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Biomedical subjects

D E Wazer

Publications and source records attributed to D E Wazer.

At least 55 records · Page 3Linked to original sources
PubMed1995

The influence of quantitative tumor volume measurements on local control in advanced head and neck cancer using concomitant boost accelerated superfractionated irradiation.

PURPOSE: Current methods to clinically define head and neck tumor bulk are qualitative and imprecise. Although the American Joint Committee on Cancer (AJCC) staging system is important for this purpose, limitations exist. This study will investigate the prognostic value of computed tomography (CT) derived tumor volume measurements in comparison to AJCC stage and other significant variables. MATERIALS AND METHODS: Seventy-six patients with advanced head and neck squamous cell carcinoma were treated with concomitant boost accelerated superfractionated irradiation. Doses ranged from 68.4-73.8 Gy (median 70.2 Gy). Good quality pretherapy CT scans were available in 51 patients. Total tumor volume (TTV) estimates were derived from these scans using digital integration of primary tumor and metastatic lymphadenopathy. Actuarial and multivariate statistical techniques were applied to analyze local control. RESULTS: Thirty-six-month local control was 63%. TTV ranged from 5-196 cm3 (median 35 cm3) for all cases, 5-142 cm3 (median 17 cm3) for those controlled, and 16-196 cm3 (median 47 cm3) for local failures. There was a significant increase in failures above 35 cm3. Univariate analysis found that TTV, T-stage, N-stage, and primary site were each significant prognostic variables. Local control for TTV < or = 35 cm3 was 92% at 36 months vs. 34% for TTV > 35 cm3 (p = 0.0001). Multivariate analysis, however, found that TTV, primary site, and sex were important as independent variables; T and N stage were not independently significant unless TTV was removed from the model. CONCLUSIONS: This study demonstrates the prognostic significance of TTV in advanced carcinoma of the head and neck. This variable appears to be a more predictive than AJCC clinical stage. Quantitative tumor volume measurements may prove to be a useful parameter in future analyses of head and neck cancer.

Carcinoma, Squamous Cell↗
PubMed1995

Immortalization of distinct human mammary epithelial cell types by human papilloma virus 16 E6 or E7.

Multiple mammary epithelial cell (MEC) types are observed both in mammary ducts in vivo and in primary cultures in vitro; however, the oncogenic potential of different cell types remains unknown. Here, we used human papilloma virus 16 E6 and E7 oncogenes, which target p53 and Rb tumor suppressor proteins, respectively, to immortalize MECs present in early or late passages of human mammary tissue-derived cultures or in milk. One MEC subtype was exclusively immortalized by E6; such cells predominated in late-passage cultures but were rare at early passages and apparently absent in milk. Surprisingly, a second cell type, present only in early-passage tissue-derived cultures, was fully immortalized by E7 alone. A third cell type, observed in tissue-derived cultures and in milk, showed a substantial extension of life span with E7 but eventually senesced. Finally, both E6 and E7 were required to fully immortalize milk-derived MECs and a large proportion of MECs in early-passage tissue-derived cultures, suggesting the presence of another discrete subpopulation. Identification of MECs with distinct susceptibilities to p53- and Rb-targeting human papillomavirus oncogenes raises the possibility that these cells may serve as precursors for different forms of breast cancer.

Breast↗
PubMed1994

Breast conservation in elderly women for clinically negative axillary lymph nodes without axillary dissection.

BACKGROUND: A prospective study was initiated to explore an approach of limited therapy in elderly patients with early clinical stage breast cancer. METHODS: Between 1982 and 1989, 73 women with American Joint Committee on Cancer Stage I/II, clinically negative axillary lymph nodes aged 65 years or older (median age, 74 years) were enrolled in a treatment program consisting of tumor excision, breast and regional lymph node irradiation, and, in 66 patients, tamoxifen. Patients were assessed for disease outcome and complications. RESULTS: At a median follow-up of 54 months, 8-year rates of local and regional lymph node control were 92.5% and 100%, respectively. Eight-year probabilities of disease free, overall, and breast cancer specific survival were 84%, 52.5%, and 93.8%, respectively. There was minimal morbidity associated with either regional irradiation or tamoxifen. CONCLUSIONS: An approach to early breast cancer in the elderly that seeks to limit the aggressiveness of local and systemic therapies appears to result in a satisfactory disease outcome with few complications.

Age Factors↗
PubMed1994

Fine tuning of linear accelerator accessories for stereotactic radiotherapy.

PURPOSE: Experience with the University of Wisconsin's stereotactic radiotherapy (SRT) accessory system was applied to build a new system, facilitate alignment of linac photon beams with a Brown-Roberts-Wells (BRW) stereotaxy, and increase the versatility and stability of the stereotaxy. METHODS AND MATERIALS: High tensile strength stainless steel was used in the floor stand to increase the range of gantry rotation relative to ranges allowed by truss-mounted stands. The collimator assembly and floor stand were each fitted with two-axis gimbal and translation adjustments in addition to the floor stand's three-axis adjustments. The head ring positioning assembly was fitted with two braces to prevent the head ring from deforming with patient motion. Six MV linac photon beam characteristics were measured with a computer-controlled scanning system and a diode in water, at source to surface distances (SSD) of 80 and 100 cm, and for 13 divergent collimators ranging in diameter from 1-4 cm at 100 cm SSD. Quality assurance software was applied to screen data for questionable consistency or symmetry. Integrity of the stereotaxy was evaluated with target simulation films and repeated measurements which were part of the quality assurance of clinical treatments. A method was developed using a glass etched contact reticle to obtain average simulated target to beam center distances (delta av) from target simulation films. RESULTS AND CONCLUSION: New aspects of the current system have improved the ability to fine tune and analyze stereotactic alignment. Beam characteristics met stringent output criteria and penumbral widths were the same or narrower than penumbral widths reported elsewhere. The precision of measuring delta av was 0.1 mm, and delta av averaged over 50 target simulation films was 0.7 +/- 0.1 mm. Results suggest that it may be useful to determine delta av from target simulation films with the method described here.

Humans↗
PubMed1994

Local excision of rectal carcinoma. Early results with combined chemoradiation therapy using 5-fluorouracil and leucovorin.

PURPOSE: This study was undertaken to evaluate the treatment morbidity, functional outcome, and recurrence risk of patients undergoing local excision and combined chemoradiation therapy for rectal carcinoma. METHODS: Eighteen patients underwent local excision of their rectal carcinoma. Four patients underwent local excision alone (T1-2, N0-X, low risk), 10 patients underwent local excision with postoperative chemoradiation therapy using 5-fluorouracil and leucovorin (T1-2, N0-X, high risk), and 4 patients underwent local excision, chemoradiation therapy, and six months of additional 5-fluorouracil and leucovorin (T3 or N1). RESULTS: Of the four patients undergoing local excision alone, there was no treatment morbidity or alteration in functional outcome. Of the 14 patients receiving chemoradiation therapy, three reported early Grade 3-4 toxicity manifested by cystitis, proctitis, or perineal skin desquamation. At six months, two patients reported persistent rectal urgency and occasional fecal incontinence, and 11 patients reported increasing stool frequency (average, 3: range, 2-8). The six months of additional 5-fluorouracil and leucovorin were well tolerated and did not appear to further affect functional outcome. There were no local recurrences, although one patient developed distant metastatic disease. CONCLUSION: This treatment regimen, while generally well tolerated, is associated with significant acute toxicity in certain patients. We have identified specific causative factors which can be modified to decrease acute morbidity, including the elimination of leucovorin during the combined chemoradiation therapy.

Adenocarcinoma↗
PubMed1994

Tumor cell-specific loss of p53 protein in a unique in vitro model of human breast tumor progression.

Mutations of the p53 gene are the most frequent genetic lesion in breast cancer. Here, we examined p53 expression in a unique in vitro model of tumor progression derived from a single breast cancer patient (21T series). While the normal mammary epithelial, fibroblast and mesothelial cells derived from this patient expressed easily detectable functional p53 protein, the primary as well as metastatic tumor cell lines demonstrated a lack of p53 protein synthesis. 21T tumor cells failed to exhibit G1 cell cycle arrest upon exposure to gamma-irradiation, and their growth was suppressed by transfection of a normal p53 cDNA, demonstrating a lack of p53-mediated function in these cells. No p53 gene deletion or rearrangements were detectable. PCR and sequence analysis of the entire coding region of p53 gene revealed a novel mutation, an insertion of a single T within codon 33, which resulted in a frame-shift and early termination. The same mutation was observed in all 21T tumor cell lines. These results demonstrate a tumor cell-specific loss of p53 protein due to a frame-shift mutation, and suggest that p53 loss may occur at a relatively early step in breast tumorigenesis before metastatic seeding or emergence of tumor heterogeneity. In addition, the availability of normal and tumor-derived epithelial cells with known p53 sequences from a single breast cancer patient should facilitate understanding of the p53 regulation in mammary cells.

Breast↗
PubMed1994

Loss of p53 protein during radiation transformation of primary human mammary epithelial cells.

The causative factors leading to breast cancer are largely unknown. Increased incidence of breast cancer following diagnostic or therapeutic radiation suggests that radiation may contribute to mammary oncogenesis. This report describes the in vitro neoplastic transformation of a normal human mammary epithelial cell strain, 76N, by fractionated gamma-irradiation at a clinically used dose (30 Gy). The transformed cells (76R-30) were immortal, had reduced growth factor requirements, and produced tumors in nude mice. Remarkably, the 76R-30 cells completely lacked the p53 tumor suppressor protein. Loss of p53 was due to deletion of the gene on one allele and a 26-bp deletion within the third intron on the second allele which resulted in abnormal splicing out of either the third or fourth exon from the mRNA. PCR with a mutation-specific primer showed that intron 3 mutation was present in irradiated cells before selection for immortal phenotype. 76R-30 cells did not exhibit G1 arrest in response to radiation, indicating a loss of p53-mediated function. Expression of the wild-type p53 gene in 76R-30 cells led to their growth inhibition. Thus, loss of p53 protein appears to have contributed to neoplastic transformation of these cells. This unique model should facilitate analyses of molecular mechanisms of radiation-induced breast cancer and allow identification of p53-regulated cellular genes in breast cells.

Animals↗
PubMed1994

The role of radiation in breast conserving therapy.

Conservation therapy, consisting of tumor excision followed by irradiation, is an accepted alternative to mastectomy for many women with early breast cancer. The goals of this treatment approach are tumor control and acceptable breast cosmesis. Optimal results require appropriate patient selection and careful attention to a number of treatment-related variables.

Breast Neoplasms↗
PubMed1993

Breast conservation therapy for early stage breast carcinoma with outstanding 10-year locoregional control rates: a case for aggressive therapy to the tumor bearing quadrant.

PURPOSE: Between 1982 and 1988 233 American Joint Committee on Cancer Stage I and II invasive breast carcinomas were prospectively treated in 225 women with conservative tumor excision, careful assessment of histopathological margins, and dose-adjusted irradiation to maximum doses of 70 Gy to the tumor bearing quadrant of the breast. METHODS AND MATERIALS: The pathological stages at presentation were T1N0 and T1N1 in 57% and 13% and T2N0 and T2N1 in 19% and 10% of the patients, respectively. All patients were irradiated according to a policy that, beyond the 50 Gy to the whole breast and draining lymphatics, the tumor-bearing quadrant was boosted in adjustment to the histopathological margin. Normal tissue margins of < 2 mm were considered positive, margins 2-5 mm close, and margins > 5 mm negative and were boosted with 20, 15, and 10 Gy, respectively. Patients in whom the margin could not be assessed were re-excised or boosted to 20 Gy. Re-excisions with no residual carcinoma were not boosted. Most patients boosted to 20 Gy to the tumor-bearing quadrant received interstitial 192-Ir implantations. RESULTS: The actuarial local control rates in the treated breast were 97.5% at 10 years with three recurrences having occurred at a median of 4.5 years after completion of radiotherapy. An additional two patients failed regionally outside the irradiation portals. The overall and disease-free survival of the whole group is 87.5% and 77%, respectively. CONCLUSION: The approach to breast conservation therapy followed in this study has resulted in outstanding local control rates and suggests that there may be a subset of patients that could be irradiated to the tumor bearing quadrant only.

Adult↗
PubMed1993

Alterations in growth phenotype and radiosensitivity after fractionated irradiation of breast carcinoma cells from a single patient.

PURPOSE: To investigate growth regulation and radiosensitivity in surviving clonogens after fractionated irradiation. METHODS AND MATERIALS: Four breast carcinoma cell lines isolated from the primary tumor (21NT, 21PT) and metastases (21MT-1, 21MT-2) of a single patient were exposed to cumulative radiation doses of 30 Gy yielding cell lines designated-IR with respect to their parent. The irradiated lines were then compared to their parent for serum-and growth factor-requirements under defined media conditions, ability to proliferate in soft agar, concentration of TGF-alpha in conditioned medium, and radiosensitivity. RESULTS: The irradiated lines showed no change in proliferative doubling times under serum- and growth factor-supplemented media conditions. A single line, 21MT-1-IR, acquired a limited ability to proliferate in serum-and growth factor-deplete medium with a day 2-4 doubling time of 44.5 hr. Three lines, 21MT-1-IR, 21MT-2-IR, and 21NT-IR, formed colonies in soft agar in contrast to none of the unirradiated parent lines. There were significant 6-8 fold increases in conditioned media TGF-alpha concentrations for 21MT-2-IR and 21NT-IR cells. The 21MT-1-IR and 21NT-IR cells were significantly less radiosensitive than their respective parent lines. This decrease in radiosensitivity appeared to be at least partially mediated by a released factor as the radiosensitivity of 21MT-1 cells was significantly decreased by pre-incubation with conditioned medium from 21MT-1-IR cells. CONCLUSION: Radiation-induced changes in growth phenotype vary with respect to clonal origin of the cell line and may influence the radiosensitivity of surviving clonogens after fractionated treatment.

Breast Neoplasms↗
PubMed1993

Radiation-enhanced expression of major histocompatibility complex class I antigen H-2Db in B16 melanoma cells.

Exposure of eukaryotic cells to ionizing radiation induces several cellular responses including DNA repair, arrest of DNA synthesis, and increased synthesis of specific cellular proteins. We derived from the murine melanoma cell line B16-F10 a clonal isolate (M1) that was exposed to a total dose of 5000 cGy in 25 fractions, according to a protocol that reflects the standard for current radiotherapeutic regimens. We measured, by flow cytometry of fluorescence-stained cells, the surface expression of the two major histocompatibility complex class I antigens H-2Db and H-2Kb in irradiated M1 cells and untreated M1 controls. We found that after 2000 cGy, expression of H-2Db antigen was enhanced in irradiated cells versus controls. Radiation-induced expression of H-2Db antigen appeared to be selective, since no up-regulation of the H-2Kb antigen was detectable, and persisted for at least 5 weeks following the last irradiation. Enhanced H-2Db antigen expression correlated with increased steady-state levels of H-2Db mRNA in irradiated cells. These results are consistent with the notion that enhanced expression of major histocompatibility complex class I antigens is part of a long-lasting stress response elicited in cells by radiation.

Animals↗
PubMed1993

Reirradiation of head and neck neoplasms using twice-a-day scheduling.

Between 1985 and 1988, we have explored the value of twice-a-day (BID) irradiation for the retreatment of head and neck neoplasms. In this pilot study of ten patients we used a schedule of BID irradiation at fraction sizes between 1.4 and 1.6 Gy separated by at least 6 h. Of the four patients were treated with curative intent, three patients received 30 Gy in 20 fractions over twelve days followed within ten days by an interstitial/intracavitary Ir-192 implant boost to doses of 30 to 40 Gy and one patient was treated with a 32 Gy BID boost. Four patients were reirradiated with aggressive palliation and received 45 Gy in 30 fractions over 26 days including a break in the third week. The remaining two patients were treated with palliative intent to 30 Gy in 20 fractions over twelve days. Eight patients were treated for recurrent/persistent or second carcinomas, one for a recurrent glomus jugulare tumor. At a median follow-up of 36 months, ranging from six to 61 months, nine of ten patients experienced excellent symptomatic relief. Five patients are alive and free of tumor, one patient is alive with distant metastases, and two each are dead from local or systemic tumor progression. All four patients retreated for cure are alive with no evidence of local disease. The tolerance and tumor control rate of the BID reirradiation schedule were good with severe late sequelae in only one patient.

Aged↗
PubMed1993

Demonstration of unilateral sialadenitis on postradiotherapy gallium-67-citrate imaging.

Intense, asymetric uptake of 67Ga-citrate in the right parotid and submandibular glands was observed in an asymptomatic patient who had undergone locoregional radiotherapy for Stage IA Hodgkin's disease 8 mo earlier. In view of the modified minimantle radiation field and adjunctive 99mTc salivary imaging, a unilateral radiation-induced sialadenitis best explained this unusual scintigraphic appearance.

Aged↗
PubMed1992

Boron neutron capture therapy for murine malignant gliomas.

Boron neutron capture therapy (BNCT) involves administration of a boron compound followed by neutron irradiation of the target organ. The boron atom captures a neutron, which results in the release of densely ionizing helium and lithium ions that are highly damaging and usually lethal to cells within their combined track length of approximately 12 microns. Prior to Phase I clinical trials for patients with malignant gliomas, mice with glioma 261 intracerebral tumors were fed D,L-3-(p-boronophenyl)alanine and irradiated with total tumor doses of 1000-5000 RBE-cGy of single fraction thermal neutrons to determine the maximum tolerated dose and effect on survival. These mice were compared to mice that received D,L-3-(p-boronophenyl)alanine alone, neutron irradiation alone, photon irradiation alone, or no treatment. Additional normal mice received escalating doses of neutron irradiation to determine its toxicity to normal brain. BNCT caused a dose-dependent, statistically significant prolongation in survival at 1000-5000 RBE-cGy. At 3000 RBE-cGy, median survival rates of the BNCT and untreated control groups were 68 and 22 days, respectively, with a long-term survival rate of 33%. At 4000 RBE-cGy, median survival was 72 and 21 days, respectively, with a long-term survival rate of 43%. At lower radiation doses, the extended survival was comparable between the BNCT and photon-irradiated mice; however, at 3000 and 4000 RBE-cGy the median survival of BNCT-treated mice was significantly greater than photon-irradiated mice. The maximum tolerated single fraction dose to normal brain was approximately 2000 RBE-cGy.

Animals↗
PubMed1992

Concomitant boost technique using accelerated superfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck.

Of 142 patients irradiated for American Joint Committee on Cancer Stage III or IV head and neck carcinoma, 100 patients were eligible for analysis with a minimum follow-up of 12 months. In one group, 50 patients were treated with conventional once-a-day (QD) fractionation to doses in excess of 6600 cGy. The other 50 patients were treated prospectively with accelerated superfractionated radiation therapy using a concomitant boost twice-a-day schedule (BID). Patients received conventional fractionation (180 cGy/fraction) combined with a boost field of 160 cGy/fraction BID after a 4-hour to 6-hour interval 3 days per week during part of their treatment course. After 3 years, locoregional tumor control was 62% in the BID group versus 33% in the QD group (P = 0.003). Disease-free survival was 60% and 30%, respectively, for the BID and QD groups (P = 0.002), and adjusted survival was 66% and 38%, respectively, for the BID and QD groups (P = 0.03). Overall survival approached statistical significance in favor of the BID group (P = 0.06). Complete tumor responses were observed in 63% of patients treated in the BID group 1 to 3 months after completion of radiation therapy. Of these, 84% remain free of local recurrence. Of the 19 patients with persistent disease 1 to 3 months after treatment, 47% remain locally controlled. Superfractionated accelerated radiation therapy produced superior local control and disease-free and adjusted survival rates relative to a group of patients treated QD.

Carcinoma, Squamous Cell↗
PubMed1992

Expression of oestrogen receptor and transforming growth factor-alpha in MCF-7 cells after exposure to fractionated irradiation.

The expression of critical growth controlling genes was studied in MCF-7 cells after exposure to cumulative radiation doses of 20 and 60 Gy yielding cell lines called MCF-IR-1 and MCF-IR-3, respectively. The irradiated cell lines exhibited increased plating efficiencies but no differences in growth rates. MCF-IR-1/-IR-3 cells showed a reduced oestrogen responsiveness as indicated by their diminished response to tamoxifen-induced growth arrest and 17 beta-oestradiol (E2)-induced growth stimulation. The reduced expression of oestrogen receptor (ER) was determined by quantitative immune peroxidase staining of single cells and by total cellular E2 binding. There was also a radiation dose-dependent increase in the radiosensitivity of MCF-IR-3 cells as determined by the radiobiological parameters alpha, beta, and D (mean inactivation dose). Using RNA protection assays the irradiated cell lines produced steady-state ER mRNA at reduced levels while the levels of TGF-alpha were unchanged in MCF-IR-1 cells but increased 2.8-fold in MCF-IR-3 cells. A similar pattern was seen for TGF-alpha protein. While the current analyses cannot differentiate between radiation-induced altered gene expression or cell selection the results demonstrate that reduced ER expression and increased TGF-alpha expression are associated with the survival of MCF-7 cells after fractionated irradiation in vitro. In contrast, the MCF-IR cells were found to be more radiosensitive in acute survival experiments.

Breast Neoplasms↗
PubMed1992

Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma.

PURPOSE: The study was undertaken to assess the relationship among cosmesis and complications to factors related to disease presentation, surgical and radiotherapeutic technique, and adjuvant systemic therapy in conservative treatment for early-stage breast carcinoma. PATIENTS AND METHODS: Between 1982 and 1988, 234 women with stage I/II breast carcinoma were treated with conservation therapy by a highly standardized protocol of limited excision and radiotherapy. Radiation boost and/or reexcision were determined by careful quantitation of the normal tissue margin around the primary tumor. Boosts to 20 Gy were preferentially performed with interstitial iridium-192 (192Ir) implants. Axillary node dissections were performed in all patients aged less than 70 years. Adjuvant therapy consisted of cyclophosphamide, methotrexate, (doxorubicin), and fluorouracil (CM[A]F) six to eight times for node-positive premenopausal women and tamoxifen for node-positive or -negative postmenopausal women. Median follow-up was 50 months (range, 20 to 80 months). Cosmesis was graded by defined criteria, and complications were individually scored. RESULTS: Factors found to impact cosmesis adversely were palpable tumors (P = .046), volume of breast tissue resected (P = .027), reexcision of the tumor bed (P = .01), number of radiation fields (P = .03), radiation boost (P = .01), and chest wall separation (P = .01). There was a trend toward worse cosmesis (P = .062) in patients receiving tamoxifen. Cosmesis was not adversely affected by interstitial implant in spite of a higher prescribed dose. Factors influencing complication risk were axillary node dissection (P = .02), number of lymph nodes harvested (P = .05), and chemotherapy (P = .03). CONCLUSIONS: Optimal cosmesis and minimal complication risk require careful attention to the technical details of surgery and radiotherapy. The impact of systemic therapies needs to be more thoroughly examined.

Adult↗