There are qualitative and quantitative differences in the biological damage observed after exposu... more There are qualitative and quantitative differences in the biological damage observed after exposure to high LET radiation as compared to that caused by low LET radiations. This review is concerned with these differences, which are ultimately reflected at the biochemical, cellular and even whole animal levels. In general, high LET radiations seem to produce biochemical damage which is more severe and possibly less repairable. Experimental data for those effects are presented in terms of biochemical RBE's with consideration of both early and late manifestations. An LET independent process by which significant biochemical damage may result from protons, neutrons and negative pion mesons is discussed.
A retrospective comparison of treatment policies in two institutions revealed a change in the rel... more A retrospective comparison of treatment policies in two institutions revealed a change in the reliance on radiotherapy. Since 1978, high-energy, high-dosage radiotherapy has played a prominent role in the primary therapy of squamous cell carcinoma of the supraglottic larynx. Statistically, the overall determinate survival rate has improved compared with results during the preceding period, but the death rate from intercurrent disease and second primary cancers has remained unchanged. Improved cancer control and patient survival were restricted to clinical tumor stages III, T4N0, and T4N1. The choice of primary therapy and the radiation dose and fractionation pattern were important variables influencing the survival. A description of the data is followed by a critical analysis of the significance of the findings, in view of the fact that the treatments were performed in two different institutions at different time periods.
We compared two groups of patients with squamous cell carcinoma of the larynx. Group 1 consisted ... more We compared two groups of patients with squamous cell carcinoma of the larynx. Group 1 consisted of 483 patients treated from 1958 through 1978. Primary surgery was selected in 41%, pre-or postoperative radiation therapy in 16% and primary radiation therapy in 43%. Group 2 consisted of 247 patients treated from 1978 through 1983. Primary surgery was selected in only 1.6%, pre-or postoperative radiation therapy in 23%, and primary radiation therapy, with surgery in reserve for residual or recurrent carcinoma, in 76%. Although the results were comparable for patients with early stage tumors in the two groups, significantly higher local-regional tumor control rates and corrected survival rates were recorded for patients with advanced tumors in group 2. More patients survived with a cancer-free functional larynx, the surgical salvage rates were higher, the complication rates and the death rates lower in group 2 compared to group 1.
Approximately 20 mg/kg was found to be-the LD 56 dose for mice. Human doses were always kept belo... more Approximately 20 mg/kg was found to be-the LD 56 dose for mice. Human doses were always kept below 5 ,ug/kg. SKELETAL SCANS Bone scans were performed with 1-2 mCi of 135mBa containing 0.1-0.3 mg Ba. Rapid whole-body scanning was done serially at two, six, twenty-four, forty-eight, and seventy-two hr. Gastrointestinal activity interfered with scanning of the pelvic region but was seen predominantly in the colon in later scans. Figure 2 shows two-hour and two-day scans of a patient interpreted as normal. Optimal scans were obtained between one and two days with the use of a laxative to evacuate the bowel. The 268-keV photons were suitable for imaging with the gamma camera. Figure 3 shows a camera image obtained at forty-eight hours, showing lesions of the thoracic spine. DISCUSSION To achieve its potential role in medicine, bone scanning requires a new agent with advantages over those presently available. It should allow rapid whole-body scanning with a reduced radiation dose for the detection of early bone lesions. Barium 135m has not solved these problems, but it may be the current agent of choice.
Micronuclei (MN) production in the peripheral blood T-lymphocytes of patients receiving pelvic ra... more Micronuclei (MN) production in the peripheral blood T-lymphocytes of patients receiving pelvic radiotherapy for localized prostate cancer increases with increasing integral radiation dose to the prostate/pelvic area, thereby demonstrating a linear, in vivo, clinical dose response relationship for this biological dosimetry system. Use of this lymphocyte assay system may have practical implications to evaluating and monitoring of treatment planning by encouraging conformal radiation therapy techniques in order to decrease systemic toxicity to the patient's immune system from pelvic radiotherapy.
Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology, 1993
We investigated the variations in DNA ploidy by flow cytometry (FC) among cell suspensions acquir... more We investigated the variations in DNA ploidy by flow cytometry (FC) among cell suspensions acquired by different disaggregation methods from the same tumor specimens. Cell suspensions (n = 121) of 40 solid tumors were obtained by mechanical mincing (n = 33), enzymatic digestion (n = 19), in vitro fine needle aspiration (FNA) (n = 34) or scraping (n = 35) of the tumor tissues. Mechanical disaggregation gave the highest cell yield, whereas enzymatic digestion provided the best cell viability. The mean values for the G0/G1 coefficient of variation, DNA indices and percent S phase were not significantly different in cell suspensions obtained with the four methods. However, the yield of malignant cells ranged from 60.4 +/- 5.3% (SEM) (enzymatic) to 82.3 +/- 3.1% (scraping). Tissue aliquots of 32 tumors were disaggregated by three to four methods, and the combined results of DNA ploidy obtained from different cell preparations showed that 22 tumors were nondiploid, but concordance with an...
A technique employing serial ultrasonic B-scans and a computer for measuring volumes of internal ... more A technique employing serial ultrasonic B-scans and a computer for measuring volumes of internal anatomical structures is described. Phantom studies indicate that this method is accurate to within 5% for phantom volumes in the 200-2000 ern" range. The technique was applied to monitor the spleen-tumor volume in a patient with chronic lymphocytic leukemia and the liver-tumor volume in a patient with retroperitoneal rhabdomyosarcoma. The data suggest that the method is clinically useful for determining normal organ and tumor volumes and for evaluating response to therapy.
Archives of Otolaryngology - Head and Neck Surgery, 1975
As an attemp to improve the quantitative and qualitative evaluation of neoplastic neck nodes, we ... more As an attemp to improve the quantitative and qualitative evaluation of neoplastic neck nodes, we are evaluating ultrasound B-scans. Clinical examples are presented to demonstrate how "B-scans" may be used to evaluate lymph node size and response to therapy. Qualitatively, such scans may also be of value as a means of establishing lymph node boundaries and position with respect to other neck structures.
Retrospective analysis of patient records at two hospitals was performed with the principal goal ... more Retrospective analysis of patient records at two hospitals was performed with the principal goal of clarifying the role of primary radiotherapy in patients with squamous cell carcinoma of the supraglottic larynx. Primary surgery was frequently performed during the first period from 1958 to 1978. Primary radiotherapy with surgery in reserve was the prevailing therapy during the second period from 1978 to 1993. Fewer recurrences were observed during the second period. The improved results were apparent mainly in patients with the more advanced stages (III, T4N0 and T4N1). Analysis of many factors suggest that the more frequent choice of primary radiotherapy with surgery in reserve, or applied as preoperative treatment, with optimal dosage and technique, might have contributed to the improved results.
Since subclinical hepatic metastases are frequently present at time of diagnosis of pancreatic ca... more Since subclinical hepatic metastases are frequently present at time of diagnosis of pancreatic carcinoma, any meaningful effort to improve survival must include 'prophylactic' liver therapy in addition to treatment of the pancreatic primary. We report the results of a prospective, unrandomized clinical trial of a 2-week liver and pancreas infusion (by hepatic artery) of 5-fluorouracil (5-FU) and pancreatic irradiation to 50-60 Gy, combined with prophylactic irradiation of the liver with approximately 20 Gy. Of 21 evaluable patients, 17 completed therapy without excessive toxicity and had a median survival of 50 weeks. Contrary to historical controls, the liver in our series was rarely the first site of failure (6%), suggesting that the combination of hepatic artery 5-fluorouracil and 20 Gy liver radiation may suppress subclinical (microscopic) liver metastases without significant hepato-toxicity. When radiation doses to the pancreas were increased above 50 Gy there was improvement in primary tumor control, although failure in the pancreatic bed remained the most common site of failure. Future clinical investigation of this form of combined therapy for eradication of micro-metastasis in the liver, combined with more aggressive local pancreatic therapy, would seem appropriate.
The acute radiation syndrome (ARS) occurs after whole-body or significant partial-body irradiatio... more The acute radiation syndrome (ARS) occurs after whole-body or significant partial-body irradiation (typically at a dose of >1Gy). ARS can involve the hematopoietic, cutaneous, gastrointestinal and the neurovascular organ systems either individually or in combination.There is a correlation between the severity of clinical signs and symptoms of ARS and radiation dose. Radiation induced multi-organ failure (MOF) describes the progressive dysfunction
15540 Background: Since formation of micronuclei (MN) in interphase cells is a reflection of DNA ... more 15540 Background: Since formation of micronuclei (MN) in interphase cells is a reflection of DNA damage, it has been postulated that enhanced peripheral blood lymphocytes (PBL) radiosensitivity might correlate with the development of radiation morbidity. Methods: We conducted the cytokinesis-block (CB) MN assay of PBL in 54 prostate cancer (PC) patients ( mean age ± SEM: 68 ± 1.6 yrs) who had no previous exposure to cytotoxic agents. Patients received standardized pelvic radiotherapy (RT) (41.4 -50.4 Gy) with mean follow-up of 29.1± 3.3 mos. Blood samples were drawn before RT and at designated intervals after RT initiation. Gastrointestinal (GI) and genitourinary (GU) morbidity were determined using RTOG criteria. Results: Average reactors (AR, n = 14) were defined as patients who did not develop morbidity. Grade 1 (G1R, n = 19) and Grade 2 reactors (G2R, n = 21) were defined as those who developed Grade 1 or Grade 2 GI or GU morbidity, respectively. Results of the MN yield in PBL b...
One primary goal of preoperative radiotherapy for hypernephroma is to reduce the volume of tumor ... more One primary goal of preoperative radiotherapy for hypernephroma is to reduce the volume of tumor and, therefore, improve the possibility of resection. It is important that this goal be accomplished promptly so that 4 to 6 weeks after radiation therapy nephrectomy can be attempted. A longer waiting period may allow fibrosis of the normal surrounding tissues and make surgery more difficult. In addition, longer waiting periods could theoretically increase the probability of metastasis. Therefore, we plan to continue clinical investigation on the use of combined intra-arterial actinomycin D and radiotherapy as a possible useful means of improving the possibility of prompt surgical resection, since theoretically this regimen may be a method of increasing the effective radiation dose to the hypernephroma without increasing the effective radiation dose to surrounding normal tissue, such as bowel. The method may also have merit as an improved means of palliating selected patients with metastases who are symptomatic from a bulky primary hypernephroma.
Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis, 1968
SHORT COMMUNICATIONS cleases (Fig. I). Kinetin however, completely reversed the abscisin II effec... more SHORT COMMUNICATIONS cleases (Fig. I). Kinetin however, completely reversed the abscisin II effect and retarded senescence so that the activity of chromatin-associated nucleases in leaves floated on abscisin II plus kinetin was drastically suppressed and was comparable to the activity of these enzymes in barley leaves floated on kinetin alone 4. The increase of chromatin-associated nucleases in barley leaves by abscisin II and its reversal by kinetin suggest that many effects z,3,~,s of abscisin II which are reversed by cytokinins could also be explained on the basis of the effect of abscisin II and cytokinins on chromatin-associated nucleases. Whether other nuclear enzymes are also influenced by abscisin II and cytokinins, however, remains to be determined.
The liver is a common first site of metastatic involvement of colorectal adenocarcinoma. Progress... more The liver is a common first site of metastatic involvement of colorectal adenocarcinoma. Progressive hepatic destruction and eventual failure to control metastatic disease are responsible for 25%–33% of the 20 000 deaths each year in the United States from this tumor [6, 12]. Clinical trials utilizing systemic 5-fluorouracil (5-FU) for colorectal metastases began at the University of Wisconsin shortly after the discovery of this drug in 1957 [11]. Response rates of up to 20% were observed following systemic administration; however, systemic 5-FU administration was limited by toxicity, including mucositis, diarrhea, and myelosuppression. In addition, progressive hepatic disease continued to be a major cause of clinical failure [1,4].
There are qualitative and quantitative differences in the biological damage observed after exposu... more There are qualitative and quantitative differences in the biological damage observed after exposure to high LET radiation as compared to that caused by low LET radiations. This review is concerned with these differences, which are ultimately reflected at the biochemical, cellular and even whole animal levels. In general, high LET radiations seem to produce biochemical damage which is more severe and possibly less repairable. Experimental data for those effects are presented in terms of biochemical RBE's with consideration of both early and late manifestations. An LET independent process by which significant biochemical damage may result from protons, neutrons and negative pion mesons is discussed.
A retrospective comparison of treatment policies in two institutions revealed a change in the rel... more A retrospective comparison of treatment policies in two institutions revealed a change in the reliance on radiotherapy. Since 1978, high-energy, high-dosage radiotherapy has played a prominent role in the primary therapy of squamous cell carcinoma of the supraglottic larynx. Statistically, the overall determinate survival rate has improved compared with results during the preceding period, but the death rate from intercurrent disease and second primary cancers has remained unchanged. Improved cancer control and patient survival were restricted to clinical tumor stages III, T4N0, and T4N1. The choice of primary therapy and the radiation dose and fractionation pattern were important variables influencing the survival. A description of the data is followed by a critical analysis of the significance of the findings, in view of the fact that the treatments were performed in two different institutions at different time periods.
We compared two groups of patients with squamous cell carcinoma of the larynx. Group 1 consisted ... more We compared two groups of patients with squamous cell carcinoma of the larynx. Group 1 consisted of 483 patients treated from 1958 through 1978. Primary surgery was selected in 41%, pre-or postoperative radiation therapy in 16% and primary radiation therapy in 43%. Group 2 consisted of 247 patients treated from 1978 through 1983. Primary surgery was selected in only 1.6%, pre-or postoperative radiation therapy in 23%, and primary radiation therapy, with surgery in reserve for residual or recurrent carcinoma, in 76%. Although the results were comparable for patients with early stage tumors in the two groups, significantly higher local-regional tumor control rates and corrected survival rates were recorded for patients with advanced tumors in group 2. More patients survived with a cancer-free functional larynx, the surgical salvage rates were higher, the complication rates and the death rates lower in group 2 compared to group 1.
Approximately 20 mg/kg was found to be-the LD 56 dose for mice. Human doses were always kept belo... more Approximately 20 mg/kg was found to be-the LD 56 dose for mice. Human doses were always kept below 5 ,ug/kg. SKELETAL SCANS Bone scans were performed with 1-2 mCi of 135mBa containing 0.1-0.3 mg Ba. Rapid whole-body scanning was done serially at two, six, twenty-four, forty-eight, and seventy-two hr. Gastrointestinal activity interfered with scanning of the pelvic region but was seen predominantly in the colon in later scans. Figure 2 shows two-hour and two-day scans of a patient interpreted as normal. Optimal scans were obtained between one and two days with the use of a laxative to evacuate the bowel. The 268-keV photons were suitable for imaging with the gamma camera. Figure 3 shows a camera image obtained at forty-eight hours, showing lesions of the thoracic spine. DISCUSSION To achieve its potential role in medicine, bone scanning requires a new agent with advantages over those presently available. It should allow rapid whole-body scanning with a reduced radiation dose for the detection of early bone lesions. Barium 135m has not solved these problems, but it may be the current agent of choice.
Micronuclei (MN) production in the peripheral blood T-lymphocytes of patients receiving pelvic ra... more Micronuclei (MN) production in the peripheral blood T-lymphocytes of patients receiving pelvic radiotherapy for localized prostate cancer increases with increasing integral radiation dose to the prostate/pelvic area, thereby demonstrating a linear, in vivo, clinical dose response relationship for this biological dosimetry system. Use of this lymphocyte assay system may have practical implications to evaluating and monitoring of treatment planning by encouraging conformal radiation therapy techniques in order to decrease systemic toxicity to the patient's immune system from pelvic radiotherapy.
Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology, 1993
We investigated the variations in DNA ploidy by flow cytometry (FC) among cell suspensions acquir... more We investigated the variations in DNA ploidy by flow cytometry (FC) among cell suspensions acquired by different disaggregation methods from the same tumor specimens. Cell suspensions (n = 121) of 40 solid tumors were obtained by mechanical mincing (n = 33), enzymatic digestion (n = 19), in vitro fine needle aspiration (FNA) (n = 34) or scraping (n = 35) of the tumor tissues. Mechanical disaggregation gave the highest cell yield, whereas enzymatic digestion provided the best cell viability. The mean values for the G0/G1 coefficient of variation, DNA indices and percent S phase were not significantly different in cell suspensions obtained with the four methods. However, the yield of malignant cells ranged from 60.4 +/- 5.3% (SEM) (enzymatic) to 82.3 +/- 3.1% (scraping). Tissue aliquots of 32 tumors were disaggregated by three to four methods, and the combined results of DNA ploidy obtained from different cell preparations showed that 22 tumors were nondiploid, but concordance with an...
A technique employing serial ultrasonic B-scans and a computer for measuring volumes of internal ... more A technique employing serial ultrasonic B-scans and a computer for measuring volumes of internal anatomical structures is described. Phantom studies indicate that this method is accurate to within 5% for phantom volumes in the 200-2000 ern" range. The technique was applied to monitor the spleen-tumor volume in a patient with chronic lymphocytic leukemia and the liver-tumor volume in a patient with retroperitoneal rhabdomyosarcoma. The data suggest that the method is clinically useful for determining normal organ and tumor volumes and for evaluating response to therapy.
Archives of Otolaryngology - Head and Neck Surgery, 1975
As an attemp to improve the quantitative and qualitative evaluation of neoplastic neck nodes, we ... more As an attemp to improve the quantitative and qualitative evaluation of neoplastic neck nodes, we are evaluating ultrasound B-scans. Clinical examples are presented to demonstrate how "B-scans" may be used to evaluate lymph node size and response to therapy. Qualitatively, such scans may also be of value as a means of establishing lymph node boundaries and position with respect to other neck structures.
Retrospective analysis of patient records at two hospitals was performed with the principal goal ... more Retrospective analysis of patient records at two hospitals was performed with the principal goal of clarifying the role of primary radiotherapy in patients with squamous cell carcinoma of the supraglottic larynx. Primary surgery was frequently performed during the first period from 1958 to 1978. Primary radiotherapy with surgery in reserve was the prevailing therapy during the second period from 1978 to 1993. Fewer recurrences were observed during the second period. The improved results were apparent mainly in patients with the more advanced stages (III, T4N0 and T4N1). Analysis of many factors suggest that the more frequent choice of primary radiotherapy with surgery in reserve, or applied as preoperative treatment, with optimal dosage and technique, might have contributed to the improved results.
Since subclinical hepatic metastases are frequently present at time of diagnosis of pancreatic ca... more Since subclinical hepatic metastases are frequently present at time of diagnosis of pancreatic carcinoma, any meaningful effort to improve survival must include 'prophylactic' liver therapy in addition to treatment of the pancreatic primary. We report the results of a prospective, unrandomized clinical trial of a 2-week liver and pancreas infusion (by hepatic artery) of 5-fluorouracil (5-FU) and pancreatic irradiation to 50-60 Gy, combined with prophylactic irradiation of the liver with approximately 20 Gy. Of 21 evaluable patients, 17 completed therapy without excessive toxicity and had a median survival of 50 weeks. Contrary to historical controls, the liver in our series was rarely the first site of failure (6%), suggesting that the combination of hepatic artery 5-fluorouracil and 20 Gy liver radiation may suppress subclinical (microscopic) liver metastases without significant hepato-toxicity. When radiation doses to the pancreas were increased above 50 Gy there was improvement in primary tumor control, although failure in the pancreatic bed remained the most common site of failure. Future clinical investigation of this form of combined therapy for eradication of micro-metastasis in the liver, combined with more aggressive local pancreatic therapy, would seem appropriate.
The acute radiation syndrome (ARS) occurs after whole-body or significant partial-body irradiatio... more The acute radiation syndrome (ARS) occurs after whole-body or significant partial-body irradiation (typically at a dose of >1Gy). ARS can involve the hematopoietic, cutaneous, gastrointestinal and the neurovascular organ systems either individually or in combination.There is a correlation between the severity of clinical signs and symptoms of ARS and radiation dose. Radiation induced multi-organ failure (MOF) describes the progressive dysfunction
15540 Background: Since formation of micronuclei (MN) in interphase cells is a reflection of DNA ... more 15540 Background: Since formation of micronuclei (MN) in interphase cells is a reflection of DNA damage, it has been postulated that enhanced peripheral blood lymphocytes (PBL) radiosensitivity might correlate with the development of radiation morbidity. Methods: We conducted the cytokinesis-block (CB) MN assay of PBL in 54 prostate cancer (PC) patients ( mean age ± SEM: 68 ± 1.6 yrs) who had no previous exposure to cytotoxic agents. Patients received standardized pelvic radiotherapy (RT) (41.4 -50.4 Gy) with mean follow-up of 29.1± 3.3 mos. Blood samples were drawn before RT and at designated intervals after RT initiation. Gastrointestinal (GI) and genitourinary (GU) morbidity were determined using RTOG criteria. Results: Average reactors (AR, n = 14) were defined as patients who did not develop morbidity. Grade 1 (G1R, n = 19) and Grade 2 reactors (G2R, n = 21) were defined as those who developed Grade 1 or Grade 2 GI or GU morbidity, respectively. Results of the MN yield in PBL b...
One primary goal of preoperative radiotherapy for hypernephroma is to reduce the volume of tumor ... more One primary goal of preoperative radiotherapy for hypernephroma is to reduce the volume of tumor and, therefore, improve the possibility of resection. It is important that this goal be accomplished promptly so that 4 to 6 weeks after radiation therapy nephrectomy can be attempted. A longer waiting period may allow fibrosis of the normal surrounding tissues and make surgery more difficult. In addition, longer waiting periods could theoretically increase the probability of metastasis. Therefore, we plan to continue clinical investigation on the use of combined intra-arterial actinomycin D and radiotherapy as a possible useful means of improving the possibility of prompt surgical resection, since theoretically this regimen may be a method of increasing the effective radiation dose to the hypernephroma without increasing the effective radiation dose to surrounding normal tissue, such as bowel. The method may also have merit as an improved means of palliating selected patients with metastases who are symptomatic from a bulky primary hypernephroma.
Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis, 1968
SHORT COMMUNICATIONS cleases (Fig. I). Kinetin however, completely reversed the abscisin II effec... more SHORT COMMUNICATIONS cleases (Fig. I). Kinetin however, completely reversed the abscisin II effect and retarded senescence so that the activity of chromatin-associated nucleases in leaves floated on abscisin II plus kinetin was drastically suppressed and was comparable to the activity of these enzymes in barley leaves floated on kinetin alone 4. The increase of chromatin-associated nucleases in barley leaves by abscisin II and its reversal by kinetin suggest that many effects z,3,~,s of abscisin II which are reversed by cytokinins could also be explained on the basis of the effect of abscisin II and cytokinins on chromatin-associated nucleases. Whether other nuclear enzymes are also influenced by abscisin II and cytokinins, however, remains to be determined.
The liver is a common first site of metastatic involvement of colorectal adenocarcinoma. Progress... more The liver is a common first site of metastatic involvement of colorectal adenocarcinoma. Progressive hepatic destruction and eventual failure to control metastatic disease are responsible for 25%–33% of the 20 000 deaths each year in the United States from this tumor [6, 12]. Clinical trials utilizing systemic 5-fluorouracil (5-FU) for colorectal metastases began at the University of Wisconsin shortly after the discovery of this drug in 1957 [11]. Response rates of up to 20% were observed following systemic administration; however, systemic 5-FU administration was limited by toxicity, including mucositis, diarrhea, and myelosuppression. In addition, progressive hepatic disease continued to be a major cause of clinical failure [1,4].
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Papers by Albert L Wiley