Mucosal mast cells are indispensable for the timely termination of Strongyloides ratti infection.

Mast cells and basophils are innate immune cells with overlapping functions that contribute to anti-helminth immunity. Mast cell function during helminth infection was previously studied using mast cell-deficient Kit-mutant mice that display additional mast cell-unrelated immune deficiencies. Here, we use mice that lack basophils or mucosal and connective tissue mast cells in a Kit-independent manner to re-evaluate the impact of each cell type during helminth infection. Neither mast cells nor basophils participated in the immune response to tissue-migrating Strongyloides ratti third-stage larvae, but both cell types contributed to the early expulsion of parasitic adults from the intestine. The termination of S. ratti infection required the presence of mucosal mast cells: Cpa3Cre mice, which lack mucosal and connective tissue mast cells, remained infected for more than 150 days. Mcpt5Cre R-DTA mice, which lack connective tissue mast cells only, and basophil-deficient Mcpt8Cre mice terminated the infection after 1 month with wild-type kinetics despite their initial increase in intestinal parasite burden. Because Cpa3Cre mice showed intact Th2 polarization and efficiently developed protective immunity after vaccination, we hypothesize that mucosal mast cells are non-redundant terminal effector cells in the intestinal epithelium that execute anti-helminth immunity but do not orchestrate it.

Therapeutic outcome and side-effects after radiotherapy, chemotherapy and/or hyperthermia treatment of head and neck tumour xenografts.

The aim of the study was to optimise the still unsatisfactory therapeutic results in head and neck cancer by studying the results and the side-effects of radiotherapy, chemotherapy and/or local hyperthermia treatment of human tumour xenografts. Mice carrying human-derived head and neck squamous cell carcinoma xenografts with a mean volume of 100 mm(3) received 5x2 Gy, cisplatin or ifosfamide and/or local hyperthermia at 41/41.8 degrees C. Haematocrit and tumour volumes were determined two or three times per week, respectively, until day 25 or day 60. At day 60, the highest number of complete remissions (CRs) (80%) was observed in the triple modality therapy group with radiation, local hyperthermia at 41.8 C and cisplatin at a dosage of 2 mg/kg body weight (b.w.). Therapeutic side-effects were moderate weight loss and a mild anaemia. Thus, with regard to the long-term tumour-free survival, the most effective treatment was the combination of radiotherapy, cisplatin and local hyperthermia at 41.8 C.

Tumor oxygenation after radiotherapy, chemotherapy, and/or hyperthermia predicts tumor free survival.

PURPOSE: To investigate the influence of different treatment modalities (radiotherapy, chemotherapy, and hyperthermia) on the oxygenation of human tumor xenografts and to correlate it with the tumoricidal effect we conducted this study. METHODS AND MATERIALS: Human-derived head-and-neck squamous cell carcinoma xenografts (implanted in nude mice/nine groups of 10 mice) were treated with various treatment modalities and combinations of them (radiation with 5 x 2 or 10 x 2 Gy, hyperthermia at 41 degrees C or 41.8 degrees C, chemotherapy with ifosfamide [32 mg/kg] or cisplatin [2 mg/kg]). The tumor volume was evaluated 3 times per week until Day 60. Tumor pO(2) was measured at Day 1, 5, 8, and 12 with a polarographic pO(2) histograph. RESULTS: Within treatment time (maximum, 10 days) the median pO(2) increased in all groups (except the control group), concomitantly the fraction of measurements of pO(2) that were less than 10 mm Hg showed a constant decrease (p < or = 0.001). The highest difference between the median pO(2) values and the fraction of measurements of pO(2) that were less than 10 mm Hg at the start and 1 week after the end of therapy occurred in the groups with radiochemothermotherapy (triple-modality therapy; p< or = 0.001). At Day 60, the highest rate of complete remissions was observed in the triple-modality therapy groups. CONCLUSION: Tumor oxygenation under a single or combined cancer treatment is correlated with treatment efficacy in terms of complete remissions at Day 60. The posttherapeutic fraction of measurements of pO(2) that were less than 10 mm Hg correlates even better with the long term tumor free survival than the median pO(2) values or the pretherapeutic fraction of measurements of pO(2) that were less than 10 mm Hg.

Local hyperthermia, radiation, and chemotherapy in recurrent breast cancer is feasible and effective except for inflammatory disease.

PURPOSE: To investigate the feasibility and effectiveness of radiochemothermotherapy (triple-modality therapy) in patients with inoperable recurrent breast cancer. PATIENTS AND METHODS: Patients with inoperable recurrent lesions, World Health Organization (WHO) performance status of 2 or greater, life expectancy of more than 3 months, adequate bone marrow, hepatic and renal function were eligible for this Phase I/II study. Conventionally fractionated or hyperfractionated radiotherapy (RT) was performed. Once-weekly local hyperthermia (HT) combined with chemotherapy (CT; epirubicin 20 mg/m(2), ifosfamide 1.5 g/m(2)) was applied within 30 min after RT. RESULTS: Twenty-five patients, all heavily pretreated (18/25 preirradiated), received a mean total dose of 49 Gy. The median number of HT/CT sessions was 4. Skin toxicity was low, whereas bone marrow toxicity was significant (leucopenia Grade 3/4 in 14/1 patients). The overall response rate was 80% with a complete response (CR) rate of 44%. Response rates in patients with noninflammatory disease (n = 14; CR 10 patients, partial response [PR] 3 patients) were far better than in patients with inflammatory disease (n = 11; CR 1 patient, PR 6 patients). CONCLUSIONS: In patients with recurrent breast cancer, triple-modality therapy is feasible with acceptable toxicity. High remission rates can be achieved in noninflammatory disease, however, local control is limited to a few months. Whether the addition of chemotherapy has a clear-cut advantage to radiothermotherapy alone remains an open question.

Local hyperthermia, hyperfractionated radiation, and cisplatin in preirradiated recurrent lymph node metastases of recurrent head and neck cancer.

Large tumor size is a negative prognostic variable for attaining complete regression (CR) with local hyperthermia (HT) and radiotherapy (RT). Such poor prognosis lesions (i.e., >7 cm(2) or >14 cm(3)) have an expected CR rate of similar to 30+/-8%. To improve on this result we added cisplatin to HT and RT with standard fractionation (std Fx) in an earlier study, and observed a 19% CR rate in head and neck (H&N) patients. We now report the results of a second generation trial combining HT, cisplatin (40 mg/m(2)) and hyperfractionated RT in a series of 13 pretreated poor prognosis H&N patients. Therapy encompassed 44 triple modality sessions and was well tolerated: toxicity included one episode of grade-3 skin reaction and one grade 1 leukopenia. Although the overall remission rate was 92%, the CR rate was only 8%; this resulted in early closure of this trial concluding that hyperfractionated RT had no (over std Fx RT) benefit in this combined modality approach.

A preclinical model for experimental chemotherapy of human head and neck cancer.

We developed a mouse model in a representative human derived head and neck cancer cell line for preclinical studies to evaluate antitumor response, tumor-free survival and host toxicity of alkylating agents, antimetabolites, platinum analogs and taxanes alone or in combination. Ninety athymic NMRI mice were inoculated with human derived oral squamous cell carcinoma cells growing on the hind paw to an average volume of 180 +/- 80 mm3. Animals were stratified according to tumor volume into 10 groups (n=6-10) and treated with ifosfamide (65 mg/kg b.w.), docetaxel (24 mg/kg b.w.), cisplatin (2 mg/kg b.w.), carboplatin (6 or 10 mg/kg b.w.), methotrexate (1 mg/kg b.w.), and fluorouracil (15 mg/kg b.w.) intravenously in single agent or combination (ifosfamide plus docetaxel or ifosfamide plus carboplatin) treatment schedules or controls. Tumor volume was measured 3 times per week for 60 days. The average tumor volume, the overall survival time and the response rates (CR, PR) of the treated animals were compared with the data obtained from untreated controls and statistically evaluated. Untreated tumors showed rapid and exponential tumor growth. Single agent therapies with ifosfamide, cisplatinum, and docetaxel lead to significant tumor regression and improved overall survival. Low dose carboplatin monotherapy induced significant tumor growth delay, but not significant tumor regression. Most impressive tumor-free survival was achieved by combination treatment with ifosfamide and docetaxel. This preclinical study demonstrates an animal model capable of differentiating various chemotherapy regimens.

Backscatter dose from metallic materials due to obliquely incident high-energy photon beams.

If metallic material is exposed to ionizing radiation of sufficient high energy, an increase in dose due to backscatter radiation occurs in front of this material. Our purpose in this study was to quantify these doses at variable distances between scattering materials and the detector at axial beam angles between 0 degree (zero angle in beams eye view) and 90 degrees. Copper, silver and lead sheets embedded in a phantom of perspex were exposed to 10 MV-bremsstrahlung. The detector we developed is based on the fluorescence property of pyromellitic acid (1,2,4,5 benzenetetracarboxylic acid) after exposure to ionizing radiation. Our results show that the additional doses and the corresponding dose distribution in front of the scattering materials depend quantitatively and qualitatively on the beam angle. The backscatter dose increases with varying beam angle from 0 degree to 90 degrees up to a maximum at 55 degrees for copper and silver. At angles of 0 degree and 55 degrees the integral backscatter doses over a tissue-equivalent depth of 2 mm are 11.2% and 21.6% for copper and 24% and 28% for silver, respectively. In contrast, in front of lead there are no obvious differences of the measured backscatter doses at angles between 0 degree and 55 degrees. With a further increase of the beam angle from 55 degrees to 90 degrees the backscatter dose decreases steeply for all three materials. In front of copper a markedly lower penetrating depth of the backscattered electrons was found for an angle of 0 degree compared to 55 degrees. This dependence from the beam angle was less pronounced in front of silver and not detectable in front of lead. In conclusion, the dependence of the backscatter dose from the angle between axial beam and scattering material must be considered, as higher scattering doses have to be considered than previously expected. This may have a clinical impact since the surface of metallic implants is usually curved.

Advanced non-seminomatous germ cell cancer of the testis with brain metastases: feasibility of additional brain irradiation and whole body hyperthermia plus chemotherapy.

Patients with brain metastases in disseminated non-seminomatous germ cell cancer of the testis are treated by combined modality, e.g., cisplatin-containing chemotherapy, whole brain irradiation and/or surgical excision. However, cure rates of patients refractory to that standard treatment are low (5-year survival rate <30%). Preclinical data on the use of hyperthermia combined with selected cytotoxic drugs clearly show increased tumor cell killing compared to chemotherapy alone with no increase in toxicity to normal tissue. These results are consistent with the concept that whole body hyperthermia (WBH) at 41.8 degrees C is non-myelosuppressive and can potentiate the tumoricidal effects of specific chemotherapeutic agents, thus improving the therapeutic index. We report on a patient with embryonal testicular cancer presenting with lung, liver and brain metastases who initially underwent orchiectomy, whole brain irradiation and cisplatin-containing chemotherapy. Restaging revealed minor regression of brain and lung metastases and no change of liver metastases. However, beta-HCG values dropped from initial 400000 mIU/ml to 12 mIU/ml with a normal alpha-fetoprotein all the time. Then, two cycles of whole body hyperthermia (WBH) plus chemotherapy were performed, followed by one cycle of chemotherapy without WBH. Radiotherapy, WBH and chemotherapy were well tolerated, especially no neurologic sequelae occurred. After more than 5 years of follow-up, the patient is still alive and disease-free. WBH plus chemotherapy seems to be feasible and may contribute to long-term survival in patients with advanced stages of non-seminomatous germ cell cancer refractory to standard treatment.

Rationale and clinical status of local hyperthermia, radiation, and chemotherapy in locally advanced malignancies.

The combination of ionizing irradiation and local hyperthermia therapy has been demonstrated to be efficacious in a variety of localized neoplasms. One of the most consistent conclusions from this experience, however, is the finding that large tumor size is a significant negative prognosticator for attaining complete tumor regression. During the past decade investigators have begun to look at the possibility of adding chemotherapy to thermo-radiotherapy in order to improve the efficacy of treatment in patients with large tumors. This review article summarizes the recent clinical experience with such triple modality therapy.

[Radiochemotherapy of penis carcinoma]. / Radiochemotherapie des Peniskarzinoms.

Some authors report successful use of radiochemotherapy in patients with penile cancer. The most promising chemotherapeutic agents in penile cancer are cisplatin, methotrexate, bleomycin, vinblastine, and vincristine. There are different protocols for the use of chemotherapeutic agents such as mono- or polychemotherapy in combination with radiotherapy. Operative treatment is still the primary approach in patients with penile cancer. However, in some patients with relevant co-morbidity who wish to receive organ-sparing therapy, radiochemotherapy may be applied when low-stage tumors (carcinoma in situ or T1) are present. There is no chemotherapeutic agent of choice to be recommended. The results of radiochemotherapy in patients with T2 tumors or higher are not satisfactory because local tumor control often cannot be achieved.

[Radiochemotherapy of urothelial carcinoma]. / Radiochemotherapie beim Urothelkarzinom.

Radical cystectomy is the current standard therapy for muscle invasive or locally advanced transitional cell carcinoma of the bladder. Organ-preserving monotherapeutic alternatives (e.g. transurethral resection, radiotherapy) do not lead to similar cure rates. In selected cases, a trimodal approach using transurethral resection and combined radio- and chemotherapy can be as efficient as cystectomy.

[Radiotherapy of penis carcinoma]. / Strahlentherapie des Peniskarzinoms.

Penile cancer is rare. Thus, there are no therapeutic recommendations fulfilling the requirements of evidence-based medicine. The empirically based therapeutic approach consists of local excision, laser therapy, or radiotherapy with comparable local control rates. Radiation is delivered by external beam radiotherapy or as brachytherapy. After radiotherapy, 5-year survival rates of 66-92% and organ preservation in 55-84% are reported. Serious long-term sequelae are necrosis (3-23%) and urethral stenosis (6-45%) requiring surgery. In the adjuvant treatment of the locoregional lymph nodes, lymphadenectomy and radiotherapy of both inguinal regions are therapeutic options. Inguinal lymph node metastases may be irradiated pre- or postoperatively to reduce the local recurrence rates. In addition, palliative radiotherapy of the primary tumor, lymph node, or distant metastases is of use for incurable patients. New combined therapies, e.g., radiochemothermotherapy, are currently under clinical evaluation and may offer a curative and organ-preserving therapeutic option to patients with locally advanced tumors.

[Radiotherapy of urothelial carcinomas of the urinary bladder]. / Strahlentherapie von Urothelkarzinomen der Harnblase.

Radiotherapy of bladder cancer is a locally effective therapeutic approach. It is increasingly becoming part of the multimodal protocols aimed at the preservation of both organ and organ function. In this context, it is an alternative to cystectomy. The addition of chemotherapy to radiotherapy enhances the curative potential of this non-surgical approach and may be useful especially in older, multimorbid patients. If chemotherapy can not be applied, the use of radiotherapy alone is reasonable, although in advanced tumors the results are disappointing. After the transurethral resection of bladder cancer, postoperative radiotherapy should be considered in muscle-invasive cancer as well as when other negative prognostic factors occur. The prerequisites for an effective, minimally toxic, state of the art radiotherapy are a subtle treatment-planning procedure and an accurate delivery of the radiation.

[Treatment results following breast-conserving therapy in primary breast cancer]. / Behandlungsergebnisse nach brusterhaltender Therapie des primären Mammakarzinoms.

OBJECTIVE: To evaluate mono-institutional results concerning tumor free survival, overall survival, local tumor control and rate of distant metastasis following breast-conserving therapy. PATIENTS AND METHODS: Retrospectively, 274 breast cancer patients who were treated between 1990-1997 in our institution were analysed. The whole breast was homogeneously irradiated (2.0 Gy to 50 Gy), followed by a boost of 10-16 Gy to the tumor bed. Mean follow-up was 55 months. Overall survival, local tumor control and rate of distant metastasis were analysed. RESULTS: Cause-specific survival at 5 years after treatment was 93 %. Within 3 to 60 months following treatment, 18 (7 %) patients suffered from ipsilateral breast recurrence. 24 (9 %) patients developed contralateral carcinoma. Survival from local recurrence (single manifestation) was 78 % at 5 years after treatment, 20 % at 7 years. Occurrence of local failures was significantly correlated to receptor status, contralateral carcinoma, distant metastasis and surgical technique and not to tumor size, margins, grading, nodal status, age or lymphangiosis. 9 % of the patients developed distant metastases, predominantly bone metastases (71 %). Survival from distant metastasis was 64 % at 5 years, 10 % at 7 years. Occurrence of distant metastasis was significantly correlated to grading, tumor size, receptor status, lymphangiosis or local recurrence. CONCLUSION: Our institutional results show that tumor free survival, overall survival, local tumor control and distant failure rate achieved by breast conserving therapy are within the range of literature data.

[The value of radiotherapy in the treatment of esthesioneuroblastoma]. / Die Stellung der Radiotherapie in der Behandlung des Asthesioneuroblastoms.

Three cases of aesthesioneuroblastoma highlight the problems of treatment of these extremely rare tumours. These tumours of the olfactory epithelium arise in the nasal cavity and invade the paranasal sinuses, the orbit and the skull base. As symptoms occur late in the disease, most cases are advanced when diagnosed. Early cases can be treated by surgery, by irradiation or by a combination of, but the local control rate is about 60% regardless of the treatment. Chemotherapy should be used in addition to operation and irradiation, especially in advanced cases with nodal and distant metastases. An irradiation dose of 40-60 Gy is recommended. CT-aided treatment planning, sophisticated irradiation techniques, the use of high-energy photons and reliable immobilization measures are indispensable. A 5-year survival rate for all stages of 50% is reported. The recurrence rate in advanced stages is high, so that the benefits and risks of the different, combined treatment modalities must be evaluated carefully.

[Multiple malignomas--an analysis of 352 patients]. / Mehrfachmalignome--eine Analyse von 352 Patienten.

8234 patients were irradiated between 1977 and 1988 in the Department of Radiotherapy at Würzburg, 211 patients (2.56%) developed multiple primary malignant tumors. The records of 1599 patients from the year 1958 to 1976 were reviewed and another 141 multiple tumors were found. On the whole, 352 patients with 326 cases of two tumors, 21 cases with three tumors, 4 cases with four tumors and one case with five tumors were observed. Both sexes were affected equally, but the peak age of these patients was found to be the sixth and seventh decade. The mean interval for a second primary was 5.7 years, from the second to the third and from the third to fourth tumor it was 1.6 and 0.5 years, respectively. 18 patients with a second malignoma in a formerly irradiated area were diagnosed, especially men with tumors in the aerodigestive tract and women with tumors in the pelvic region. The data of our clinic do not indicate an elevated risk for radiation-induced malignancies.

[Computed tomographic determination of the target volume and the evaluation of remission after radiation of bronchial carcinoma]. / Computertomographische Zielvolumenbestimmung und Remissionsbeurteilung nach Radiatio beim Bronchialkarzinom.

434 CT examinations of 133 patients with histologically proven bronchogenic carcinoma (22 out of 133 with small cell lung cancer) were analysed before and after radiotherapy. The study evaluates the use of CT for determining target volume, tumour volume and remission rate: 1. Concerning determination of target volume conventional roentgen diagnostic simulator methods are much inferior to CT aided planning: as for our patients changes of the target volume were necessary in 50%, in 22% the changes were crucial. This happened more often in non-small cell lung cancer than in small cell carcinomas. 2. The response rate (CR + PR) after radiotherapy (based on the calculated tumour volumes by CT) was 70 to 80%. The rate of CR of the primary was 45% (non-small cell carcinoma) and 67% (small cell carcinoma). 3. The crucial point for the evaluation of tumour remission after radiotherapy is the point of time. One to three months and four to nine months after irradiation we found complete remissions in 19% and 62%, respectively. Hence, the evaluation of treatment results earlier than three months after radiotherapy may be incorrect. We deem it indispensable to use CT for determination of target, calculation of dose distribution and accurate evaluation of tumour remission and side effects during and after irradiation of patients with bronchogenic carcinoma.