Photo-induced toxicity of titanium dioxide nanoparticles to Daphnia magna under natural sunlight.

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.

Survival of colorectal cancer cell lines treated with paclitaxel, radiation, and 5-FU: effect of TP53 or hMLH1 deficiency.

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).

Bilateral breast carcinoma: risk factors and outcomes for patients with synchronous and metachronous disease.

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.

The number of positive margins influences the outcome of women treated with breast preservation for early stage breast carcinoma.

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.

A dosimetry system for 192IR interstitial breast implants performed at the time of lumpectomy.

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.

Correlation of flow cytometry to clinical factors, hormone receptors, and histopathological grade in stage I and II invasive breast carcinoma.

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.

Ten-year results in 1070 patients with stages I and II breast cancer treated by conservative surgery and radiation therapy.

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.

Multiple field hyperthermia combined with radiotherapy in advanced carcinoma of the breast.

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.

Perioperative implantation of iridium-192 as the boost technique for stage I and II breast cancer: results of a 10-year study of 655 patients.

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.

Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease. A Southwest Oncology Group randomized study.

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.

Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast.

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.

The role of radiotherapy in the treatment of breast cancer: results of perioperative implantation.

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.

'Patchwork' fields in thermoradiotherapy for extensive chest wall recurrences of breast carcinoma.

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.

Thermoradiation therapy for superficial malignant tumors.

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.

Early-stage breast cancer: local control after conservative surgery and radiation therapy with immediate interstitial boost.

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%.

A review of the etiology of breast cancer.

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.

A review of the role of radiation therapy in the treatment of patients with 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.

Computer-CT planning of the electron boost in definitive breast irradiation.

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.