The effect of mycophenolate mofetil on podocytes in nephrotoxic serum nephritis.

Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca2+-actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca2+ concentration ([Ca2+]i), the experimental design was repeated in mice expressing podocyte-specific Ca2+ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca2+ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca2+]i imaging in podocytes showing decreased Ca2+ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca2+]i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.

A unitary perturbation theory approach to real-time evolution problems.

We discuss a new analytical approach to real-time evolution in quantum many-body systems. Our approach extends the framework of continuous unitary transformations such that it amounts to a novel solution method for the Heisenberg equations of motion for an operator. It is our purpose to illustrate the accuracy of this approach by studying dissipative quantum systems on all timescales. In particular, we obtain results for non-equilibrium correlation functions for general initial conditions. We illustrate our ideas for the exactly solvable dissipative oscillator and, as a non-trivial model, for the dissipative two-state system.

Palliative treatment of unresectable bile duct tumours.

PURPOSE: Report on outcome of intraluminal high-dose-rate iridium-192 (HDR-Ir192) brachytherapy with or without external radiotherapy in patients with unresectable bile duct tumours suffering from symptoms of malignant obstructive jaundice. MATERIAL AND METHODS: Fourteen patients (mean age: 63 years) who were unsuitable for surgical resection on preoperative evaluation/laparotomy or inoperable due to poor general condition were referred for palliative radiotherapy. After percutaneous transhepatic drainage, HDR-Ir192 brachytherapy was performed with a single dose of 2.5 Gy. Brachytherapy was given twice a day with at least a 6-h interval for 2 days, 2 or 3 days apart, up to a total dose of 10 Gy. Five patients received small-volume external radiotherapy (RT) (45 - 50.4 Gy/1.8 Gy) additionally. RESULTS: Palliation with relief of the aggravating symptoms of obstructive jaundice was achieved in all patients. The actuarial 2-year survival rate of all patients was 11.9 % with a median survival of 6.5 months. Patients treated with brachytherapy alone had a median survival of 4.5 months as compared with 6.5 months after combined internal and external irradiation (log rank, P = 0.95). CONCLUSION: Patients with advanced unresectable bile duct cancer face a dismal prognosis; however, biliary drainage, and intraluminal brachytherapy with or without external RT, seem to be able to improve quality of life in the remaining time span.

Hyperbaric oxygen--an effective tool to treat radiation morbidity in prostate cancer.

PURPOSE: We report the results of hyperbaric oxygen therapy (HBO) used in the treatment of radiation cystitis and proctitis following irradiation of prostate cancer. MATERIALS AND METHODS: Between June 1995 and March 2000, 18 men (median age 71 years) with radiation proctitis (n=7), cystitis (n=8), and combined proctitis/cystitis (n=3) underwent HBO therapy in a multiplace chamber for a median of 26 sessions (range 2-60). The treatment schedule (2.2-2.4 atmospheres absolute, 60 min bottom time, once-a-day, 7 days a week) was set at a lower limit of 20 sessions; the upper limit was left open to symptom-related adjustment. Prior to HBO treatment, RTOG/EORTC late genitourinal (GU) morbidity was Grade 2 (n=3), Grade 3 (n=6) or Grade 4 (n=2); modified RTOG/EORTC late gastrointestinal (GI) morbidity was either Grade 2 (n=4) or Grade 3 (n=6). RESULTS: Sixteen patients underwent an adequate number of sessions. RTOG/EORTC late GU as well as modified GI morbidity scores showed a significant improvement after HBO (GI, P=0.004; GU, P=0.004; exact Wilcoxon signed rank test); bleeding ceased in five out of five patients with proctitis and in six out of eight patients with cystitis; one of those two patients, in whom an ineffective treatment outcome was obtained, went on to have a cystectomy. CONCLUSIONS: HBO treatment seems to be an effective tool to treat those patients with late GI and GU morbidity when conventional treatment has led to unsatisfactory results. Particularly in patients with radiation cystitis, HBO should not be delayed too long, as in the case of extensive bladder shrinkage improvement is hard to achieve.

[Radiotherapy of endocrine orbitopathy--state of the art]. / Bestrahlungsbehandlung der endokrinen Orbitopathie--State of the Art.

Since several decades, radiotherapy is included in the multimodal treatment concept of Graves' disease. By using orbital irradiation alone or in combination with oral corticosteroids up to two thirds of the patients respond to the treatment and achieve improvement of soft tissue signs and extraocular muscle impairment.

Radiotherapy as adjunct to surgery for malignant carotid body paragangliomas presenting with lymph node metastases.

PURPOSE: Three cases of malignant carotid body paragangliomas with nodal metastases are reported. PATIENTS AND METHODS: Between 1985 and 1994, 3 female patients (51 to 65 years of age) were referred for postoperative radiotherapy after complete (2) or incomplete (1) surgical excision of a malignant carotid paraganglioma (Shamblin III). Preoperative angiographic embolization of the tumor-supplying arteries was performed in all cases. In 2 patients resection of the internal carotid artery and reconstruction by saphenous vein graft was necessary. Continuous course radiotherapy of the tumor bed (50 to 56 Gy/2 Gy) and regional lymph nodes (50 Gy) using photon beams was delivered in 2 patients. The third patient having had incomplete resection cancelled radiotherapy after 4 Gy. RESULTS: Within an observation time of 110 and 119 months no evidence of recurrence was obtained in both patients irradiated postoperatively. The third patient died of progressive disease. Twelve months after the withdrawn irradiation she presented with a tumor progression into the brain and an ulcerated mass on the right side of the neck and was irradiated consecutively for palliation (Figures 1a to 1f). In none of the patients severe acute or late radiation-induced complications were observed. CONCLUSION: In patients with malignant paraganglioma moderate dose postoperative radiotherapy of the tumor bed and regional lymph nodes is well tolerated. It seems to be effective to prolong local control after surgery, to eradicate microscopic lymphatic disease and eventually to postpone further spreading.

The prognostic significance of peritoneal seeding and size of postsurgical residual in patients with stage III epithelial ovarian cancer treated with surgery, chemotherapy, and high-dose radiotherapy.

OBJECTIVE: The aim of this study was to retrospectively analyze the prognostic importance of age, histologic type and grade, ascites, lymph node status, size and type of postoperative residual disease, and radiation dose on disease-specific (DSS) and progression-free survival (PFS) in stage III epithelial ovarian cancer patients who had been treated with radical surgery, postoperative chemotherapy, and high-dose radiotherapy. METHODS: Consolidation radiotherapy including whole abdominal radiation, pelvic, and upper abdominal boosts was employed in 46 patients who showed no evidence of residual or progressive disease after completion of multiagent chemotherapy. The median follow-up for all patients was 36 months and 103 months for patients at risk. The prognostic impact of pretreatment and treatment parameters on DSS and PFS was tested in univariate and multivariate analyses. RESULTS: The 5-year DSS and PFS rates for all patients were 38 and 33%, and for patients with 0-< or =2 cm residual tumor 65 and 61%, respectively. In univariate analysis, initial peritoneal seeding (both: P = 0.02), ascites (P = 0.03; 0.01), size of residual (0-< or =2 cm vs >2 cm), and residual miliary subdiaphragmatic (MDS) and localized peritoneal seeding (LPS) in the upper abdomen (P = 0.0002; 0.0003) were significantly correlated with DSS and PFS. Dose of radiation (< or =30 vs >30 Gy) correlated with DSS only (P = 0.02). In multivariate analysis size of residual disease (0-< or =2 cm vs >2 cm and/or MDS or LPS) remained the only independent prognostic factor for DSS and PFS (both; P = 0. 001). CONCLUSION: Patients with localized peritoneal seeding who were rendered free of disease elsewhere had an outcome equally poor as that of patients with gross residuals (>2 cm) in the upper abdomen. If our findings can be confirmed, attempted resection of all localized seeding in patients who are otherwise cytoreducible to no or minimal residual disease may be considered in combination with Taxol-containing regimens as are now being utilized for patients with gross disease.

Radiotherapy for invasive thymoma and thymic carcinoma. Clinicopathological review.

PURPOSE: This study reports clinicopathological features and outcome of thymic tumors. Twenty-seven patients with invasive thymoma and 6 patients with thymic carcinoma who had received radiotherapy either primary or postoperatively were analyzed retrospectively. PATIENTS AND METHODS: All 33 patients were irradiated with a mean dose of 50 Gy after complete resection (16 patients), partial resection (9 patients) or biopsy (8 patients). Staging was done according to the Masaoka classification; there were 12 Stage II, 12 Stage III and 9 Stage IV patients. RESULTS: In patients with invasive thymoma Stage II to IV (median follow-up 54.4 months) Kaplan-Meier estimates of overall survival (OS), disease-specific (DSS) and disease-free survival (DFS) at 5 years were 63.7% (95% confidence interval [CI], 42 to 84%), 88.3% (CI, 75 to 100%) and 77.4% (CI, 58 to 95%), respectively. Among the prognostic factors tested, such as age, myasthenia gravis, completeness of surgery and histologic subclassification, total radiation dose, and Masaoka Stage, the latter was the only significant predictor of improved survival (p = 0.04). Considering local control, radiation dose was a significant prognostic factor (p = 0.0006). In patients with thymic carcinoma (median follow-up 43.4 months) 5-year DSS, and DFS were 22.2% (CI, 0 to 60%) and 16.7% (CI, 0 to 46%), respectively. Thymoma as compared to thymic carcinoma had a statistically significant better DSS (p = 0.007) and DFS (p = 0.0007). CONCLUSION: Postoperative radiotherapy with sufficient doses plays an important role as adjuvant treatment in complete or incomplete resected invasive Stage II to III thymoma. In unresectable thymoma Stage III to IV as well as in thymic carcinoma a multimodality approach should be considered to improve survival.

Chemotherapy versus radiotherapy versus observation for high-risk cervical carcinoma after radical hysterectomy: A randomized, prospective, multicenter trial.

BACKGROUND: Adjuvant treatment modalities after radical hysterectomy have long been used in an attempt to eradicate microscopic tumor residuals in patients at high risk for recurrence. However, it has not been clearly demonstrated that adjuvant radiation, adjuvant chemotherapy, or both improve the outcome. To evaluate the effect of adjuvant treatment in patients with high-risk cervical cancer after radical hysterectomy, the Austrian Gynecologic Oncology Group conducted a prospective, randomized, multicenter clinical trial between 1989 and 1995. MATERIAL AND METHODS: Seventy-six patients with stage IB-IIB cervical cancer treated with radical hysterectomy with pelvic lymph node metastases and/or vascular invasion randomly received adjuvant chemotherapy (400 mg/m2 carboplatin, and 30 mg bleomycin), standardized external pelvic radiation therapy, or no further treatment. RESULTS: After a median follow-up of 4.1 years (range, 2-7) there were no statistically significant differences (P = 0.9530) in disease-free survival among the three treatment arms. CONCLUSION: The data suggest that adjuvant chemotherapy or radiation do not improve survival or recurrence rates in high-risk cervical cancer patients after radical hysterectomy. The most important treatment for these patients seems to be radical abdominal hysterectomy with systematic pelvic lymphadenectomy.

Consolidation radiotherapy after carboplatin-based chemotherapy in radically operated advanced ovarian cancer.

OBJECTIVE: The aim of the study was to evaluate the effect of additional radiotherapy after chemotherapy on the relapse-free and overall survival rates of patients with advanced ovarian cancer. METHODS: Between 1985 and 1992 64 patients with radically operated ovarian cancers (4 stage IC, 2 stage II, 54 stage III, and 4 stage IV) were enrolled in a randomized study. Radical surgery comprised total abdominal hysterectomy and bilateral salpingo-oophorectomy, omentectomy, and pelvic and paraaortic lymphadenectomy. All patients received adjuvant chemotherapy with carboplatin IV 400 mg/m2, epirubicin IV 70 mg/m2 on day 1 and prednimustine orally 100 mg/m2 on days 3 to 7 at 1-month intervals. Thirty-two patients without residual disease were randomized to whole abdominal radiation (30 Gy, administered over 4 weeks). An additional 21.6 Gy were delivered to the pelvis and 12 Gy to the paraaortic region up to the diaphragm for total doses of 51.6 and 42 Gy, respectively. Cancer-related survival was calculated with the Kaplan-Meier and Cox proportional hazards methods. RESULTS: The relapse-free and overall survival rates of patients who received adjuvant chemoradiotherapy were significantly higher than those of patients who received adjuvant chemotherapy only (68% vs 56% at 2 years and 49% vs 26% at 5 years, P = 0.013, and 87% vs 61% at 2 years and 59% vs 33% at 5 years, P = 0.029). The differences were most pronounced in patients with stage III disease (77% vs 54% at 2 years and 45% vs 19% at 5 years, P = 0. 0061, and 88% vs 58% at 2 years and 59% vs 26% at 5 years, P = 0. 012). Toxicities were acceptable. CONCLUSION: Sequential combination of platinum-based chemotherapy with open-field abdominal radiotherapy is a promising adjuvant regimen for patients with advanced ovarian cancer.

Adjuvant radiotherapy in male breast cancer.

PURPOSE: To determine retrospectively the outcome of postoperative radiation therapy in male breast cancer. Local/distant control was assessed with attention to age, stage, lymph node involvement, histopathological differentiation and hormone receptor status. MATERIALS AND METHODS: Thirty-one male patients were irradiated postoperatively at the chest wall (mean dose 50 Gy) and 16 patients received radiation to regional lymph nodes. Tumour distribution by stage was: stage 0 (9.7%), stage I (22.6%), stage II (32.2%) and stage III (35.5%). Nine patients were subjected to additional hormone therapy and three patients to chemotherapy. RESULTS: Local control was achieved in 30/31 (96.8%) patients. Kaplan-Meier estimates of overall survival (OS), disease specific (DSS) and disease free survival (DFS) at 5 years were 77% (95% confidence interval (CI), 0.61-0.93), 84% (CI, 0.69-0.98) and 73% (CI, 0.57-0.91), respectively. Five-year DFS for stage 0 + I, II and III was 100, 56.3 and 67.3%, respectively. Favourable results were observed in patients with negative axillary nodes with 5-year OS/DFS of 90.9% (CI, 0.74-1.0). For lymph node positive patients DFS was 71% (CI, 0.4-1.0). Patients who presented lymph node metastases with extracapsular extension the 5-year OS was 80% (CI, 0.45-1.00), but the DFS was 0%. Stage of disease, lymph node involvement and histological differentiation were found to have statistically significant influence on DFS, but not on OS. CONCLUSION: Application of postoperative radiotherapy approved in females resulted in one local relapse in our study population. Other treatment modalities (hormone therapy/chemotherapy) should continue to be considered a necessary treatment option for appropriately selected patients.

The costs of radiosurgical treatment: comparison between gamma knife and linear accelerator.

Radiosurgical treatment can be carried out by means of a Gamma Knife or a Linear Accelerator. The Linear Accelerator may be either a single-purpose appliance, exclusively employed in radiosurgery, or an adapted appliance, which is used primarily for fractioned radiotherapy, and only additionally for radiosurgical purposes. The first alternative will be referred to briefly as a "dedicated Linac", the latter as an "adapted Linac". Cost accounting data for these alternatives will be discussed under three main categories: investment costs, operating costs, and finally staffing costs. Costs are only considered to the extent that this is necessary to facilitate a comprehensive cost comparison. Factors for which the costs remain the same or at least broadly the same will from the outset not be taken into consideration. These include, for instance, the costs of general or special administration, diagnosis, and image processing. The results and conclusions of this study therefore cannot be employed immediately in the evaluation of cost reimbursement schemes of the type carried out by agencies responsible for social insurance. Here, appropriate complete cost analyses especially for this purpose are required. The final comprehensive cost comparison reveals that the adapted Linac is the most favourable alternative with small annual quantities of patients. With larger numbers of patients the Gamma Knife represents the most favourable from a cost accounting angle. The dedicated Linac accordingly does not have a cost advantage for any of the examined numbers of patients. Clearly the lowest treatment costs per patient can be achieved by employing a Gamma Knife and using it to capacity.

Prognostic factors in patients with carcinoma of the uterine cervix treated with external beam irradiation and IR-192 high-dose-rate brachytherapy.

PURPOSE: Prognostic factors in cancer of the cervix for patients treated with external beam irradiation (EBR) and low-dose-rate (LDR) brachytherapy have been characterized. However, despite the increasing use of high-dose-rate (HDR) intracavitary placements (ICP), few studies with adequate follow-up have analyzed prognostic factors. This study investigates pretreatment and treatment factors for their correlation with treatment outcome after EBR and HDR-ICP. METHODS AND MATERIALS: Between September 1985 and December 1994, 181 patients with carcinoma of the cervix FIGO stages IB-IV received EBR and HDR brachytherapy. Hemoglobin (Hb) levels were maintained above a level of 11 g/dl during the treatment by transfusion. Patient age ranged from 34 to 84 years (median: 66). The median follow-up time for patients at risk is 69 months (range: 23-140). Pretreatment and treatment parameters analyzed to determine their prognostic value included age, FIGO stage, tumor size, tumor type and grade, pretreatment Hb level, number of HDR-ICP, total dose from HDR-ICP, overall dose to point A, and overall treatment time. Also evaluated was the prognostic value of enlarged lymph nodes noted on pretreatment CAT scan of the abdomen and pelvis. Endpoints studied in uni- and multivariate analyses were disease-specific survival (DSS), freedom from disease (FFD), pelvic control (PC), and probability of distant metastases (DM). RESULTS: At 5 years the DSS, FFD, and PC rates for all patients were 60%, 58%, and 67%, respectively. The 5-year FFD by stage was: IB: 94%; II: 63%; IIIB: 43%; and IV: 0%. The PC rates were 94%, 66%, 59%, and 0%, respectively. In univariate analysis the prognostic factors identified for FFD were FIGO stage, tumor size, initial Hb level, and enlarged pelvic and/or paraaortic nodes (all: p < 0.0001). Age was inversely correlated with outcome (p = 0.0081). The 5-year FFD rates for tumors (< 3, > or = 3 < 6, > or = 6 cm) were 97%, 65%, and 24%; patients with initial Hb levels < or = 11g/dl had a FFD of 26% versus 69% for patients with levels > 11g/dl; and those with pelvic and/or paraaortal nodes > or = 1 cm had a survival of 32% versus 68% in patients with negative readings. The same factors were also prognostically significant for DSS, PC, and DM. Patients with persistent disease or pelvic failures had a significantly higher incidence of DM than patients in whom pelvic disease was controlled (p < 0.0001).Histological and treatment parameters including overall treatment time were not of prognostic significance for any of the endpoints studied. In multivariate analysis tumor size was the most powerful parameter for DSS, FFD, PC (p < 0.0001) and DM (p = 0.0001), followed by low initial Hb level (DSS: p = 0.0004, FFD: p = 0.0009, PC: p = 0.0012, DM: p = 0.0265), and enlarged pelvic and/or paraaortic nodes which were predictive for DSS (p = 0.0210) and DM (p = 0.0011). CONCLUSION: This study confirms that prognostic factors for patients treated with HDR brachytherapy are similar to those reported in previous series that employed LDR brachytherapy. The significance of tumor size, pretreatment Hb level, and enlarged pelvic and/or paraaortic lymph nodes on CAT scan over FIGO stage of disease were demonstrated. Future prospective trials should be undertaken to confirm the validity of these factors and to elucidate their therapeutic implications.

[The photon therapy of subfoveal choroidal neovascularization in age-dependent macular degeneration. The results of a prospective study in 40 patients]. / Photonentherapie der subfovealen choroidalen Neovaskularisation bei altersabhängiger Makuladegeneration. Ergebnisse einer prospektiven Studie an 40 Patienten.

AIM: To determine the effect of external beam radiotherapy on subfoveal choroidal neovascularization in age-related macular degeneration. PATIENTS AND METHODS: Between September 1995 and July 1996, 40 patients (9 males and 31 females; mean age 74 years, range 61 to 83 years) were included in a prospective study. Eight patients had classic, well-defined neovascularisations, 32 patients had occult lesions. Complete ophthalmic investigations included visual acuity contrast sensitivity as well as fluorescein and indocyanine green angiographic examinations prior to treatment and 1, 3, 6, and 12 months after radiotherapy. External beam radiotherapy (8-MV photons) was delivered with a total dose of 14.4 Gy in 8 fractions of 1.8 Gy per day (Figures 1 and 2). The field size averaged 5.5 x 4.5 cm. RESULTS: No treatment related morbidity during or after treatment was obtained. After 6 months follow-up the visual acuity was improved in 2 (5%) patients and maintained at pretreatment level in 17 (42%) patients. However, 12 months post treatment a stable situation was found in 6 (15%) patients and a decrease in visual acuity in 34 (85%) patients (Table 1). The central visual fields deteriorated significantly from 16.5 decibel (dB) to 12.4 dB. The enlargement of exudates and neovascular membranes increased 5- to 7-fold. At 12 months after treatment, 3 (7.5%) patients stated that they had improved vision subjectively, 12 (30%) patients had no change and 25 (62.5%) patients suffered from subjective decrease in visual acuity. CONCLUSIONS: Using a total dose of 14.4 Gy/1.8 Gy no difference concerning visual acuity and exudative changes in comparison to the natural history on age-related macular degeneration was obtained after 12 months. However, the results of multicenter studies are to be awaited.

Endocavitary Ir-192 radiation and laser treatment for palliation of obstructive rectal cancer.

Endoscopic laser therapy (ELT) either alone or combined with endocavitary Ir-192 radiation is performed for advanced, inoperable rectal cancer and when patients are ineligible for surgery due to severe concomitant medical illness. During the period from January 1984 to January 1997 we treated 81 patients (51 males, 30 females). Sixty-seven patients had ELT only using a ND-Yag Laser system. Twenty-five patients (average age: 80.5 years) were ineligible for surgery (Group I). Forty-two patients (74.1 years) had an advanced locally inoperable tumour (Group II). Fourteen patients (76.5 years) underwent a combined therapeutic regime with endocavitary Ir-192 afterloading following ELT (Group III). Adequate desobliteration was achieved in 100% (groups I and III) and 97% (group II) of the patients. The average interval to aftertreatment was 8.4 weeks in group I and 9.4 weeks in group II, compared to 11.5 weeks in group III. Serious complications (perianal abscess, rectovaginal fistula) occurred in 3.7%, minor complications (laser-induced bleedings, unclear fever) in 12.3%. All laser-induced bleedings could be dealt with using laser therapy. The frequency of treatment was governed by tumour mass and the patient's survival. The results suggest that additional endocavitary radiation significantly prolongs the maintenance of normal bowel function compared with laser therapy alone.

Postoperative radiotherapy in radically resected non-small cell lung cancer.

PURPOSE: To evaluate the value of adjuvant postoperative external-beam radiation (EBR) in patients with radically resected non-small cell lung cancer (NSCLC) pT1-3 pN0-2 compared to patients with resected NSCLC without adjuvant EBR. MATERIALS AND METHODS: In 155 patients (121 male, 34 female; mean age, 59 years) 105 lobectomies, 12 bilobectomies, and 38 pneumonectomies with radical lymph node dissection of the contralateral [corrected] side were performed. Postoperative staging was done according to the TNM system and was as follows: pT1 (n=38), pT2 (n=89), pT3 (n=28); pN0 (n=39), pN1 (n=67) and pN2 (n=49). Histopathologic study revealed 68 squamous cell carcinomas, 53 adenocarcinomas, 21 large cell carcinomas, 6 adenosquamous cell carcinomas, and 7 bronchioloalveolar cell carcinomas. All patients were randomly assigned into two treatment groups: 72 patients with no further treatment (control group), and 83 patients (EBR group) with adjuvant postoperative EBR of the bronchial stump and mediastinum (50 to 56 Gy, 8 or 23 MV photons, 2 Gy/d, 5 d/wk) beginning 4 to 6 weeks after surgery. RESULTS: The overall 5-year survival rate (median observation time, 43 months) of all patients was 24.1% (EBR group, 29.7%; control group, 20.4%; p>0.05, not significant). The relative risk of the EBR group was 0.85 with a two-sided confidence interval of 0.66 to 1.09. The overall 5-year recurrence-free survival was 20.6% (EBR, 27.1%; control group, 15.6%; p=0.07). The relative risk of the EBR group was 0.80 with a confidence interval of 0.63 to 1.01. The rate of local recurrences at the bronchial stump and/or mediastinum was significantly smaller in the EBR group (n=5) than in the control group (n=17) (p<0.01). Multivariate analysis (chi2 test) demonstrated an independent influence of postoperative EBR on the incidence of local recurrences. The incidence of distant metastases was slightly but not significantly higher in patients without EBR (38 patients) compared to those who had EBR (32 patients). CONCLUSION: High-dose postoperative EBR to the mediastinum significantly reduces the risk of local recurrence at the bronchial stump and/or mediastinum. Age, sex, histologic subtype, tumor size, surgical approach, or extent of lymph node involvement had no prognostic value--only postoperative EBR had an independent influence on the risk of local recurrence. The effect of postoperative EBR was on the verge of significance with respect to recurrence-free survival and showed the same tendency in overall survival, however with an attenuated relative risk.

Carcinoma of the cervix: analysis of complications after primary external beam radiation and Ir-192 HDR brachytherapy.

BACKGROUND AND PURPOSE: There is still a concern that the use of HDR brachytherapy might result in an increase of late tissue damage. This restrospective study evaluates the incidence and severity of late complications in patients with carcinoma of the cervix who underwent combined external beam radiation (EBR) and Ir-192 HDR brachytherapy and attempts to identify pretreatment and treatment parameters correlating with late complications. MATERIAL AND METHODS: Between 1985 and 1992, 161 patients with carcinoma of the cervix (FIGO stages IB-IVB) received EBR to the pelvis (ave, max. dose 48.8 Gy) followed by 1-6 Ir-192 HDR placements (median 2). Doses to point A ranged from 8.5 to 38.7 Gy (median 17 Gy). Parameters examined included age, diabetes, obesity, history of inflammatory bowel disease or diverticulitis, prior surgery, hemoglobin level, FIGO stage, EBR dose, technique and daily dose fraction, number of HDR treatments and total dose to point A, maximum doses to bladder and rectum delivered by brachytherapy and cumulative dose to point A. Median follow-up for all patients was 37 months. Complications were rated using an in-house scoring system and according to the French-Italian Glossary (FIG). RESULTS: Actuarial 5-year survival was 93%, 57%, 46%, and 0% for stages IB, II, IIIB, and IV, respectively. Of 161 patients, 11% developed moderate and 3.7% severe sequelae (FIG: 2.5%, 3.7%). Since some patients experienced more than one complication, the overall incidence was 13.6% and 4.9% (FIG: 3.1%, 4.9%) with respective 5-year actuarial rates of 14% and 5% for moderate, and 2% and 8% for severe bowel and genitourinary tract complications (FIG: 3.5%, 0, and 2%, 8%). All severe bowel complications occurred within 1.5 years whereas urinary tract sequelae continued to develop throughout the follow-up period. FIGO stage was associated with a significant increase in late sequelae (P = 0.015). Analysis of the remaining pretreatment and treatment parameters failed to reveal any statistically significant correlation with moderate or severe sequelae. CONCLUSION: In our series using HDR brachytherapy, complication and survival rates were comparable with other series employing either LDR or HDR procedures. Of all parameters analysed, stage of disease was the only parameter significantly correlated with complications in univariate and multivariate analysis.

"Adjuvant" external radiation of the mediastinum in radically resected non-small cell lung cancer.

OBJECTIVE: The effect of postoperative external beam radiation in MO non-small cell lung cancer resected with curative intention was evaluated in a randomized trial. METHODS: In 155 patients (121 males, 34 females; mean age: 59 years) 105 lobectomies, 12 bilobectomies and 38 pneumonectomies with radical lymph node dissection to the contralateral side were carried out. Histology revealed squamous cell (n = 68), adeno- (n = 53), large cell (n = 21), adenosquamous (n = 6) or bronchioloalveolar type (n = 7) carcinomas. The pathologic stages T1 (n = 38), T2 (n = 89), T3 (n = 28); NO (n = 39), N1 (n = 67), and N2 (n = 49) were evenly distributed between the two treatment groups: group A (72 patients) had no further oncologic treatment, while group B (83 patients) had external beam radiation to the mediastinum (50-56 Gy, 8 or 23 MeV photons, 2 Gy/day, 5 days a week) beginning 4 weeks after the operation. RESULTS: The overall 5-year survival rate of the whole collective was 24.1% without any significant difference between the radiotherapy group B (29.7%) and the control group A (20.4%) (log-rank test: P > 0.05). The overall 5-year recurrence-free survival rate was 20.1%, with no difference between groups B and A (radiotherapy: 22.7, controls: 15.6%, long-rank test: P > 0.05). There was no difference in the incidence of distant metastases (external beam radiation: n = 32; controls: n = 38). The rate of local recurrences at the bronchial stump or in the mediastinum, however, was significantly reduced in the radiotherapy group (n = 5) compared with 17 in the controls (P < 0.01 chi-square test). A multivariate analysis confirmed the independent influence of postoperative radiotherapy on the incidence of local recurrence. CONCLUSIONS: External radiation of the mediastinum in radically resected non-small cell lung cancer reduces the risk of local recurrence, but has no influence on distant metastastic spread and overall survival.

Ammonia production from hippurate by the rat kidney in vitro.

Hippurate is known to be synthesized from benzoate and glycine in the liver and kidney. It takes part in renal ammoniagenesis by modulating the activity of gamma-glutamyl transpeptidase (gamma GT). Due to its chemical structure, however, hippurate might also serve as a substrate of renal ammoniagenesis. Hippurate may yield ammonia either having been cleaved by hippuricase or by Erlenmeyer's reaction after condensation with an aldehyde. In order to elucidate the possibility of hippurate being a substrate of renal ammoniagenesis, experiments were carried out on cortical kidney slices and on isolated tubular segments of the rat. The incubation medium (pH 7.1) was enriched with 10 mmol/l hippurate spiked with 15N-hippurate, some of the known competitive inhibitors of hippuricase, acivicin and different aldehydes. Factors known to affect hippuricase or gamma GT did not interfere with renal ammonia production. Glyceraldehyde (up to 1.0 mmol/l) but not glycerate had a stimulating effect, especially on the ammoniagenesis from hippurate. In normal rats fed a vegetarian diet, 1% of the added 15N moiety was found to be 15NH3. Renal 15NH3 production was significantly greater if, prior to the experiments, the animals were either acidotic or had a reduced renal mass or were fed animal proteins. These results indicate that hippurate may, to a certain extent, serve as substrate for ammoniagenesis.