline solution, adriamycin (ADR, 1.0 mg/kg), bleomycin (BLM, 10 units/kg), or dihydroxyanthraquinone (DHAQ, 3.0 mg/kg); and/or irradiation of the chest with 25 MV x-rays (12 Gy) at 0, 43, 93, or 199 days after drug treatment. Only animals treated with DHAQ displayed appreciable toxicity, with more animals dying at less than 200 days when radiation was added at 0 or 43 days. Although animals treated with BLM or radiation exhibited evidence of lung damage (histologically by 199 days and radiographically by 300 days), their survival was not compromised. The simultaneous administration of x-ray and BLM produced enhanced effects as compared to either agent alone. These results demonstrate an enhancement of normal tissue damage by combined treatment with radiation and chemotherapeutic agents, not only for acute toxicity but also for long-term effects. This damage was ultimately expressed as alteration of lung structure (histologically and radiographically) in the case of BLM, and as animal lethality in the case of DHAQ. In addition, there was a reduction in the degree of enhancement observed as a function of the separation in time between treatment with chemotherapeutic agents and subsequent irradiation. These factors should be considered when combined modality therapy is used for treatment of cancer in the thoracic region.