[Late toxicity following primary conservative treatment : Dysphagia and xerostomia]. / Spättoxizität nach primär konservativer Therapie : Dysphagie und Xerostomie.

Dysphagia and xerostomia are still among the most important acute and late side effects of radiotherapy. Technical developments over the past two decades have led to improved diagnostics and recognition as well as understanding of the causes of these side effects. Based on these findings and advances in both treatment planning and irradiation techniques, the incidence and severity of treatment-associated radiogenic late sequelae could be clearly reduced by the use of intensity-modulated radiotherapy (IMRT), which could contribute to marked long-term improvements in the quality of life in patients with head and neck cancer. Highly conformal techniques, such as proton therapy have the potential to further reduce treatment-associated side effects in head and neck oncology and are currently being prospectively tested within clinical trial protocols at several centers.

Cost-effectiveness analysis (CEA) of IMRT plus C12 boost vs IMRT only in adenoid cystic carcinoma (ACC) of the head and neck.

BACKGROUND: Particle therapy provides steep dose gradients to facilitate dose escalation in challenging anatomical sites which has been shown not only to improve local control but also overall survival in patients with ACC. Cost-effectiveness of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost vs IMRT alone was performed in order to objectivise and substantiate more widespread use of this technology in ACC. METHODS: Patients with pathologically confirmed ACC received a combination regimen of IMRT plus C12 boost. Patients presenting outside C12 treatment slots received IMRT only. Clinical results were published; economic analysis on patient-level data was carried out from a healthcare purchaser's perspective based on costs of healthcare utilization. Cost histories were generated from resource use recorded in individual patient charts and adjusted for censoring using the Lin I method. Cost-effectiveness was measured as incremental cost-effectiveness ratio (ICER). Sensitivity analysis was performed regarding potentially differing management of recurrent disease. RESULTS: The experimental treatment increased overall costs by € 18,076 (€13,416 - €22,922) at a mean survival benefit of 0.86 years. Despite improved local control, following costs were also increased in the experimental treatment. The ICER was estimated to 26,863 €/LY. After accounting for different management of recurrent disease in the two cohorts, the ICER was calculated to 20,638 €/LY. CONCLUSION: The combined treatment (IMRT+C12 boost) substantially increased initial and overall treatment cost. In view of limited treatment options in ACC, costs may be acceptable though. Investigations into quality of life measures may support further decisions in the future.

[What is the impact of new radiotherapy techniques?]. / Was leisten die neuen Bestrahlungstechniken?

Radiation oncology, along with surgery and chemotherapy, is one of the cornerstones in the treatment of head and neck tumors. Within the last years, this field has experienced a remarkable evolution of new technical possibilities. New imaging modalities have been introduced into radiation planning and into linear accelerators themselves. In addition, new techniques enable the tailor-made conformation of radiation beams and dose distributions to complex tumor geometries. At the same time, organs at risk can be spared, and long-term toxicities are considerably reduced. This report presents the new techniques in radiation oncology and describes the effects on new treatment options and patients' quality of life.

Phase II study of induction chemotherapy with docetaxel, cisplatin, 5-fluorouracil followed by radioimmunotherapy with cetuximab and intensity-modulated radiotherapy in combination with a carbon ion boost for locally advanced tumors of the oro-, hypopharynx and larynx.

PURPOSE: This phase II trial was designed to evaluate efficacy and safety of a highly intensified therapy in locally advanced squamous cell carcinoma of the oro-, hypopharynx and larynx. METHODS: In this prospective, mono-centric, open-label, non-randomized phase II trial the single treatment arm consisted of a combined induction chemotherapy with docetaxel, cisplatin, 5-fluorouracil, followed by bioradiation with the monoclonal antibody cetuximab, carbon ion boost (24Gy(RBE) in 8 fractions) and IMRT (50 Gy in 25 fractions). The trial was closed early due to slow accrual. RESULTS: Eight patients (median age 52.5 years) were enrolled into the trial. The median follow-up was 13 months and the 12-months locoregional tumor control, progression-free survival and overall survival rates were 100.0% each. Complete remission was achieved in 7 patients. The most commonly late radiation adverse event was xerostomia (85.7% at 12 months). Five serious adverse events with recovery were documented in 4 patients: mucositis grade 3 (n = 2), decreased lymphocyte count grade 4, febrile neutropenia grade 4 and hypersensitivity grade 3 to cetuximab (n = 1 each). Most symptom scales had their worst value at the last treatment day and recovered until the 4th follow-up visit. CONCLUSION: The study treatment was tolerable and promising. Reduced quality of life recovered for most aspects until the last follow-up visit.

Treatment of non-small cell lung cancer with intensity-modulated radiation therapy in combination with cetuximab: the NEAR protocol (NCT00115518).

BACKGROUND: Even today, treatment of Stage III NSCLC still poses a serious challenge. So far, surgical resection is the treatment of choice. Patients whose tumour is not resectable or who are unfit to undergo surgery are usually referred to a combined radio-chemotherapy. However, combined radio-chemotherapeutic treatment is also associated with sometimes marked side effects but has been shown to be more efficient than radiation therapy alone. Nevertheless, there is a significant subset of patients whose overall condition does not permit administration of chemotherapy in a combined-modality treatment. It could be demonstrated though, that NSCLCs often exhibit over-expression of EGF-receptors hence providing an excellent target for the monoclonal EGFR-antagonist cetuximab (Erbitux) which has already been shown to be effective in colorectal as well as head-and-neck tumours with comparatively mild side-effects. METHODS/DESIGN: The NEAR trial is a prospective phase II feasibility study combining a monoclonal EGF-receptor antibody with loco-regional irradiation in patients with stage III NSCLC. This trial aims at testing the combination's efficacy and rate of development of distant metastases with an accrual of 30 patients. Patients receive weekly infusions of cetuximab (Erbitux) plus loco-regional radiation therapy as intensity-modulated radiation therapy. After conclusion of radiation treatment patients continue to receive weekly cetuximab for 13 more cycles. DISCUSSION: The primary objective of the NEAR trial is to evaluate toxicities and feasibility of the combined treatment with cetuximab (Erbitux) and IMRT loco-regional irradiation. Secondary objectives are remission rates, 3-year-survival and local/systemic progression-free survival.

Carbon ion therapy (C12) for high-grade malignant salivary gland tumors (MSGTs) of the head and neck: do non-ACCs profit from dose escalation?

PURPOSE: To evaluate the use of high-dose radiotherapy using carbon ions (C12) on non-adenoid cystic malignant salivary gland tumors (MSGT). PATIENTS AND METHODS: Between 2009 and 2013, patients with biopsy-proven non-ACC MSGT histologies of the head and neck received a combined regimen of IMRT plus C12 boost. Treatment toxicity (CTC v3), response (RECIST 1.1), control and survival rates were retrospectively analyzed. RESULTS: 40 patients with pathologically confirmed non-ACC MSGT (T4: 45 %; N+: 40 %; gross residual: 58 %; mucoepidermoid carcinoma (MEC): 45 %; adenocarcinoma: 20 %) were treated with a median of 74 GyE (80 Gy BED). Chemoradiation was given in 5 patients with MEC. Grade III acute toxicity was observed in up to 15 % (mucositis, dermatitis, dysphagia), no higher-grade late toxicity occurred to date. At a follow-up of 25.5 months, LC, and PFS at 2 and 3 years are 81.5 % (LC) and 66.8 % (PFS), OS at 2 and 3 years is 83.6 % and 72.8 %. Most frequent site of disease progression was distant metastasis. Histologic subtype correlated with LC and PFS. Resection status (gross vs microscopic disease) had no significant effect on LC, PFS, or OS. CONCLUSION: The treatment is well tolerated, no higher grade late effects were observed. Considering the negative pre-selection, LC, PFS and OS are promising. While histology and site of origin significantly influenced control and survival rates, resection status did not, potentially due to the effect of dose escalation.

Intraocular lens power calculations. A practical evaluation in normal subjects at the Wilmer Institute.

The practical value of preoperative intraocular lens power calculations in "normal" eyes with less than 4.50 diopters (D) of myopia or hyperopia was evaluated in a consecutive series of 520 eyes that underwent cataract extraction and lens implantation by four experienced surgeons at The Wilmer Ophthalmological Institute. The observed postoperative results with the lenses selected by the surgeons were compared with results calculated for the measurement-predicted emmetropic power lens and for a standard 20-D lens. The need for postoperative spectacle correction of residual refractive errors was comparable for all three choices of lens. Only two eyes (0.4%) would have developed greater than 4.00 D of refractive error with either the "implanted" or "predicted-emmetropic" lenses, as would 11 eyes (2.1%) with the "standard" 20-D lens. The surgeons' deviation from the calculated emmetropic lens did not reduce postoperative refractive error.

Intraocular reticulum-cell sarcoma: clinico-pathologic study of four cases and review of the literature.

Four patients with primary intraocular reticulum-cell sarcoma were presented. All of the patients were followed at the Wilmer Institute for periods of up to ten years. All had decreased visual acuity and a uveitis that was refractory to standard forms of therapy. In one case, the correct diagnosis was made clinically. At autopsy, two of the patients had systemic reticulum-cell sarcoma, a third had intracranial reticulum-cell sarcoma, and in a fourth case the disease process was confined to the eye. The literature is reviewed and the clinico-pathologic features of the total of 14 cases are analyzed. It is emphasized that a recalcitrant uveitis was present in almost all of the cases reported. Differential diagnosis and methods of diagnosis are discussed.

Methacholine sensitivity and cAMP protein kinase in tracheal smooth muscle.

We studied regional variation in canine trachealis smooth muscle sensitivity and responsiveness to methacholine as well as basal and methacholine-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) and cAMP-dependent protein kinase activity. The trachea between the cricoid cartilage and the carina was divided into three segments of equal length (designated cervical, middle, and thoracic regions), each consisting of approximately 12-14 cartilage rings. Smooth muscle strips from each of the three regions were exposed to cumulative half-log increments of methacholine chloride. The sensitivity (-log EC50) and responsiveness (force per cross-sectional area and force per milligram protein) of the smooth muscle to methacholine in each region was determined from these data. Smooth muscle strips from cervical and thoracic regions were frozen before and after exposure to cumulative half-log increments of methacholine up to each region's previously determined EC50. Frozen samples were assayed for cAMP content or cAMP-dependent protein kinase activity. The relationship between resting tension and methacholine sensitivity and responsiveness were studied. For the size strips we used, 4 g resting tension set the average cervical and thoracic strips at 96 and 101% of their optimal length, respectively. The methacholine EC50 was not affected by a variation in resting tension. Sensitivity to methacholine was 7.1, 6.8, and 6.5 for cervical, middle, and thoracic regions, respectively. The responsiveness of the cervical and thoracic smooth muscle to methacholine was 16.4 and 16.3 g force/mm2, respectively, at an EC50 methacholine. Basal cAMP was lower in cervical smooth muscle than in thoracic. cAMP-dependent protein kinase activity ratios under both basal and EC50 methacholine-stimulated conditions were lower in cervical smooth muscle than in thoracic. We have observed in trachealis smooth muscle an inverse relationship between methacholine sensitivity and either cAMP or cAMP-dependent protein kinase activity. We suggest that cAMP and cAMP-dependent protein kinase play a role in the regulation of airway smooth muscle sensitivity to cholinergic agonists.

Accuracy of magnetic resonance imaging in the diagnosis of deep vein thrombosis in asymptomatic patients with injuries of the lower extremity. A pilot study.

This is a prospective comparative study of magnetic resonance imaging (MRI) of the deep veins versus contrast venography in consecutive patients treated for various injuries to their lower extremities, showing no clinical symptoms of deep vein thrombosis. The majority of examinations referred to in this study were performed according to the following methodology: First, the patient was subjected to MRI. Subsequently, within a 24-h interval, he/she was subjected to contrast venography. The acquired results were compared in a blinded manner. The diagnostic indices for MRI were calculated on the assumption that the results of contrast venography were sure to give an accurate indication of either presence or absence of thrombosis. Thirty-six patients were included in the study, of which 27 (15 males) completed it. The overall incidence of distal deep venous thrombosis (DVT) was 22% (6/27). One patient showed extension of a crural thrombus into the popliteal vein. MRI did not detect any of the thrombi. This lack of result was ascribed to failure to fully demonstrate all segments of the crural veins. However, MRI did show three proximal thrombi in the superficial femoral vein, which were not shown by the venograms. Thus, both the sensitivity and specificity of MRI were 0%, so MRI proved to be of no value in the diagnosis of asymptomatic deep venous thrombosis in this study.

Penetration routes of topically applied eye medications.

Tritium-labeled hydrocortisone acetate and pilcarpine hydrochloride solutions were topically applied to the eyes of rabbits. In one group of animals, the drugs were excluded from contact with the cornea by a cylindrical well glued to the eye surface. In another group, the drug solutions were allowed contact with the entire anterior surface of the eye. Total application time in all cases was five minutes, then the eyes were flushed with saline. Samples of aqueous humor, stroma, and iris-ciliary body were taken after five, 20, 35, 65, and 125 minutes and counted in a liquid scintillation counter. With hydrocortisone, up to 70 times more drug reached the stroma when the cornea was exposed; 40 times more reached the iris. Peak stromal levels occurred by 20 minutes, dropping to one third of peak value by two hours. With pilocarpine, about five times more drug reached the iris-ciliary body when corneal access was allowed; the level peaked in about five minutes. These results illustrate the important role of tear film distribution and blinking in delivering remotely applied drugs over the cornea with subsequent entry to interior sites.

Expulsive hemorrhage: its incidence in cataract surgery and a report of four bilateral cases.

Between 1978 and 1983, 13,890 cataract extractions were performed in Baltimore at JHH and the GBMC with 14 expulsive hemorrhages for an incidence of 0.10%. In the years 1963 through 1983, 180,690 cataract extractions were performed in Taxila, Pakistan with 87 expulsive hemorrhages for an incidence of 0.05%. Reasons for the significant differences in incidence are presented. The six reported cases of bilateral expulsive hemorrhage are reviewed. Four more cases are added. A classification of choroidal hemorrhage is presented.

[Hereditary motor and sensory neuropathy (Charcot-Marie-Tooth disease). Molecular-genetic aspects]. / Hereditaer motorisk sensorisk neuropati (Charcot-Marie-Tooths sygdom). Molekyloergenetiske aspekter.

Hereditary motor and sensory neuropathy (HMSN) comprises a heterogenous group of peripheral neuropathies which are classified on the basis of symptoms, mode of inheritance and electrophysiological and neuropathological investigations. HMSN type I, or Charcot-Marie-Tooth disease (CMT) type 1, is a hypertrophic and demyelinating neuropathy with reduced nerve conduction velocity, and most often with dominant inheritance. HMSN type II (CMT type 2), the neuronal or axonal form, is dominantly inherited with normal or only moderately reduced nerve conduction velocity. HMSN type III, also called Déjérine-Sottas disease, is a hypertrophic neuropathy with markedly reduced nerve conduction velocity. HMSN type I is genetically heterogenous with at least four autosomal loci and at least two X-linked loci. The most frequent form, HMSN type Ia, is associated with a specific duplication on chromosome 17, which can be detected by DNA-analysis. The genes for HMSN type Ia, Ib and an X-linked dominant form have been identified as PMP22, MPZ and GJB1 respectively. Analysis for these molecular defects will become important in the differential diagnosis of peripheral neuropathies and will surely prove invaluable in the genetic counselling of the families.

One-step synthesis of bismuth molybdate catalysts via flame spray pyrolysis for the selective oxidation of propylene to acrolein.

Flame spray pyrolysis (FSP) of Bi(III)- and Mo(VI)-2-ethylhexanoate dissolved in xylene resulted in various nanocrystalline bismuth molybdate phases depending on the Bi/Mo ratio. Besides α-Bi2Mo3O12 and γ-Bi2MoO6, FSP gave direct access to the metastable ß-Bi2Mo2O9 phase with high surface area (19 m(2) g(-1)). This phase is normally only obtained at high calcination temperatures (>560 °C) resulting in lower surface areas. The ß-phase was stable up to 400 °C and showed superior catalytic performance compared to α- and γ-phases in selective oxidation of propylene to acrolein at temperatures relevant for industrial applications (360 °C).

Review of clinical experience with ion beam radiotherapy.

The article describes both the early development of oncology as a core discipline at the University of Heidelberg Hospital and the first steps towards ion beam treatment, from the pilot project carried out in co-operation with the Gesellschaft für Schwerionenforschung Darmstadt to the initial start-up of clinical service at the Heidelberg Heavy Ion Centre (HIT). We present an overview, based on data published in the literature, of the available clinical evidence relating the use of ion beam therapy to treat major indications in active particle centres. A rationale for the use of particle therapy in each of these indications is given. In view of the limited availability of data, we discuss the necessity to conduct clinical trials. We also look forward towards the next activities to be undertaken at the HIT.

Whole-abdominal IMRT for advanced ovarian carcinoma: planning issues and feasibility.

INTRODUCTION: Despite enormous efforts to improve therapeutic strategies for patients with advanced ovarian carcinoma, outcome remains poor even with the advent cisplatinum-based chemotherapy regimen or taxanes with over 70% of patients developing local failure. Several trials were able to establish the potential benefit of adjuvant whole abdominal RT (WAI) though at the cost of sometimes marked side-effects. New technologies like IMRT have the potential of sparing normal tissues thus also potentially limiting treatment-related toxicity, hence a phase I trial was initiated to evaluate potential clinical benefit of WAI with IMRT. We intended to demonstrate that whole-abdominal IMRT is feasible and can be used in a routine clinical setting. METHODS: A water-equivalent phantom containing OARs was created simulating organ shape of the upper abdomen to investigate the necessary number of beams for the upper abdominal target irrespective of the number of segments and hence treatment times. We prescribed a total dose of 30 Gy in 1.5 Gy fractions to the median of the target. IMRT treatment plans for three patients with advanced ovarian cancer were created using 2 isocentres and between 12 and 14 beams while restricting the number of segments so as to restrict treatment times to less than 45 min. Dose to OARs such as kidneys and liver was strictly limited even below established maxima. RESULTS: In the phantom plans, no clear indication as to the optimum number of beams could be shown though there seems to be a slight trend toward a higher number of beams yielding better results. Examples demonstrating clinically inacceptable dose distributions for plans using only 9 beams. Acceptable treatment plans for real patients could be achieved using 12-14 beams and 2 isocentres. Treatment plans consisted of 264-286 segments resulting in an overall treatment time of approximately 37-45 min. Mean doses to the kidneys could be limited to 29.3% [23.1-33.2%] (right), and 26.8% [21-30.4%] (left). 50% of the liver received less than 72.4% [61-83%]. CONCLUSION: IMRT for whole abdominal irradiation in patients with advanced ovarian carcinoma is applicable and feasible though treatment planning is complex and time-consuming. There is a significant reduction of dose to critical organs by using IMRT while maintaining target volume coverage.

Experimental methods and modeling techniques for description of cell population heterogeneity.

With the continuous development, in the last decades, of analytical techniques providing complex information at single cell level, the study of cell heterogeneity has been the focus of several research projects within analytical biotechnology. Nonetheless, the complex interplay between environmental changes and cellular responses is yet not fully understood, and the integration of this new knowledge into the strategies for design, operation and control of bioprocesses is far from being an established reality. Indeed, the impact of cell heterogeneity on productivity of large scale cultivations is acknowledged but seldom accounted for. In order to include population heterogeneity mechanisms in the development of novel bioprocess control strategies, a reliable mathematical description of such phenomena has to be developed. With this review, we search to summarize the potential of currently available methods for monitoring cell population heterogeneity as well as model frameworks suitable for describing dynamic heterogeneous cell populations. We will furthermore underline the highly important coordination between experimental and modeling efforts necessary to attain a reliable quantitative description of cell heterogeneity, which is a necessity if such models are to contribute to the development of improved control of bioprocesses.