Interactions of pyrethroids with phosphatidylcholine liposomal membranes.

Interactions of several pyrethroids with membrane lipids in the form of dipalmitoylphosphatidylcholine (DPPC) liposomes have been studied using fluorescent membrane probes. Fluorescence anisotropy values and lifetimes (determined by phase-shift and demodulation techniques) of the fluorescent probe, 1,6-diphenyl-1,3,5-hexatriene, were decreased in gel phase liposomes by pyrethroids at concentrations on the order of 10 microM. The pyrethroids containing a cyano substituent were also observed to cause collisional quenching of diphenylhexatriene fluorescence. Pyrethroids differed in their effectiveness at lowering the phase transition temperature of DPPC, and in their ability to broaden the temperature range of this transition. The fluorescence intensity of DPPC-incorporated chlorophyll a was used to monitor the pretransition of DPPC and the lateral diffusion of a membrane component located in the polar headgroup region. Permethrin did not affect chlorophyll a fluorescence intensity at any temperature. It may be concluded from these results that pyrethroids are preferentially located in the interior hydrophobic regions of the lipid bilayer, and that these compounds can disorder hydrocarbon packing in the bilayer core. However, polar headgroups were not disordered, and diffusion of membrane components in the polar headgroup region was not altered.

Interactions of pyrethroids with gramicidin-containing liposomal membranes.

Fluorescence steady-state anisotropy and phase-modulation lifetime techniques have been utilized to study the interactions of pyrethroid compounds with fluid-phase phosphatidylcholine membranes containing the polypeptide gramicidin. This polypeptide is considered to be a model of hydrophobic regions of cellular integral membrane proteins. The pyrethroids disorder lipid packing in cellular membranes and gel-phase liposomes but do not disorder lipid packing in fluid-phase lipid (Stelzer, K.J. and Gordon, M.A. (1984) J. Immunopharmacol. 6, 381-410; (1985) Biochim. Biophys. Acta 812, 361-368) Irrespective of liposomal size, gramicidin incorporation resulted in a substantial increase in anisotropy of the fluorescent probe, 1,6-diphenyl-1,3,5-hexatriene (DPH), in fluid phase lipid. In the absence of gramicidin, permethrin and three other pyrethroids, allethrin, cypermethrin and fenpropathrin, increased DPH anisotropy. In these fluid phase systems, as the protein:lipid ratio was increased, the extent of the pyrethroid-mediated increase in fluorescence anisotropy diminished. Also, the pyrethroids shortened DPH fluorescence lifetimes. At high gramicidin:lipid ratios, permethrin substantially lowered anisotropy in the fluid phase lipid, relative to controls. The data suggest that pyrethroids disturb fluid-phase lipids which have been promoted to a relative state of order by proximity to an integral membrane protein. This type of order is one which is represented by DPH fluorescence anisotropy. A model based on these results is proposed to explain the effects of pyrethroids on lipid packing order in cellular membranes, as determined by DPH fluorescence anisotropy.

Stereotactic radiosurgery: a review and comparison of methods.

PURPOSE: Stereotactic radiosurgery (SRS) is an evolving modality for treating well-circumscribed intracranial lesions. Different physical methods have been developed to deliver highly localized dose distributions accurately. We review the different methods and the documented clinical results to present a coherent view of radiosurgery, and to aid physicians and physicists in the appropriate use of this modality. DESIGN: A review of the medical physics and clinical literature was conducted. The physical aspects of the different methods and their impact on treatment were summarized. Results were compiled from those individual clinical series with adequate follow-up data to compare the various modalities with respect to treatment outcome for benign tumors, metastases, and vascular malformations. RESULTS: The physical accuracy was comparable between radiosurgical methods. Differences between gamma radiation and linear accelerator methods had little effect on the dose distribution for single isocenter treatments. Charged particle methods could produce better dose localization for large lesions (> 25 cm3) than was possible with photon methods. Clinical results indicate similar lesion control rates between all radiosurgical methods. There was a progressive increase in the median size of treated lesions for gamma radiation, linear accelerator, and charged particle methods. CONCLUSION: For small lesions (< 5 cm3), physical dose distributions are similar for the photon methods, but linear accelerator methods offer more flexibility for the treatment of intermediate-sized (5 to 25 cm3) lesions in applying future technical developments. More clinical results are needed before firm conclusions can be drawn on the type of lesions to be treated, and the dose-volume parameters to be used.

A randomized prospective trial of radiation therapy for AIDS-associated Kaposi's sarcoma.

PURPOSE: The optimal dose of radiation in the treatment of AIDS-associated Kaposi's sarcoma has been controversial based on previous nonrandomized retrospective studies. METHODS AND MATERIALS: Seventy-one cutaneous AIDS-associated Kaposi's sarcoma lesions were randomly assigned to 1 of 3 radiation dose regimens--8 Gy in 1 fraction, 20 Gy in 10 fractions, and 40 Gy in 20 fractions. Lesions were measured prior to and following treatment. Complete resolution of palpable tumor was considered a complete response, regardless of residual purple pigmentation. Reduction in palpable tumor to less than 50% of pretreatment area was considered an objective response. Less than 50% reduction in tumor size was considered a nonresponse. RESULTS: Complete response was higher (p = .04) with 40 Gy (83%) and 20 Gy (79%) than with 8 Gy (50%). Absence of residual purple pigmentation was greater (p = .005) with 40 Gy (43%) than with 20 Gy (8%) or 8 Gy (8%). Lesion failure was lower (p = .03) with 40 Gy (52%) than with 20 Gy (67%) or 8 Gy (88%). Median time to failure was 43 weeks with 40 Gy, 26 weeks with 20 Gy, and 13 weeks with 8 Gy (p = .003). CONCLUSION: Fractionated radiotherapy to higher total doses resulted in improved response and control of cutaneous Kaposi's sarcoma. This dose-dependence should be considered in determining the optimal radiotherapeutic regimen for individual patients treated for epidemic Kaposi's sarcoma.

Commissioning an image-guided localization system for radiotherapy.

PURPOSE: To describe the design and commissioning of a system for the treatment of classes of tumors that require highly accurate target localization during a course of fractionated external-beam therapy. This system uses image-guided localization techniques in the linac vault to position patients being treated for cranial tumors using stereotactic radiotherapy, conformal radiotherapy, and intensity-modulated radiation therapy techniques. Design constraints included flexibility in the use of treatment-planning software, accuracy and precision of repeat localization, limits on the time and human resources needed to use the system, and ease of use. METHODS AND MATERIALS: A commercially marketed, stereotactic radiotherapy system, based on a system designed at the University of Florida, Gainesville, was adapted for use at the University of Washington Medical Center. A stereo pair of cameras in the linac vault were used to detect the position and orientation of an array of fiducial markers that are attached to a patient's biteblock. The system was modified to allow the use of either a treatment-planning system designed for stereotactic treatments, or a general, three-dimensional radiation therapy planning program. Measurements of the precision and accuracy of the target localization, dose delivery, and patient positioning were made using a number of different jigs and devices. Procedures were developed for the safe and accurate clinical use of the system. RESULTS: The accuracy of the target localization is comparable to that of other treatment-planning systems. Gantry sag, which cannot be improved, was measured to be 1.7 mm, which had the effect of broadening the dose distribution, as confirmed by a comparison of measurement and calculation. The accuracy of positioning a target point in the radiation field was 1.0 +/- 0.2 mm. The calibration procedure using the room-based lasers had an accuracy of 0.76 mm, and using a floor-based radiosurgery system it was 0.73 mm. Target localization error in a phantom was 0.64 +/- 0.77 mm. Errors in positioning due to couch rotation error were reduced using the system. CONCLUSION: The system described has proven to have acceptable accuracy and precision for the clinical goals for which it was designed. It is robust in detecting errors, and it requires only a nominal increase in setup time and effort. Future work will focus on evaluating its suitability for use in the treatment of head-and-neck cancers not contained within the cranial vault.

Treatment of locally advanced adenoid cystic carcinoma of the head and neck with neutron radiotherapy.

PURPOSE: To examine the efficacy of fast neutron radiotherapy for the treatment of locally advanced and/or recurrent adenoid cystic carcinoma of the head and neck and to identify prognostic variables associated with local-regional control and survival. METHODS AND MATERIALS: One hundred fifty-nine patients with nonmetastatic, previously unirradiated, locally advanced, and/or recurrent adenoid cystic carcinoma (ACC) of the head and neck region were treated with fast neutron radiotherapy during the years 1985-1997. One hundred fifty-one patients had either unresectable disease, or gross residual disease (GRD) after an attempted surgical extirpation. Eight patients had microscopic residual disease and were analyzed separately. Sixty-two percent of patients had tumors arising in minor salivary glands, 29% in major salivary glands, and 9% in other sites such as the lacrimal glands, tracheal-bronchial tree, etc. Fifty-five percent of patients were treated for postsurgical recurrent disease and 13% of patients had lymph node involvement at the time of treatment. The median duration of follow-up was 32 months (range 3-142 months). Actuarial curves for survival, cause-specific survival, local-regional control, and the development of distant metastases are presented for times out to 11 years. RESULTS: The 5-year actuarial local-regional tumor control rate for the 151 patients with GRD was 57%; the 5-year actuarial overall survival rate was 72%; and the 5-year actuarial cause-specific survival rate was 77%. Variables associated with decreased local-regional control in the patients with GRD as determined by multivariate analysis included base of skull involvement (p < 0.01) and biopsy only versus an attempted surgical resection prior to treatment (p = 0.03). Patients without these negative factors had an actuarial local-regional control rate of 80% at 5 years. Patients with microscopic residual disease (n = 8) had a 5-year actuarial local-regional control rate of 100%. Base of skull involvement (p < 0.001), lymph node metastases at the time of treatment (p < 0.01), biopsy only prior to neutron radiotherapy (p = 0.03), and recurrent tumors (p = 0.04) were found to be associated with a diminished cause-specific survival as ascertained by multivariate analysis. Patients with base of skull involvement and positive lymph nodes at presentation had an increased rate of the development of distant metastases at 5 years, (p < 0.01 and p < 0.001, respectively). No statistical difference in outcome was observed between major and minor salivary gland sites. CONCLUSIONS: Fast neutron radiotherapy is an effective treatment for locally advanced ACC of the head and neck region with acceptable toxicity. Further improvements in local-regional control are not likely to impact survival until more effective systemic agents are developed to prevent and/or treat distant metastatic disease.

Caffeine consumption is associated with decreased severe late toxicity after radiation to the pelvis.

PURPOSE: Recent studies have suggested that pentoxifylline, a methylxanthine, can prevent or ameliorate late radiation injury in animals and humans. Caffeine is a commonly consumed methylxanthine that provides a model for evaluating the impact of this category of drugs on radiation injury. A retrospective study was undertaken to determine if there is an association between caffeine consumption and a lower incidence of late radiation toxicity. METHODS AND MATERIALS: From 1984 through 1990, 82 patients with cervical cancer and 53 patients with endometrial cancer were treated with primary or adjuvant radiation therapy at the University of Washington. Patients were interviewed regarding ingestion of caffeine-containing beverages, and average daily caffeine consumption during the time of radiotherapy was estimated. The evaluable patients (42 cervical, 31 endometrial) were stratified by quantity of caffeine consumption for correlation with the incidence of radiation toxicity. RESULTS: Acute radiation toxicity was not associated with caffeine consumption for cervical or endometrial cancer. There was a nonstatistically significant trend toward a decrease in overall late radiation toxicity with increased caffeine intake for cervical cancer patients. Subgroup analysis revealed this trend to be attributable to a decreased incidence of severe late radiation injury in cervical cancer patients who consumed higher levels of caffeine at the time of their radiotherapy (p = 0.02). This relationship was not observable for late toxicity in the endometrial cancer patients due to the low incidence of severe late injury following radiation for that disease. CONCLUSIONS: This investigation is supportive of previous studies showing a radioprotective effect for pentoxifylline, and suggests that the mechanisms of radioprotection may be common to methylxanthines as a drug class.

Effect of high-dose pentoxifylline on acute radiation-induced lung toxicity in a rat lung perfusion model.

PURPOSE: The purpose of this study was to study the effect of high-dose oral pentoxifylline on radiation-induced acute lung injury as assessed with a rat lung perfusion model. METHODS AND MATERIALS: Adult male Sprague-Dawley rats were used throughout this study. A preliminary experiment determined that treatment with 2 g/liter pentoxifylline in drinking water resulted in an average consumption of 1.38 g/m2/day, which is comparable to the maximum tolerated dosage in humans. Seventy-two rats were irradiated to the left hemithorax with single fraction doses ranging from 10 through 18 Gy. Half were treated with 2 g/liter pentoxifylline in drinking water from 1 week before radiation through 8 weeks after radiation. Lung vascular perfusion scanning was performed at 3, 4, 5, 6, and 8 weeks after radiation using 99mTc-macroaggregated albumin. The lung perfusion ratio was defined as the number of counts due to radioactivity within the irradiated left lung region of interest divided by the number of counts within the region of the nonirradiated right lung. This lung perfusion ratio has been shown to decrease with radiation-induced lung injury. RESULTS: Although radiation led to a decreased lung perfusion ratio in all groups, those receiving pentoxifylline maintained higher ratios than irradiated controls from 3-5 weeks, especially for those receiving 15 or 18 Gy. However, from 6 through 8 weeks the irradiated controls exhibited partial recovery of lung perfusion ratio, whereas the pentoxifylline groups did not. By 8 weeks after 15 and 18 Gy, lung perfusion ratios were significantly higher for the irradiated controls than for pentoxifylline-treated rats-a reversal of the pattern observed at 3-5 weeks. CONCLUSIONS: The protection by pentoxifylline against radiation-induced acute lung injury was transient and limited to the first 5 weeks after radiation. Subsequent recovery from lung injury was inhibited by this drug at later times within the acute phase.

Femoral vessel depth and the implications for groin node radiation.

PURPOSE: To quantify, based on pretreatment computer tomographic measurements, potential groin node depths, which will aid in optimal treatment planning for patients requiring groin node radiation. METHODS AND MATERIALS: The pretreatment computer tomographic scans of 50 gynecologic cancer patients were reviewed to determine the distance of each femoral vessel beneath the overlying skin surface, as an indicator of potential groin node depth. Correlative data regarding height and weight were obtained from patient medical records, and were used to calculate the Quetelet index, defined as (weight in kg)/(height in m)2. Treatment parameters of 5 patients who failed prophylactic groin radiation in a recently published study were assessed to determine if underdosage represented a possible cause of failure. RESULTS: Individual femoral vessel depths ranged from 2.0 to 18.5 cm. When the depths of all four femoral vessels were averaged in each patient, the mean "4-vessel average" depth for this patient population was 6.1 cm. The median Quetelet index for the group was 25.6, and there was a strong correlation between femoral vessel depth and patient Quetelet index. Recalculation of doses provided to the 5 patients failing prophylactic groin radiation in the Gynecologic Oncology Group study showed that all had received potential tumor doses < 4700 cGy, with 3 patients being underdosed by > 30%. CONCLUSION: While surgery is often indicated in the management of patients with potential groin node metastases, the role of prophylactic groin radiation should not be rejected. Data from this study may aid in the optimal design and implementation of groin node radiotherapy.

Operation and permanent low activity 125I brachytheraphy for recurrent high-grade astrocytomas.

Twenty-two adult patients with recurrent high grade astrocytomas [18 glioblastoma multiforme (GBM) and 4 anaplastic astrocytoma (AA) at time of implant] underwent therapy at the University of Washington from October 1991 through March 1995, with repeat craniotomy, maximal debulking of tumor, and placement of permanent low activity 125I seeds. Median age was 41 years and median Karnofsky performance status was 90. Median survival for the entire group was 65 weeks from the time of implant. For the subgroup of GBM patients, median survival was 64 weeks from the time of implant. One-year survival from the date of implant was 57% for the entire group and 59% for those with GBM. The site of first failure after implant was local (within 2 cm of the resection cavity) in 70%, distant (noncontiguous, beyond 2 cm) in 18% and concurrently local and distant in 12%. There was one case of symptomatic radiation injury that resolved with steroid therapy, and no patient required repeat craniotomy for parenchymal necrosis. For patients with recurrent GBM, treatment with resection and permanent low activity 125I brachytherapy yielded improved survival compared to an internal historical control group treated with resection and chemotherapy (p = 0.023). Craniotomy with maximal tumor debulking and placement of low activity 125I seeds yields encouraging results with minimal morbidity in patients with recurrent high-grade astrocytomas.

The efficacy of radiotherapy as postoperative treatment for desmoid tumors.

PURPOSE: The purpose of this study was to determine if radiotherapy is a beneficial adjuvant treatment after desmoid tumor resection. METHODS AND MATERIALS: A retrospective analysis was performed on 54 patients who underwent surgery without prior radiation at our institution between 1982 and 1998 to remove a desmoid tumor. Thirty-five patients had adjuvant radiation therapy after surgery, and 19 patients had surgery alone without immediate postoperative radiation. Sixteen of the 35 patients who underwent immediate postoperative radiation treatment had at least one prior resection before reoperation at our institution. Recurrence was defined as radiographic increase in tumor size after treatment. Follow-up interval (mean 39 months) and duration of local control were measured from the date of surgery at our institution. Potential prognostic factors for time to tumor progression were analyzed. RESULTS: Adjuvant treatment with radiation was the only significant prognostic factor for local control. The five-year actuarial local control rate was 81% for the 35 patients who underwent radiation in addition to surgery, compared to 53% for the 19 patients who underwent surgery alone (p = 0.018). For the patients who did not receive adjuvant radiation, only younger age at the time of surgery was associated with increased risk of failure (p = 0.035). Gross or microscopic margin status and number of prior operations were not detected as prognostic for local failure. For patients who did receive postoperative radiation, only abdominal location was associated with increased risk of failure (p = 0.0097). CONCLUSION: Radiation treatment as an adjuvant to surgery improved local control over surgery alone. Multiple operations before adjuvant radiation did not decrease the probability of subsequent tumor control. Radiation should be considered as adjuvant therapy to surgery if repeated surgery for a recurrent tumor would be complicated by a significant risk of morbidity.

Effect of pentoxifylline on radiation-induced lung and skin toxicity in rats.

PURPOSE: There is currently substantial clinical interest in pentoxifylline as an inhibitor of radiation-related normal tissue injury. To further assess this drug's potential toxicity-sparing effects, pentoxifylline was studied in rats using a radiation-induced lung injury model. METHODS AND MATERIALS: Adult male rats were exposed to either sham irradiation or a single fraction of 21 Gy delivered to the left hemithorax. Four study groups were defined: those that received neither radiation nor pentoxifylline, those that received pentoxifylline (500 mg/L in drinking water) but no irradiation, those that underwent irradiation without pentoxifylline, and those that received both pentoxifylline and radiation. Lung injury was measured by changes in relative left:right lung perfusion ratios derived from quantitative gamma camera imaging of 99mTechnetium-macroaggregated albumin uptake in the pulmonary circulation. Serial scans were done over a 40-week period following radiation. Skin toxicity was also assessed. After 40 weeks, the animals were killed, and lung tissue was assayed for angiotensin converting enzyme activity as a marker for endothelial cell damage. RESULTS: Both groups of radiated (with or without pentoxifylline) rats showed equivalent acute sharp decreases in left:right lung perfusion ratios compared to the nonirradiated groups, reaching a mean nadir value of 0.29 at week 4. Irradiated lung perfusion in subsequent weeks in the radiation-only group showed minimal recovery, with a plateau mean ratio of 0.37 (0.36-0.39). However, there was apparent later recovery of lung perfusion in the radiation with pentoxifylline group from weeks 14 through 40, to a mean ratio of 0.47 (0.43-0.52) (p < 0.01 compared to the radiation-only group). Angiotensin converting enzyme activity correlated closely with lung perfusion data. No effect of pentoxifylline on acute or late skin toxicity was detected. CONCLUSIONS: This study suggests that pentoxifylline does not have any measurable effect on acute lung injury following hemithoracic irradiation in rats, but does result in sparing of later lung toxicity.

Combined radiotherapy and chemotherapy in the management of local-regionally advanced vulvar cancer.

PURPOSE: To determine, in a retrospective single institutional study, the role of concurrent radiotherapy and chemotherapy in the treatment of local-regionally advanced vulvar cancer. METHODS AND MATERIALS: From 1984 to 1991, 20 patients with locally extensive primary or recurrent carcinoma of the vulva were treated with initial combined radiotherapy and chemotherapy. Seven patients had Federation Internationale de Gynecologie et d'Obstretrique Stage III disease, 10 had Stage IV disease, and three were treated for recurrent disease. None of these patients were considered candidates for primary radical vulvectomy and groin node dissection. Median radiation doses to regions of microscopic disease and gross tumor were 40 Gy (range 30-54 Gy) and 54 Gy (34-70.4 Gy), respectively. All patients received 2 or 3 cycles of 5-Fluorouracil concurrently with radiotherapy. In addition, five patients received Cis-platinum, and one Mitomycin-C. Median at-risk follow-up interval was 37 months. RESULTS: Ten patients had complete resolution of tumor to initial chemoradiotherapy, and eight of these have remained free of tumor relapse. Eight other patients had partial responses, with tumor bulk reduced by > 50%, while the remaining two patients had local-regionally progressive disease. Six of the patients with partial responses had residual tumor successfully resected, although four subsequently recurred. For the entire group of 20 patients, the actuarial 3- and 5-year local control rates were 48% each, and the corresponding disease-specific survival rates were 59% and 49%. There was a suggestion that better local control was obtained in patients who received gross tumor radiation doses > or = 50 Gy. Skin reaction was the major acute toxicity and responded well to conservative management. Long-term sequalae were limited to skin and subcutaneous atrophy. CONCLUSION: These results indicate that initial combined radiotherapy and chemotherapy is effective in the management of advanced vulvar cancer.

Concurrent cisplatin, prolonged oral etoposide, and vincristine plus chest and brain irradiation for limited small cell lung cancer: a phase II study of the Southwest Oncology Group (SWOG-9229).

PURPOSE: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting. METHODS AND MATERIALS: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m2 i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m2 (days 1-14, 29-42, and 57-70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy. RESULTS: Among 56 eligible patients, 93% had SWOG performance status 0-1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimum follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3). CONCLUSION: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.

Runaway pacemaker during high-energy neutron radiation therapy.

Runaway pacemaker occurred in a patient undergoing high-energy neutron radiation therapy despite adherence to published safety guidelines. The very low estimated dose of 0.9 Gy received by the pacemaker demonstrates the extreme sensitivity of integrated circuits to this new modality of radiation therapy.

Neoadjuvant therapy: a novel and effective treatment for stage IIIb non-small cell lung cancer. Southwest Oncology Group.

Neoadjuvant therapy has become an accepted treatment for stage IIIa, but not for stage IIIb, non-small cell lung cancer, which is usually considered incurable and treated nonsurgically. We determined the feasibility of neoadjuvant therapy in the setting of stage IIIb non-small cell lung cancer in a prospective multi-institutional trial. For patients to be eligible for entry into the study, they had to have pathologically documented T1-4 N2-3 disease. Treatment consisted of: (1) cisplatin (50 mg/m2) given on days 1, 8, 29, and 36 plus VP-16 (50 mg/m2) given on days 1 to 5 and 29 to 33, together with concurrent radiotherapy (4,500 cGy; 180 cGy per daily fraction); and (2) surgical resection performed 3 to 5 weeks after induction of medical therapy, if the response was stable, partial, or complete. Of the 126 total eligible patients entered into the study, 51 patients had stage IIIb tumors (24 with T4 tumors and 27 with N3 disease). This consisted of 34 men and 17 women with a median age of 57 years. Thirty-two (63%) patients (18 with T4 tumors and 14 with N3 disease) underwent resection of the primary tumor, with a 5.2% operative mortality. There was no difference in the operative time, blood loss, and length of hospital stay for the T4 versus the N3 patients. For all 51 patients, survival at 2 years was 39%. Sites of relapse in all patients were mainly distant, even though patients with N3 disease did not initially have involved N3 nodes resected.(ABSTRACT TRUNCATED AT 250 WORDS)

Fast neutrons in prostatic adenocarcinomas: worldwide clinical experience.

Primary tumor control remains a major problem in the treatment of locally advanced prostate carcinoma. Clinical local failure rates approach 30-40% and may be significantly higher when results of prostatic biopsy or prostate-specific antigen (PSA) levels are considered. The low growth rate and cycling fraction of prostate adenocarcinoma suggest potential therapeutic advantage for the high linear energy transfer (LET) of neutrons. The Radiation Therapy Oncology Group (RTOG) performed a multi-institutional randomized trial (RTOG 77-04) comparing mixed beam (neutron plus photon) irradiation to conventional photon irradiation for the treatment of locally advanced prostate cancer. A subsequent trial by the Neutron Therapy Collaborative Working Group (NTCWG 85-23) compared pure neutron irradiation to standard photon irradiation. Both randomized trials demonstrate significant improvement in locoregional control with neutron irradiation compared to conventional photon irradiation in the treatment of locally advanced prostate carcinoma. To date, only the mixed beam trial has shown a significant survival benefit. Future analysis of the larger NTCWG trial at the 10-year point should confirm whether or not improved locoregional control translates into a survival advantage. These findings have significant implications for all local treatment strategies including dose-escalated conformal photon irradiation, prostate implantation, and neutron radiation. Given the large numbers of patients afflicted with this disease, a positive survival advantage for neutrons or mixed beam therapy would provide a strong incentive for the development of economically feasible clinical neutron facilities.

Effects of irradiation geometry on treatment plan optimization with linac-based radiosurgery.

A comparison was made of different treatment plans to determine the effect on the three-dimensional dose distributions of varying the allowed parameters in linac-based stereotactic radiosurgery with circular collimators; these parameters are arc position, length, and weighting, and collimator diameter. For the class of eccentrically shaped target volumes that are not so irregular as to require several separate isocenters, it was found that superior dose distributions could be achieved by varying arc length, arc position, arc weighting, and collimator diameter. An analysis of the results achieved with an automated planning program indicates that, in general, the variables of arc position and arc length are of greater importance than collimator size or beam weighting. However, there are cases where varying these latter two parameters does result in markedly better dose distributions. A deeper investigation into the effects of multiple collimators on the dose distribution in the area of steepest gradient demonstrated that multiple collimator sizes do not significantly degrade the dose falloff, which is in fact mostly determined by the effects of intersecting arcs.

Effect of alterations in lipid packing order by hydrophobic solutes on the association state of protein assemblies in model membranes.

The effects of two hydrophobic solutes which perturb lipid packing order, permethrin and allethrin, on the aggregated state of a lipid membrane-incorporated protein, bacteriorhodopsin (BR), have been determined by resonance energy transfer measurements. As temperature is increased from well below the main gel-fluid phase transition temperature (Tc) of the lipid, patches of aggregated BR dissociate into monomers, a few degrees below the Tc (M.P. Heyn, A. Blume, M. Rehorek and N.A. Dencher, Biochemistry 20 (1981) 7109; M.P. Heyn, R.J. Cherry and N.A. Dencher, Biochemistry 20 (1981) 840). Permethrin and allethrin were found to cause a decrease in the temperature of BR disaggregation which was associated with a decrease in the Tc of the lipid. In gel phase dipalmitoylphosphatidylcholine at 25 degrees C, the pertubing effects of permethrin on lipid packing order were associated with a decrease in the average patch radius from 123 to 33 A. It is concluded that perturbation of lipid packing order by small hydrophobic molecules may alter the stability of protein assemblies in membranes.

Radiation therapy for sarcoid of the thalamus/posterior third ventricle: case report.

There are a limited number of previously reported cases involving the use of radiation therapy for sarcoid of the brain. The case of a 22-year-old man with a thalamic/posterior third ventricle sarcoid mass that grew despite steroid medication is presented. The patient was treated with external beam radiation to a total dose of 20 Gy, with 2-Gy fractions over 14 elapsed days. A complete radiographic response was achieved 4 months after radiation was completed. Radiographic follow-up through 8 months postradiation shows no evidence of disease recurrence. Fractionated radiation therapy in low-to-moderate doses appears to be efficacious in steroid-refractory sarcoid of the brain.