Commissioning of a mobile electron accelerator for intraoperative radiotherapy.

Radiation performance characteristics of a dedicated intraoperative accelerator were determined to prepare the unit for clinical use. The linear accelerator uses standing wave X-band technology (wavelength approximately 3 centimeters) in order to minimize the mass of the accelerator. The injector design, smaller accelerator components, and low electron beam currents minimize radiation leakage. The unit may be used in a standard operating room without additional shielding. The mass of the accelerator gantry is 1250 Kg (weight approximately 2750 lbs) and the unit is transportable between operating rooms. Nominal electron energies are 4, 6, 9, and 12 MeV, and operate at selectable dose rates of 2.5 or 10 Gray per minute. D(max) depths in water for a 10 cm applicator are 0.7, 1.3, 1.7, and 2.0 for these energies, respectively. The depths of 80% dose are 1.2, 2.1, 3.1, and 3.9 cm, respectively. Absolute calibration using the American Association of Physicists in Medicine TG-51 protocol was performed for all electron energies using the 10 cm applicator. Applicator sizes ranged from 3 to 10 cm diameter for flat applicators, and 3 to 6 cm diameter for 30 degrees beveled applicators. Output factors were determined for all energies relative to the 10 cm flat applicator. Central axis depth dose profiles and isodose plots were determined for every applicator and energy combination. A quality assurance protocol, performed each day before patient treatment, was developed for output and energy constancy.

Preparing a cost analysis for the section of medical physics-guidelines and methods.

Radiation oncology is a highly complex medical specialty, involving many varied routine and special procedures. To assure cost-effectiveness and maintain support for the medical physics program, managers are obligated to analyze and defend all aspects of an institutional billing and cost-reporting program. Present standards of practice require that each patient's radiation treatments be customized to fit his/her particular condition. Since the use of personnel time and other resources is highly variable among patients, graduated levels of charges have been established to allow for more precise billing. Some radiation oncology special procedures have no specific code descriptors; so existing codes are modified or additional information attached in order to avoid payment denial. Recent publications have explored the manpower needs, salaries, and other resources required to perform radiation oncology "physics" procedures. This information is used to construct a model cost-based resource use profile for a radiation oncology center. This profile can be used to help the financial officer prepare a cost report for the institution. Both civil and criminal penalties for Medicare fraud and abuse (intentional or unintentional) are included in the False Claims Act and other statutes. Compliance guidelines require managers to train all personnel in correct billing procedures and to review continually billing performance.

An analysis of the late effects of radiotherapy in pediatric central nervous system tumors.

PURPOSE: The purpose of this study is to assess the long term results of all pediatric patients diagnosed with central nervous system (CNS) tumors treated with external beam radiotherapy either primarily or postoperatively. MATERIALS: Forty-seven pediatric patients with CNS tumors were treated between 1978 and 1989 with external beam radiotherapy to customized fields using cobalt 60, 4, 6, or 18 MV photons. Daily doses ranged from 1.5 to 2.0 Gray; total doses from 35 to 66 Gray. Ages ranged from one month to 18 years of age, with an average age of 8.2 years. Thirty-nine patients survived more than 12 months (range 36 to 178 months; median 62 months) and were included for analysis. Ten of 39 (25.6%) patients experienced Grade I to II complications and six patients had (15.7%) Grade III to IV complications for an overall incidence of 41%. The influence of field size, radiation dose, chemotherapy, age, and extent of surgical resection upon long-term complications were studied. CONCLUSION: Radiation therapy for pediatric CNS malignancies is associated with long-term complications. Significant long-term complications can be limited to an acceptable level of approximately 15%.

Retrospective analysis of patients with primary fallopian tube carcinoma treated at the University of Louisville.

Medical records of patients diagnosed with primary fallopian tube carcinoma between 1979 and 1989 were reviewed. Twenty-six patients were eligible; 8 patients were excluded after pathologic review, leaving 18 patients included in the study for this analysis. The median and mean age were 61 and 59 years, respectively, with a range of 39-80 years. There were three Stage I, five Stage II, seven Stage III, and three Stage IV patients. The most common presenting symptoms were abdominal/pelvic pain, abdominal distension, and vaginal discharge/bleeding. The primary site of the lesion was determined to be the right tube in 44% of the cases, the left tube in 39% of the patients, bilateral lesions in 11% of the patients, and indeterminate in 6%. Histologic grade was poorly differentiated (Grade III) in 13 patients, moderately differentiated (Grade II) in 4 patients, and well differentiated (Grade I) in one. No patient was correctly diagnosed preoperatively. Survival at 5 years of the entire group was 35% with a 3 year minimum followup. Corresponding disease free survival was 30%. Mean and median survival times were 74 and 37 months, respectively. The range of survival times was from 1 to 120 months. All Stage I patients, 80% (4/5) of Stage II, and 29% (2/7) of Stage III patients are alive without disease. None (0/3) of the Stage IV patients are alive. Treatment regimens consisted of intraperitoneal P-32, external beam radiotherapy, and/or chemotherapy. Radiotherapy was associated with a low incidence of treatment-related complications, the majority being gastrointestinal related. There was one chemotherapy-related death. These patients and their treatment outcomes add to the data base of numerous previous reports on fallopian tube carcinoma. Stage I and II patients fared excellently with primary surgical and adjuvant therapy. While the prognosis of Stage III and IV patients is much worse, significant levels of long term survival can be achieved with aggressive treatment.

Brachytherapy in early prostate cancer--early experience.

Use of brachytherapy with radioactive seeds in the management of early prostate cancer is commonly used in the United States. The early experience has been reported from the prostate treatment centers in Seattle for the last 10 years. In this manuscript we are reporting our early experience of 150 radioactive seed implantations in early stage prostate cancer using either Iodine 125 or Palladium 103 seeds. The average age of the patient is 66 years and the median Gleason score is 5.4 with a median PSA of 6. A brief description of the evolution of the treatment of prostate cancer as well as the preparation for the seed implantation using the volume study with ultrasound of the prostate, pubic arch study using CT scan of the pelvis and the complete planning using the treatment planning computers are discussed. We also have described the current technique which is used in our experience based on the Seattle guidelines. We plan a follow-up report with the results of the studies with longer follow-up.

Rhabdomyosarcoma in children--a ten year review.

PURPOSE: The purpose of this study is to retrospectively analyze all pediatric patients with Rhabdomyosarcoma (RMS) of various anatomic sites, treated in our department over a 10-year period, for treatment results. Anatomical site, group, and gender are individually analyzed as prognostic indicators of overall survival. MATERIALS AND METHODS: Sixteen rhabdomyosarcoma patients diagnosed by biopsy or surgical resection were reviewed. All patients were treated according to assigned IRS protocols except one. Age ranged from 1 to 19 years with a median age of 4 years. Ten patients were male and 6 were female, 14 were white and 2 black. Anatomic sites included six from the head and neck region, seven in the trunk and three in the extremities. Embryonal RMS was present in all but one which was classified as undifferentiated. All patients had surgery (biopsy-5, partial-1 or complete resection-10) and chemotherapy (VA, VAC, VAC plus Adriamycin, or VAC plus Adriamycin, CIS Platinum and VP-16). Ten patients received irradiation consisting of 3060 cGy to 5850 cGy using shrinking fields with 1.8 to 2.0 Gy/day/5 day/wk. RESULTS: Patients tolerated the treatment well and there were no late complications. Only one patient had a recurrence in the primary site with a median follow-up of 61 months (range 5-118 months) for the whole group. The 5-year disease free survival and actuarial survival for all patients treated were 73% and 87% respectively, with four patients developing metastasis and three of those dead of disease. CONCLUSION: This study represents a heterogeneous group of patients with RMS treated over a 10-year-period. The results correlate with those found in the most recent published IRS data for embryonal histology. From experience gained from earlier studies, newer IRS protocols have tailored treatment protocols to specific site with more intense therapy used for difficult treatment sites.

Wilms' tumor in an adult: a case report and review of the literature.

Wilms' tumor in an adult is extremely rare, with less than 250 cases reported in the world literature. Treatment guidelines for pediatric Wilms' tumor are well established; those for adults are not. This article presents the case of a 19-year-old male diagnosed with Wilms' tumor after complaints of hematuria. He was categorized as Stage IV after nephrectomy and received post-operative radiotherapy and chemotherapy consisting of Vincristine, Adriamycin, and Actinomycin-D. Two years later he was found to have metastases to brain and lungs. He was treated with radiotherapy and bone marrow transplantation, and died of septic shock. The literature regarding Wilms' tumor in adults is reviewed, and current therapy is discussed.

Murine intestinal crypt survival after combined taxol plus radiation exposure.

Taxol is active against a number of cancers, some of which are also radiosensitive. The role of combined Taxol and radiotherapy has not been established. A theoretical benefit exists, however, due to the G2/M phase specificity of Taxol, and radiation-sensitizing effects have been observed in vitro. This study focused on the combined Taxol/radiation effect on murine intestinal epithelium. HA/ICR random-bred male mice were used to examine the temporal effect of injecting Taxol (40 mg/kg) before and after irradiation (12.5 Gy). The microcolony assay was used to determine the effect of single and combined modalities. Control groups consisted of no treatment, drug solvent only (Cremophor/ethanol/saline), radiation only, and Taxol only. A complete radiation dose-response study of treatment with and without Taxol was performed 12 hr after injection. Preirradiation Taxol appears not to enhance intestinal cell killing, and may even offer some protection when injected at 4 hr prior to irradiation. Postirradiation Taxol was found to enhance radiation response most dramatically at times greater than 12 hr. Dose-response data appeared to confirm the increased radiation effect of combined treatment. In conclusion, Taxol administered prior to irradiation results in either no sensitization or possible protection of the normal tissue response. Postirradiation Taxol appears to sensitize intestinal crypts when injected at least 12 hr after gamma irradiation. These data suggest that care should be exercised when using Taxol after irradiation.

CA-125 levels after surgical exploration and radioactive chromic phosphate in ovarian cancer patients.

Trends in CA-125 levels after completion of therapy in ovarian cancer patients who received intraperitoneal radioactive chromic phosphate therapy (32P) after primary surgical resection or second-look surgery were evaluated. Ninety patients who underwent surgical exploration and 32P were reviewed. Twenty-nine patients were excluded due to insufficient number of CA-125 levels or recurrence within 12 months, with 61 patients with serial CA-125 levels and no evidence of disease for 12 months available for analysis. 32P followed initial resection in 24 patients (16 Stage I, 3 Stage II, 5 Stage III). 32P followed chemotherapy and second-look procedures in 37 patients (4 Stage I, 3 Stage II, 27 Stage III, 3 Stage IV). Elevated CA-125 levels were present in 25 (41%) patients within 12 months of 32P (46% after primary exploration, 38% after second-look). The degree of CA-125 elevation (U/ml) was 30-100 (23%), 100-200 (11%), and >200 (7%). Of the 25 patients with an elevated CA-125, the elevation persisted more than 4 months in 11 (44%). All but two patients had normal CA-125 levels by 12 months. An abnormal elevation in CA-125 was seen in 33% of patients 4 months after receiving 32P and abdominal surgery, with values ranging as high as 500 U/ml. Although elevations in CA-125 are reported following surgery alone, the duration of elevation appears to be longer with 32P. Therefore, persistent elevations of CA-125 following 32P between 4 and 12 months should be judged with caution as they may not reflect recurrent disease.

Radiation therapy for pituitary adenomas. A retrospective study of the University of Louisville experience.

A retrospective analysis of treatment outcome was performed on patients treated with radiation for pituitary adenomas at the University of Louisville from January 1988 to December 1992. The study population included 27 patients. Twenty received radiation as a component of their initial treatment while seven received radiation as part of their treatment for recurrent disease. Nineteen patients were treated with post-operative radiation, and eight were treated with radiation alone. Follow-up interval ranged from 1 month to 109 months, with a median of 28 months. All three patients with stage I disease were controlled with radiation alone (1/3) or combined surgery and postoperative radiation (2/3), whereas six of eight stage II patients had disease control following surgery and postoperative radiation. Both patients with stage III adenomas treated with radiation alone had local control, whereas local control was achieved in six of seven with post-operative radiation. Three of five patients with recurrent disease had local control with radiation alone, whereas both patients undergoing surgery and postoperative radiation had local control. This retrospective analysis supports previous findings that radiation therapy alone or combined with transphenoidal resection is effective in long-term control of pituitary adenomas. It further suggests that immediate radiation therapy may be superior to radiation for surgical or medical failures.

Radiation palliation of cervical cancer.

Radiation is a useful modality for palliation of local-regional disease in patients with cervical cancer who require palliation because of distant metastases, extensive local-regional disease, medical consideration, or patient concerns. Two radiation schedules have been reported on for the treatment of advanced pelvic disease including cervical cancer. The large single-dose schedule consisted of 10-Gy fractions repeated at monthly intervals to a maximum of 30 Gy. This schedule has produced good palliative results with symptomatic improvement in approximately 50% of patients and objective response in 35%-80%. However, severe late toxicity was shown to be as high as 42% (actuarial). The second schedule tested by the Radiation Therapy Oncology Group consisted of 3.7-Gy fractions given twice a day for 2 days (14.8 Gy) repeated after 2-4 weeks for a maximum of 44.4 Gy. There were 284 patients accrued, and the subgroup of 61 cervical cancer patients is analyzed in this article. The subjective response (50%-100% complete response) and objective response (53%) were similar to those observed with the large single-fraction schedule. The late toxicity was significantly lower (7%-actuarial). For patients who may survive 6 months or longer, this second schedule is preferable.

Results of irradiation in patients with high-grade gliomas evaluated by magnetic resonance imaging.

Evidence shows that most high-grade gliomas are a diffuse process. Prior studies reported a median survival with surgery and postoperative radiotherapy of 8.6 months for glioblastoma multiforme (GBM) and 36.2 months for anaplastic astrocytoma (AA). Since MRI delineated the glioma better than CT scan, using MRI-based radiotherapy treatment planning allows for more precise treatment volumes. We retrospectively reviewed the records of the first 36 patients with malignant glioma, who had a presurgery MRI-based radiotherapy treatment planning. These patients were diagnosed between January 1986 and February 1991. Minimum follow up was 14 months and median survival was 15.4 months for GBM (7-42 months) and 27.4 months for AA (7-53 months). We feel that the trend for increased median survival in GBM (15.4 vs 8.6 months) is partly due to better definition of the tumor volume by using MRI. Larger studies are needed to confirm this finding.

Radiation therapy for pancreatic cancer: a retrospective study of the University of Louisville experience.

Although multiple regimens and approaches have been used in attempts to treat pancreatic cancer, the 5-year disease-free survival is dismal. With an increase in incidence of pancreatic cancer over the past 35 years, researchers continue their efforts to find an effective treatment for this aggressive disease. Between January 1983 and January 1993, we treated 77 patients with radiotherapy for pancreatic cancer. Only 35 of these patients had localized adenocarcinoma and were treated for cure. In this group of 35 patients, 5 received < 4,000 cGy (mean survival of 5.6 months) and 30 received > or = 4,000 cGy (mean survival of 14.7 months). Twenty-four of these 30 received > or = 5,000 cGy, resulting in a mean survival of 15.4 months, and 17 of these 24 received > or = 6,000 cGy, with a mean survival of 15.7 months. Some palliation of symptoms was achieved in 57% of all patients. These results at the University of Louisville Brown Cancer Center are comparable to other published results, but the prognosis for patients with pancreatic cancer remains bleak.

Late effect of multiple daily fraction palliation schedule for advanced pelvic malignancies (RTOG 8502).

PURPOSE: Determine late complication incidence for pelvic palliation using accelerated multiple daily fraction radiation [Radiation Therapy Oncology Group (RTOG) 8502]. METHODS AND MATERIALS: Prospective evaluation of a palliative radiation schedule for advanced pelvic malignancies was conducted from 1985 to 1989 by RTOG 8502. The dose was 44.40 Gy in 12 fractions (3.7 Gy BID) with a rest after 14.80 Gy and 29.60 Gy. The pilot part of the study allowed for a variable rest interval of 3-6 weeks. The rest interval was then randomized between 2 and 4 weeks to determine effect on tumor control. No difference in tumor control was identified (p = 0.59). The pilot segment accrued 151 patients and the randomized segment accrued 144 patients. A total of 290 cases were analyzable (four ineligible or canceled) for late effects. To minimize actuarial bias, only patients surviving 90 days (193) were analyzed for late effect risk. The primary site consisted of gynecologic (40%), colorectal (28%), genitourinary (25%), and miscellaneous (7%). The extent of tumor consisted of pelvis only (62%) and additional tumor outside the pelvis (38%). Most of the patients were elderly (76% > 60 years, 47% > 70 years). Karnofsky performance status (KPS) was > or = 80 in 60% of patients and < 80 in 40%. RESULTS: None of the patients with < 30 Gy (less than three courses) developed late toxicity. A total of 11/193 (6%) developed Grade 3+ late toxicity (nine Grade 3, one Grade 4, one Grade 5). Actuarial analysis of complication rate by survival time for Grades 3, 4, and 5 shows a cumulative incidence for complications after 6 months that plateaus at 6.9% by 18 months. The cumulative incidence for Grades 4 and 5 is 2.0% by 12 months. The difference in late effect for the 2-week rest vs. 4-week rest was not statistically different (p = .47). Patient factors evaluated for increased risk of late complications included prior surgeries, age, sex, KPS and primary. None were found to have significant statistical correlations with late effects. CONCLUSION: The crude late complications rate is 6%. Actuarial analysis using cumulative incidence shows 6.9% by 18 months. This represents a significant decrease in late complications from 49% seen with higher dose per fraction (10 Gy x 3) piloted by Radiation Therapy Oncology Group (7905) for a similar group of patients. Long-term analysis of late complication indicates this schedule can be used in the pelvis with relatively low incidence of complication. This schedule has significant logistic benefits and has been shown to produce good tumor regression and excellent palliation of symptoms.

Use of P-32 in stage III epithelial carcinoma of the ovary.

From 1982 through 1989, 56 patients with Stage III epithelial carcinoma of the ovary received intraperitoneal chromic phosphate following chemotherapy and second look (52 pts) or as the only postsurgical management (4 pts). Median follow-up was 48 months (range of 24 to 108 months). The 4 patients treated following primary surgery with P-32 without chemotherapy had microscopic abdominal disease (3 pts) or complete reduction of gross abdominal disease (1 pt), and their 5-year survival was 100%. Of the 52 patients treated with P-32 following PAC chemotherapy, 23 were pathologic negative, 15 had microscopic residual, and 14 had gross residual at second look. The 5-year survival following second look was 75% for negative, 48% for microscopic, and 32% for gross residual. There were 4 Grade 3 GI complications (7%). There were no complications in the 38 patients who received the P-32 within 12 hr of surgery. The use of P-32 as an adjuvant for Stage I and II epithelial carcinoma of ovary has been found to be effective in prior GOG trials. We have expanded the selection criteria in patients with Stage III carcinoma to include those who can be surgically reduced to microscopic residual at primary surgery or second look following chemo reduction. Because of multiple prognostic variables affecting survival in Stage III ovarian cancer, a randomized study with control arm would be necessary to draw firm conclusions regarding the effectiveness of P-32. The 5-year survival in this group of patients compares favorably to published reports.

Irradiation in the management of anal cancer with literature review.

Sixteen patients with a diagnosis of anal cancer were treated from 1981 to 1990 with combination of surgery, irradiation, and chemotherapy. Median age was 56 years (range 42 to 78 years). There were 3 males and 13 females. Fourteen patients were white and 2 were black. The stage of the primary was: T1-4, T2-9, T3-3. Eleven patients had the tumor in anal canal and 5 patients at the anal verge. Twelve patients had squamous cell carcinoma and 4 had cloacogenic carcinoma. Four patients had planned abdomino perineal resection (APR) after pre-operative chemotherapy (mitomycin C-15 mgm/m2 day 1; 5-fluorouracil, 750 mgm/m2, 24 hour infusion, days 1 to 5, repeated q15 days), and irradiation (30 gy in 15 fractions in 3 weeks). One patient had wide excision of the primary site after the pre-op chemotherapy and irradiation. Ten of 11 patients received higher dose of irradiation (45 to 55 Gy in 4 1/2 to 5 1/2 weeks, 5 days/week) in combination with chemotherapy and anal sphincter conservation surgery. One patient refused chemotherapy and was treated with surgery and high dose irradiation. The median follow-up was 28 months (range 3-125 months). Fifteen patients (94%) had local control. Thirteen are NED from 3 to 125 months and 2 died of intercurrent disease without cancer at 3 and 14 months. One patient with local recurrence at 9 months had salvage surgery, but died of disease. Except for moderate diarrhea and perineal reactions, there were no major complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I-II study of multiple daily fractions for palliation of advanced head and neck malignancies.

PURPOSE: To assess palliation of advance head and neck malignancies with the use of rapid hyper fractionation studies similar to the RTOG 85-02. MATERIALS AND METHODS: 37 patients with 39 lesions were entered into the non-randomized Phase I-II protocol, between 1984 and 1991. Previously untreated malignancies were present in 24 lesions, primary recurrent diseases in six patients, metastasis to the head and neck in five patients and skin primaries in the remaining two cases. At presentation 15 of 37 patients (or 17 of 39 lesions) were in operable due to poor medical status, eight patients were considered technically in operable due to extent of disease, 10 patients had distant metastasis and four patients refused surgery. The protocol uses twice a day fraction (370 cGy per fraction) for 2 consecutive days totalling 1,480 cGy per course. Three courses were given at 3-week intervals for a final tumor dose of 4,440 cGy in twelve fraction over 8-9 weeks. RESULTS: Eleven of 39 lesions had complete response; 19 lesions had partial response; 4 lesions had no response; 3 lesions progressed under treatment. Response could not be assessed in two patients. The average survival after completion of therapy was 4.5 months ranging from 2 weeks to 31 months. Palliation was achieved in 33 of 39 lesions. The acute reactions were minimal and no late or long term complications were noted. CONCLUSION: The absence of significant complications with reasonable response in the high rate of palliation suggests that this rapid hyper fractionation palliation study should be studied for further evaluation.

Effect of rest interval on tumor and normal tissue response--a report of phase III study of accelerated split course palliative radiation for advanced pelvic malignancies (RTOG-8502)

From August 1985 through September 1989, 284 patients with advanced pelvic malignancies were entered into a trial (RTOG 8502) of palliative split course radiation (4440 cGy in three courses of 1480 cGy/2 days/4 fractions with a rest of 2-4 weeks between courses). The initial 148 patients were part of a Phase II acceptable response rate and minimal acute or late toxicity (IJRBP 17:659-662, 1989). The present analysis is a report of the subsequent 136 patients randomized between rest intervals of 2 weeks versus 4 weeks to determine if length of rest would influence tumor response or patient toxicity. The patients were stratified for performance status (Karnofsky Performance Status) and histology. The patients were evenly matched for age and sex. There was a trend toward increased acute toxicity incidence in patients with shorter rest interval (5/68 versus 0/68; p = .07). Late toxicity was not significantly different between the two groups. Decreasing the interval between courses did not result in a significant improvement in tumor response (CR+PR = 34% vs. 26%, p = n.s.). More patients in the 2 week groups completed all three courses (72% vs. 63%). Not surprisingly, patients completing cell three courses had a significantly higher overall response rate than for patients completing less than three courses (42% vs. 5%) and higher complete response rate (17% vs. 1%). A multivariate analysis indicated performance status as the significant predictor for number of courses completed. For Karnofsky Performance Status greater than or equal to 80, the survival at 12 months was 40% for the 2 week interval and 25% for the 4 week interval. Performance status and histology were the only significant variables in a multivariate analysis of survival.

Complications in the use of intra-abdominal 32P for ovarian carcinoma.

From 1982 through 1989, 94 patients at the University of Louisville with ovarian neoplasm had abdominal instillation of 15 mCi chromic 32P as part of their management. The timing of the 32P was immediately postoperative in 55 patients and delayed greater than 24 hr in 39 patients. This is an analysis of factors contributing to gastrointestinal (GI) complications. GI complications were graded according to RTOG guidelines. There was a total of 11 GI complications grade 3 or worse for an overall incidence of 12%. Factors analyzed include timing of 32P delivery, age, stage, number of previous surgeries, use of Hyskon at surgery, addition of external beam radiation, and subsequent use of chemotherapy. There were significantly fewer complications when 32P was given on the same day as surgery than when 32P administration was delayed more than 12 hr following surgery (4% vs 21%), P = 0.007. This difference held significance when adjusted for the number of previous surgeries, use of Hyskon, external beam radiation, and stage. None of the other factors had a significant effect on complication rate. There have been no incidences of contamination even though 32P instillation in the immediate post-operative period had increased risk of contamination due to wound leakage or reoperation. In our experience, the delivery of 32P in the immediate postoperative period resulted in a significant reduction in abdominal complications.