Biomedical subjects

K E Rosenzweig

Publications and source records attributed to K E Rosenzweig.

At least 19 recordsLinked to original sources

PubMed2004

Response to radiation.

Computed tomography (CT) has traditionally been the standard radiographic modality for diagnosing and monitoring non-small cell; lung cancer (NSCLC) after treatment. Given the limitations of CT, the utility of 18F-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) has been investigated for the management of NSCLC, with promising findings. Its adjunctive role with CT in diagnosing and staging disease is well established. FDG-PET also has been found to be a valuable tool for radiation treatment planning because it improves the precision of lesion definition. More recently, its value for determining clinical response both during and after treatment has been explored. This review highlights the various applications of FDG-PET in the diagnosis and management of NSCLC as corroborated by clinical data, with considerations of future directions.

Carcinoma, Non-Small-Cell Lung↗

PubMed2004

Quantitation of respiratory motion during 4D-PET/CT acquisition.

We report on the variability of the respiratory motion during 4D-PET/CT acquisition. The respiratory motion for five lung cancer patients was monitored by tracking external markers placed on the abdomen. CT data were acquired over an entire respiratory cycle at each couch position. The x-ray tube status was recorded by the tracking system, for retrospective sorting of the CT data as a function of respiration phase. Each respiratory cycle was sampled in ten equal bins. 4D-PET data were acquired in gated mode, where each breathing cycle was divided into ten 500 ms bins. For both CT and PET acquisition, patients received audio prompting to regularize breathing. The 4D-CT and 4D-PET data were then correlated according to their respiratory phases. The respiratory periods, and average amplitude within each phase bin, acquired in both modality sessions were then analyzed. The average respiratory motion period during 4D-CT was within 18% from that in the 4D-PET sessions. This would reflect up to 1.8% fluctuation in the duration of each 4D-CT bin. This small uncertainty enabled good correlation between CT and PET data, on a phase-to-phase basis. Comparison of the average-amplitude within the respiration trace, between 4D-CT and 4D- PET, on a bin-by-bin basis show a maximum deviation of approximately 15%. This study has proved the feasibility of performing 4D-PET/CT acquisition. Respiratory motion was in most cases consistent between PET and CT sessions, thereby improving both the attenuation correction of PET images, and co-registration of PET and CT images. On the other hand, in two patients, there was an increased partial irregularity in their breathing motion, which would prevent accurately correlating the corresponding PET and CT images.

Biophysical Phenomena↗

PubMed2004

Four-dimensional (4D) PET/CT imaging of the thorax.

We have reported in our previous studies on the methodology, and feasibility of 4D-PET (Gated PET) acquisition, to reduce respiratory motion artifact in PET imaging of the thorax. In this study, we expand our investigation to address the problem of respiration motion in PET/CT imaging. The respiratory motion of four lung cancer patients were monitored by tracking external markers placed on the thorax. A 4D-CT acquisition was performed using a "step-and-shoot" technique, in which computed tomography (CT) projection data were acquired over a complete respiratory cycle at each couch position. The period of each CT acquisition segment was time stamped with an "x-ray ON" signal, which was recorded by the tracking system. 4D-CT data were then sorted into 10 groups, according to their corresponding phase of the breathing cycle. 4D-PET data were acquired in the gated mode, where each breathing cycle was divided into ten 0.5 s bins. For both CT and PET acquisitions, patients received audio prompting to regularize breathing. The 4D-CT and 4D-PET data were then correlated according to respiratory phase. The effect of 4D acquisition on improving the co-registration of PET and CT images, reducing motion smearing, and consequently increase the quantitation of the SUV, were investigated. Also, quantitation of the tumor motions in PET, and CT, were studied and compared. 4D-PET with matching phase 4D-CTAC showed an improved accuracy in PET-CT image co-registration of up to 41%, compared to measurements from 4D-PET with clinical-CTAC. Gating PET data in correlation with respiratory motion reduced motion-induced smearing, thereby decreasing the observed tumor volume, by as much as 43%. 4D-PET lesions volumes showed a maximum deviation of 19% between clinical CT and phase- matched 4D-CT attenuation corrected PET images. In CT, 4D acquisition resulted in increasing the tumor volume in two patients by up to 79%, and decreasing it in the other two by up to 35%. Consequently, these corrections have yielded an increase in the measured SUV by up to 16% over the clinical measured SUV, and 36% over SUV's measured in 4D-PET with clinical-CT Attenuation Correction (CTAC) SUV's. Quantitation of the maximum tumor motion amplitude, using 4D-PET and 4D-CT, showed up to 30% discrepancy between the two modalities. We have shown that 4D PET/CT is clinically a feasible method, to correct for respiratory motion artifacts in PET/CT imaging of the thorax. 4D PET/CT acquisition can reduce smearing, improve the accuracy in PET-CT co-registration, and increase the measured SUV. This should result in an improved tumor assessment for patients with lung malignancies.

Aged↗

PubMed2002

Evaluation of respiratory movement during gated radiotherapy using film and electronic portal imaging.

PURPOSE: To evaluate the effectiveness of a commercial system(1) in reducing respiration-induced treatment uncertainty by gating the radiation delivery. METHODS AND MATERIALS: The gating system considered here measures respiration from the position of a reflective marker on the patient's chest. Respiration-triggered planning CT scans were obtained for 8 patients (4 lung, 4 liver) at the intended phase of respiration (6 at end expiration and 2 at end inspiration). In addition, fluoroscopic movies were recorded simultaneously with the respiratory waveform. During the treatment sessions, gated localization films were used to measure the position of the diaphragm relative to the vertebral bodies, which was compared to the reference digitally reconstructed radiograph derived from the respiration-triggered planning CT. Variability was quantified by the standard deviation about the mean position. We also assessed the interfraction variability of soft tissue structures during gated treatment in 2 patients using an amorphous silicon electronic portal imaging device. RESULTS: The gated localization films revealed an interfraction patient-averaged diaphragm variability of 2.8 +/- 1.0 mm (error bars indicate standard deviation in the patient population). The fluoroscopic data yielded a patient-averaged intrafraction diaphragm variability of 2.6 +/- 1.7 mm. With no gating, this intrafraction excursion became 6.9 +/- 2.1 mm. In gated localization films, the patient-averaged mean displacement of the diaphragm from the planning position was 0.0 +/- 3.9 mm. However, in 4 of the 8 patients, the mean (over localization films) displacement was >4 mm, indicating a systematic displacement in treatment position from the planned one. The position of soft tissue features observed in portal images during gated treatments over several fractions showed a mean variability between 2.6 and 5.7 mm. The intrafraction variability, however, was between 0.6 and 1.4 mm, indicating that most of the variability was due to patient setup errors rather than to respiratory motion. CONCLUSIONS: The gating system evaluated here reduces the intra- and interfraction variability of anatomy due to respiratory motion. However, systematic displacements were observed in some cases between the location of an anatomic feature at simulation and its location during treatment. Frequent monitoring is advisable with film or portal imaging.

Algorithms↗

PubMed2002

Effect of respiratory gating on reducing lung motion artifacts in PET imaging of lung cancer.

Positron emission tomography (PET) has shown an increase in both sensitivity and specificity over computed tomography (CT) in lung cancer. However, motion artifacts in the 18F fluorodioxydoglucose (FDG) PET images caused by respiration persists to be an important factor in degrading PET image quality and quantification. Motion artifacts lead to two major effects: First, it affects the accuracy of quantitation, producing a reduction of the measured standard uptake value (SUV). Second, the apparent lesion volume is overestimated. Both impact upon the usage of PET images for radiation treatment planning. The first affects the visibility, or contrast, of the lesion. The second results in an increase in the planning target volume, and consequently a greater radiation dose to the normal tissues. One way to compensate for this effect is by applying a multiple-frame capture technique. The PET data are then acquired in synchronization with the respiratory motion. Reduction in smearing due to gating was investigated in both phantoms and patient studies. Phantom studies showed a dependence of the reduction in smearing on the lesion size, the motion amplitude, and the number of bins used for data acquisition. These studies also showed an improvement in the target-to-background ratio, and a more accurate measurement of the SUV. When applied to one patient, respiratory gating showed a 28% reduction in the total lesion volume, and a 56.5% increase in the SUV. This study was conducted as a proof of principle that a gating technique can effectively reduce motion artifacts in PET image acquisition.

Algorithms↗

PubMed2001

Induction chemotherapy plus three-dimensional conformal radiation therapy in the definitive treatment of locally advanced non-small-cell lung cancer.

PURPOSE: To evaluate our institution's experience using chemotherapy in conjunction with three-dimensional conformal radiation therapy (3D-CRT). METHODS AND MATERIALS: From 1991 to 1998, 152 patients with Stage III non-small-cell lung cancer (NSCLC) were treated with 3D-CRT at Memorial Sloan-Kettering Cancer Center. A total of 137 patients (90%) were surgically staged with either thoracotomy or mediastinoscopy. The remainder were staged radiographically. Seventy patients were treated with radiation therapy alone, and 82 patients received induction chemotherapy before radiation. The majority of chemotherapy-treated patients received a platinum-containing regimen. Radiation was delivered with a 3D conformal technique using CT-based treatment planning. The median dose in the radiation alone group was 70.2 Gy, while in the combined modality group, it was 64.8 Gy. RESULTS: The median follow-up time was 30.5 months among survivors. Stage IIIB disease was present in 36 patients (51%) in the radiation-alone group and 57 patients (70%) in the combined-modality group. Thirty-nine patients had poor prognostic factors (KPS < 70 or weight loss > 5%), and they were equally distributed between the two groups. The median survival times for the radiation-alone and the combined-modality groups were 11.7 months and 18.1 months, respectively (p = 0.001). The 2-year rates of local control in the radiation-alone and combined-modality groups were 35.4% and 43.1%, respectively (p = 0.1). Grade 3 or worse nonhematologic toxicity occurred in 20% of the patients receiving radiation alone and in 16% of those receiving chemotherapy and radiation. Overall, there were only 4 cases of Grade 3 or worse esophagitis. CONCLUSION: Despite more Stage IIIB patients in the combined-modality group, the addition of chemotherapy to 3D-CRT produced a survival advantage over 3D-CRT alone in Stage III NSCLC without a concomitant increase in toxicity. Chemotherapy thus appears to be beneficial, even in patients who are receiving higher doses of radiation therapy than are typically given with conventional techniques. Because locoregional failure remains a major challenge in patients with advanced disease, 3D-CRT in conjunction with chemotherapy may allow safe treatment to the dose levels required to further enhance local control.

Adult↗

PubMed2001

Elective nodal irradiation in the treatment of non-small-cell lung cancer with three-dimensional conformal radiation therapy.

PURPOSE: Dose escalation using three-dimensional conformal radiation therapy (3D-CRT) has been investigated as a means to improve local control. However, with higher doses, the risk of toxicity increases. Early in our experience, we ceased treating elective nodal areas (lymph node stations without evidence of tumor involvement) in an effort to decrease toxicity while treating the gross tumor to higher doses. This report measures the rate of regional failure without elective radiation therapy to uninvolved lymph nodes. METHODS AND MATERIALS: A total of 171 patients with non-small-cell lung cancer treated with 3D-CRT at Memorial Sloan-Kettering Cancer Center between 1991 and 1998 were reviewed. Only lymph node regions initially involved with tumor either by biopsy (55%) or radiographic criteria (node > or =15 mm in the short axis on CT) were included in the clinical target volume. Elective nodal failure was defined as a recurrence in an initially uninvolved lymph node in the absence of local failure. RESULTS: Only 11 patients (6.4%) with elective nodal failure were identified. With a median follow-up of 21 months in survivors, the 2-year actuarial rates of elective nodal control and primary tumor control were 91% and 38%, respectively. In patients who were locally controlled, the 2-year rate of elective nodal control was 85%. The median time to elective nodal failure was 4 months (range, 1-19 months). Most patients failed in multiple lymph node regions simultaneously. CONCLUSION: Local control remains one of the biggest challenges in the treatment of non-small-cell lung cancer. Most patients in our series developed local failure within 2 years of radiation therapy. The omission of elective nodal treatment did not cause a significant amount of failure in lymph node regions not included in the clinical target volume. Therefore, we will continue our policy of treating mediastinal lymph node regions only if they are clinically involved with tumor.

Adult↗

PubMed2001

Failure of a 3D conformal boost to improve radiotherapy for nasopharyngeal carcinoma.

PURPOSE: To determine whether the use of 3-dimensional (3D) boost for patients with nasopharynx cancer improves local control and reduces the risk of long-term complications. METHODS AND MATERIALS: From 1988 to 1998, 68 patients with nasopharynx cancer received conventional external beam therapy followed by a 3D boost. Disease characteristics of treated patients were as follows: WHO I histology 7%, WHO II 62%, WHO III 31%, clinical AJCC stage T1--2 45%, T3--4 55%, N0--1 63%, N2--3 37%, M0 100%. The median radiation dose was 70 Gy (68--75.6 Gy). Thirty-five patients (52%) received cisplatin-based chemotherapy. The median follow-up of surviving patients was 42 months (12--118 months). RESULTS: Five-year actuarial local control was 77%, regional control was 97%, progression-free survival was 56%, and overall survival was 58%. Stage was the only identifiable prognostic factor: 5-year progression-free survival was 65% for Stages I--III vs. 40% for Stage IV (p = 0.01). The incidence of Grade 3-4 complications was 25% and included hearing loss, trismus, dysphagia, chronic sinusitis, and cranial neuropathy. These results are comparable to outcomes reported with conventional radiation techniques for similarly staged patients. CONCLUSION: The lack of a major benefit with the 3D boost may be related to the fact that CT planning was only used for a fraction of the total dose. We are now using intensity modulated radiation therapy to deliver the entire course of radiation. Intensity modulated radiation therapy achieves better conformal distributions than conventional 3D planning, allowing dose escalation and increased normal tissue sparing.

Adolescent↗

PubMed2001

Accelerated concomitant boost radiotherapy and chemotherapy for advanced nasopharyngeal carcinoma.

PURPOSE: To evaluate the feasibility and efficacy of concomitant boost radiotherapy (RT) plus cisplatin-based chemotherapy compared with standard fractionation RT for patients with advanced nasopharyngeal cancer. PATIENTS AND METHODS: From 1988 through 1999, 50 patients with American Joint Committee on Cancer stage II-IVb nasopharyngeal carcinoma were treated with 70-Gy concomitant boost RT (1.8 Gy/d, weeks 1 through 6; 1.6 Gy second daily fraction, weeks 5 through 6) and two cycles of concurrent cisplatin 100 mg/m(2) days 1 and 22. Thirty-seven patients also received three cycles of cisplatin-based adjuvant chemotherapy. These 50 patients were compared with a nonrandomized cohort of 51 patients with nasopharyngeal cancer treated with 70-Gy standard fractionation RT (1.8 Gy/d) without chemotherapy from 1988 through 1995. The groups were well matched for prognostic factors except stage, for which the concomitant boost RT/chemotherapy group was more advanced (54%, T3-4; 54%, N2-3; 44%, stage IV) compared with the standard RT group (31%, T3-4, P =.03; 22%, N2-3, P <.001; 20%, stage IV, P <.01). RESULTS: With a median follow-up of 42 months (range, 12 to 129 months), the 3-year actuarial local control, progression-free survival, and survival rates were 89% v 74% (P <.01), 66% v 54% (P =.01), and 84% v 71% (P =.04) for the concomitant boost RT/chemotherapy group and the standard RT patients, respectively. Acute grade 3 mucositis was more prevalent with combined therapy, 84% v 43% (P <.001), resulting in a higher rate of temporary gastrostomy tube placement, 46% v 20% (P <.01). CONCLUSION: Concomitant boost RT with cisplatin-based chemotherapy is feasible and improves local-regional control as well as survival for patients with advanced nasopharyngeal cancer compared with standard RT alone.

Adolescent↗

PubMed2001

Three-dimensional conformal radiation therapy (3D-CRT) for early-stage non-small-cell lung cancer.

The standard treatment for early-stage non-small-cell lung cancer is surgical resection. However, many patients are inoperable due to medical comorbidities. Thirty-two medically inoperable patients with early-stage non-small-cell lung cancer were treated with 3-dimensional conformal radiation therapy between January 1991 and December 2000. The median dose was 70.2 Gy, and the median follow-up time in survivors was 30 months. The 2-year actuarial local control, overall survival, and cancer-specific survival rates were 43%, 54%, and 57%, respectively. The 5-year actuarial local control, overall survival, and cancer-specific survival rates were 43%, 33%, and 39%, respectively. This report suggests that local control is improved with high-dose conformal radiation therapy when compared to other institutions' retrospective experiences.

Journal Article↗

PubMed2000

Technical aspects of the deep inspiration breath-hold technique in the treatment of thoracic cancer.

PURPOSE: The goal of this paper is to describe our initial experience with the deep inspiration breath-hold (DIBH) technique in conformal treatment of non-small-cell lung cancer with particular emphasis on the technical aspects required for implementation. METHODS AND MATERIALS: In the DIBH technique, the patient is verbally coached through a modified slow vital capacity maneuver and brought to a reproducible deep inspiration breath-hold level. The goal is to immobilize the tumor and to expand normal lung out of the high-dose region. A physicist or therapist monitors and records patient breathing during simulation, verification, and treatment using a spirometer with a custom computer interface. Examination of internal anatomy during fluoroscopy over multiple breath holds establishes the reproducibility of the DIBH maneuver for each patient. A reference free-breathing CT scan and DIBH planning scan are obtained. To provide an estimate of tumor motion during normal tidal breathing, additional scan sets are obtained at end inspiration and end expiration. These are also used to set the spirometer action levels for treatment. Patient lung inflation is independently verified over the course of treatment by comparing the distance from the isocenter to the diaphragm measured from the DIBH digitally reconstructed radiographs to the distance measured on the portal films. Patient breathing traces obtained during treatment were examined retrospectively to assess the reproducibility of the technique. RESULTS: Data from the first 7 patients, encompassing over 250 treatments, were analyzed. The inferred displacement of the centroid of gross tumor volume from its position in the planning scan, as calculated from the spirometer records in over 350 breath holds was 0.02 +/- 0.14 cm (mean and standard deviation). These data are consistent with the displacements of the diaphragm (-0.1 +/- 0.4 cm; range, from -1.2 to 1.1 cm) relative to the isocenter, as measured on the (92) portal films. The latter measurements include the patient setup error. The patient averaged displacement of the tumor during free breathing, determined from the tumor displacement between end inspiration and end expiration, was 0.8 +/- 0.5 cm in both the superior-inferior and anterior-posterior directions and 0.1 cm (+/- 0.1 cm) medial-laterally. CONCLUSION: Treatment of patients with the DIBH technique is feasible in a clinical setting. With this technique, consistent lung inflation levels are achieved in patients, as judged by both spirometry and verification films. Breathing-induced tumor motion is significantly reduced using DIBH compared to free breathing, enabling better target coverage.

Carcinoma, Non-Small-Cell Lung↗

PubMed2000

The deep inspiration breath-hold technique in the treatment of inoperable non-small-cell lung cancer.

PURPOSE: Conventional radiotherapeutic techniques are associated with lung toxicity that limits the treatment dose. Motion of the tumor during treatment requires the use of large safety margins that affect the feasibility of treatment. To address the control of tumor motion and decrease the volume of normal lung irradiated, we investigated the use of three-dimensional conformal radiation therapy (3D-CRT) in conjunction with the deep inspiration breath-hold (DIBH) technique. METHODS AND MATERIALS: In the DIBH technique, the patient is initially maintained at quiet tidal breathing, followed by a deep inspiration, a deep expiration, a second deep inspiration, and breath-hold. At this point the patient is at approximately 100% vital capacity, and simulation, verification, and treatment take place during this phase of breath-holding. RESULTS: Seven patients have received a total of 164 treatment sessions and have tolerated the technique well. The estimated normal tissue complication probabilities decreased in all patients at their prescribed dose when compared to free breathing. The dose to which patients could be treated with DIBH increased on average from 69.4 Gy to 87.9 Gy, without increasing the risk of toxicity. CONCLUSIONS: The DIBH technique provides an advantage to conventional free-breathing treatment by decreasing lung density, reducing normal safety margins, and enabling more accurate treatment. These improvements contribute to the effective exclusion of normal lung tissue from the high-dose region and permit the use of higher treatment doses without increased risks of toxicity.

Carcinoma, Non-Small-Cell Lung↗

PubMed2000

Use of PET to monitor the response of lung cancer to radiation treatment.

Approximately 170,000 people are diagnosed with lung cancer in the United States each year. Many of these patients receive external beam radiation for treatment. Fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is increasingly being used in evaluating non-small cell lung cancer and may be of clinical utility in assessing response to treatment. In this report, we present FDG PET images and data from two patients who were followed with a total of eight and seven serial FDG PET scans, respectively, through the entire course of their radiation therapy. Changes in several potential response parameters are shown versus time, including lesion volume (V(FDG)) by PET, SUVav, SUVmax, and total lesion glycolysis (TLG) during the course of radiotherapy. The response parameters for patient 1 demonstrated a progressive decrease; however, the response parameters for patient 2 showed an initial decrease followed by an increase. The data presented here may suggest that the outcome of radiation therapy can be predicted by PET imaging, but this observation requires a study of additional patients.

Aged↗

PubMed1999

Induction chemotherapy employing dose-intense cisplatin with mitomycin and vinblastine (MVP400), followed by thoracic surgery or irradiation, for patients with stage III nonsmall cell lung carcinoma.

BACKGROUND: Cisplatin-based induction chemotherapy before surgery or irradiation has improved the survival of patients with Stage III nonsmall cell lung carcinoma (NSCLC). Encouraged by earlier results with preoperative MVP (cisplatin [120 mg/m(2) or 25 mg/m(2)/week], vinblastine, and mitomycin) for Stage IIIA patients with clinically apparent mediastinal (N2) disease, the authors conducted a Phase II trial of the safety and efficacy of induction MVP400 with the dose intensity of cisplatin doubled from 25 to 50 mg/m(2) per week. METHODS: From October 1992 to March 1996, 37 patients with Stage IIIA (26) or Stage IIIB (11) NSCLC began the MVP400 induction chemotherapy program. Four doses of cisplatin (100 mg/m(2)), 7 doses of vinblastine, and 2 doses of mitomycin were given over 9 weeks. Patients received either surgery or irradiation after induction treatment. RESULTS: Overall, the response rate was 65% (95% confidence interval, 49-81%) with a complete resection rate of 67%. The median survival was 17 months, with 66% of patients alive at 1 year. Complete resection and Stage IIIA involvement were favorable prognostic indicators for survival. No Stage IIIB patients underwent a complete resection. Myelosuppression was the most common side effect. There were no treatment-related deaths. CONCLUSIONS: Although high response and complete resection rates were again demonstrated, results with the MVP400 regimen were not improved over those achieved with MVP regimen tested earlier with Stage IIIA (N2) patients. The authors continue to recommend MVP as an induction chemotherapy regimen for clinical trials.

Adult↗

PubMed1997

Diabetes insipidus secondary to Langerhans' cell histiocytosis: is radiation therapy indicated?

Langerhans' cell histiocytosis (LCH) is a proliferative disease of Langerhans' cells that has multiple clinical manifestations including diabetes insipidus (DI). This study reviews the effectiveness of hypothalamic-pituitary radiation therapy (HPRT) as a treatment of LCH-induced DI in the modern era. A retrospective review was done of 116 pediatric patients with LCH seen from 1975 to 1992. Seventeen of the 116 patients (15%) were diagnosed with complete or partial diabetes insipidus. Diagnosis was made either by water deprivation test or on clinical grounds. Fourteen patients received hypothalamic-pituitary irradiation as treatment for DI. The median interval from the onset of DI symptoms (polyuria and polydipsia) to treatment was 30 days. The median interval from the onset of diagnosis to treatment was 4 days. With a mean follow-up of 7.3 years (range, 2.4-14.3), only two patients had a complete response to therapy, as defined as no need for antidiuretic hormone (ADH) replacement therapy. No patient had a partial response, defined as a decrease in the dose of ADH replacement. Of the two responders, neither had a complete ADH deficiency, suggesting "early" disease. In addition, both received RT within 3 days. We feel that the standard treatment of RT to all patients with LCH-induced DI is no longer justified. Our series has shown no benefit in treating patients with a long history of DI. Rather, an improved rationale would be rapid initiation of hypothalamic-pituitary irradiation in patients with new symptoms of DI and an abnormal water deprivation test.

Adolescent↗

PubMed1997

Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay.

Members of the phosphatidylinositol (PI) 3-kinase gene family, including the ataxia telangiectasia gene and the DNA-dependent protein kinase (DNA-PK), are involved in regulating cellular radiosensitivity. We have investigated two structurally unrelated PI 3-kinase inhibitors, wortmannin and LY294002, to determine whether they inhibit DNA-PK and increase cellular radiosensitivity. The PI 3-kinase inhibitors wortmannin and LY294002 were effective radiosensitizers of human tumor cells, with sensitizer enhancement ratios (at 10% survival) of 2.8 and 1.9, respectively, in SW480 cells. Wortmannin and LY294002 inhibited the kinase activity of purified DNA-PK and inactivated cellular DNA-PK kinase activity. Inhibition of cellular DNA-PK activity occurred at the same concentrations of wortmannin that caused radiosensitization, and this correlation was found in a range of tumor cell lines. However, cells deficient in either DNA-PK (scid cells) or the ataxia telangiectasia protein were also partly sensitized to radiation by wortmannin, indicating the involvement of more than one protein kinase in the mechanism of action of wortmannin. Wortmannin also affected the G2-M checkpoint. SW480 cells had a reversible G2-M delay of 20 h following irradiation. However, wortmannin-treated SW480 cells had a prolonged G2-M delay; more than 75% of cells were arrested in G2 at 50 h postirradiation. This suggests the accumulation of significant unrepaired DNA damage following inhibition of PI 3-kinase family members. Therefore, PI 3-kinase inhibitors may represent a new class of radiosensitizers that inhibit the repair of DNA damage.

Androstadienes↗

PubMed1995

Prostate specific antigen following radiotherapy for local prostate cancer.

The clinical recurrence-free survival rates were compared to the combined clinical and biochemical recurrence-free survival rates in 285 patients with stages A2 (T1b), B (T2) and C (T3) prostate cancer treated with radiation therapy. For stages A2 (T1b) and B (T2) disease the 10-year clinical recurrence-free survival rate was 48% and the corresponding 10-year clinical and biochemical recurrence-free survival rate was 33%. For stage C (T3) disease these rates were 33% and 22%, respectively. These results demonstrate that approximately a third of the patients who are considered recurrence-free by standard clinical criteria at 10 years after radiation therapy have elevated prostate specific antigen values and are at significant risk for later clinical failure.

Actuarial Analysis↗

PubMed1992

Molecular cascades in UV-induced melanogenesis: a central role for melanotropins?

When human skin is exposed to ultraviolet (UV) light, a highly complex cascade of events ensues that culminates, among other things, in increased skin melanin content. From analyses at the tissue and cellular level, it has been shown that following exposure to UV light there is an increase in the number of active melanocytes in the basal layer of the epidermis, and individual melanocytes are stimulated to produce more melanin. In addition, the rate of transfer of melanosomes from melanocytes to keratinocytes is apparently increased, although the role of UV light in this process remains to be demonstrated. Recent biochemical evidence is reviewed on factors that regulate these processes. A plausible explanation for the effects of UV on pigmentation is that there are mechanisms in the skin for the orderly, regulated reception of UV signals that are then transduced to initiate the cascade. The signals involve both melanocytes and keratinocytes, and available evidence supports a model in which melanotropins and their receptors play a central role in the process.

Humans↗