Depth as a driver of evolution and diversification of ancient squat lobsters (Decapoda, Galatheoidea, Phylladiorhynchus).

The exceptional hidden diversity included in the squat lobster genus Phylladiorhynchus and its wide bathymetric and geographic range make it an interesting group to thoroughly study its evolutionary history. Here we have analyzed the entire currently known species diversity of Phylladiorhynchus using an integrative approach that includes morphological and molecular characters. The aim was to establish whether depth range (bathymetry) has played a role in their morphological and molecular evolution and in their diversification pathways. Phylogenetic analyses recovered the genus as monophyletic and as the sister group of Coralliogalathea, conforming with current systematic hypotheses, although their placement in a monophyletic Galatheidae is doubted. All the analyzed species represent well-supported lineages, structured in ten clades, correlated in most part with the morphological phylogeny. The reconstruction of ancestral habitat showed that the most recent common ancestor of Phylladiorhynchus most likely lived in shallow water environments. The divergence time estimation analyses dated the origin of the genus back to the Upper Jurassic, preceding the origin of all the other galatheoid lineages. Morphological analyses suggested that species from deeper waters exhibit greater morphological divergences and lower genetic divergences in comparison to species from shallower waters. In Phylladiorhynchus, the colonization of deeper waters has taken place independently multiple times since the Lower-Cretaceous. Our reconstruction of ancestral habitat suggests that shallow water ancestors might show an acceleration in the molecular rate of evolution and a slowdown in the rates of morphological evolution in comparison to deep sea lineages. However, although lineages from shallow and deep sea habitats show slight differences in diversification trends, bathymetry does not significantly affect the diversification rate in Phylladiorhynchus according to our diversification analyses.

Treatment with a heat-killed preparation of Mycobacterium vaccae after fear conditioning enhances fear extinction in the fear-potentiated startle paradigm.

The hygiene hypothesis or "Old Friends" hypothesis proposes that inflammatory diseases are increasing in modern urban societies, due in part to reduced exposure to microorganisms that drive immunoregulatory circuits and a failure to terminate inappropriate inflammatory responses. Inappropriate inflammation is also emerging as a risk factor for anxiety disorders, affective disorders, and trauma-and stressor-related disorders, including posttraumatic stress disorder (PTSD), which is characterized as persistent re-experiencing of the trauma after a traumatic experience. Traumatic experiences can lead to long-lasting fear memories and fear potentiation of the acoustic startle reflex. The acoustic startle reflex is an ethologically relevant reflex and can be potentiated in both humans and rats through Pavlovian conditioning. Mycobacterium vaccae is a soil-derived bacterium with immunoregulatory and anti-inflammatory properties that has been demonstrated to enhance fear extinction in the fear-potentiated startle paradigm when given prior to fear conditioning. To determine if immunization with M. vaccae after fear conditioning also has protective effects, adult male Sprague Dawley rats underwent fear conditioning on days -37 and -36 followed by immunizations (3x), once per week beginning 24 h following fear conditioning, with a heat-killed preparation of M. vaccae NCTC 11659 (0.1 mg, s.c., in 100 µl borate-buffered saline) or vehicle, and, then, 3 weeks following the final immunization, were tested in the fear-potentiated startle paradigm (n = 12 per group). Rats underwent fear extinction training on days 1 through 6 followed by spontaneous recovery 14 days later (day 20). Rats were euthanized on day 21 and brain tissue was sectioned for analysis of Tph2, Htr1a, Slc6a4, Slc22a3, and Crhr2 mRNA expression throughout the brainstem dorsal and median raphe nuclei. Immunization with M. vaccae did not affect fear expression on day 1. However, M. vaccae-immunized rats showed enhanced enhanced within-session fear extinction on day 1 and enhanced between-session fear extinction beginning on day 2, relative to vehicle-immunized controls. Immunization with M. vaccae and fear-potentiated startle had minimal effects on serotonergic gene expression when assessed 42 days after the final immunization. Together with previous studies, these data are consistent with the hypothesis that immunoregulatory strategies, such as immunization with M. vaccae, have potential for both prevention and treatment of trauma- and stressor-related psychiatric disorders.

[Pathology didactics : Development and pilot study of a pathology didactics curriculum (PaDiCu)]. / Pathologiedidaktik : Entwicklung und Pilotierung eines Pathologiedidaktikcurriculums (PaDiCu).

BACKGROUND: Pathologists are lifelong teachers. However, specialist training contains hardly any didactic learning objectives. Here, the competency-based learning objectives that a pathology didactics curriculum could include were examined. MATERIALS AND METHODS: Learning objectives were determined through expert discussions and literature research. Four teaching units were designed: A) Interactive small-group seminars; B) The timely application of what has been learned under supervision; C) A longitudinal component by providing digital resources; D) Workshops and seminars by third-party providers. RESULTS: Initially, 11 small group seminars were designed: 1. + 2. General and special presentation techniques, 3. Public speaking, 4. Activation of audience, 5. Macro- and microphotography, image processing and graphic design, 6. Pathology teaching concept, 7. Standardized case conferences, 8. Standards for teaching events, 9. Standardized evaluation, 10. Research of pathology education, 11. Digitalization of teaching and pathology. Pilot seminars were appreciated and positively evaluated. CONCLUSION: For the first time, competence-based didactic learning objectives were identified for pathology. The pathology didactics curriculum (PaDiCu) could be disseminated with little effort.

How do Swiss medical schools prepare their students to become good communicators in their future professional careers: a questionnaire and interview study involving medical graduates, teachers and curriculum coordinators.

BACKGROUND: Since 2011, the Swiss Catalogue of Learning Objectives (SCLO) has provided the framework for assessing communication skills in the Swiss Medical Federal Licensing Examination (FLE). This study evaluates how far the communication curricula of five Swiss medical schools match the SCLO and international recommendations. It also explores their strengths, weaknesses, opportunities and threats (SWOT). METHODS: A mixed method approach was used. In a first step, curriculum coordinators/key communication skills teachers and medical graduates were asked to fill out a questionnaire based on communication related objectives from the SCLO and a review of European consensus statements on communication training. Second, information was collected from all Swiss medical schools to identify which communication skills were taught in which formats and at what time points within the 6-year curricula. Finally, 3-4 curriculum coordinators/key communication skills teachers from each medical school were interviewed about their communication curriculum, using SWOT analysis. RESULTS: Sixteen teachers/coordinators (response rate 100%) and 389 medical graduates (response rate 43%) filled out the questionnaire. Both the teachers/coordinators and the graduates considered that two thirds of the communication items listed in the questionnaire were covered in their curricula. Between sixty and two hundred structured hours were dedicated to communication, predominantly in small group and experiential formats. Assessment relied on both MCQs and OSCEs. Most of the training occurred during the first three years of medical school. Teachers felt that the need for communication skills training was now well-recognized by their institution and was taught with appropriate teaching methods. However, recruitment and training of teachers, continuity of communication skills training during clinical years, and the adoption of a common frame of reference among the five medical schools, remained a challenge. CONCLUSION: Although the Swiss medical schools all offered a partly longitudinal communication skills training, with appropriate teaching methods, this study indicates that the communication skills actually taught do not fully match the SCLO or international recommendations. There was less training for complex communication skills training during the clinical years, and ensuring quality and coherence in the teaching remained a challenge.

Incidence and viral aetiologies of acute respiratory illnesses (ARIs) in the United States: a population-based study.

We conducted prospective, community-wide surveillance for acute respiratory illnesses (ARIs) in Rochester, NY and Marshfield, WI during a 3-month period in winter 2011. We estimated the incidence of ARIs in each community, tested for viruses, and determined the proportion of ARIs associated with healthcare visits. We used a rolling cross-sectional design to sample participants, conducted telephone interviews to assess ARI symptoms (defined as a current illness with feverishness or cough within the past 7 days), collected nasal/throat swabs to identify viruses, and extracted healthcare utilization from outpatient/inpatient records. Of 6492 individuals, 321 reported an ARI within 7 days (4·9% total, 5·7% in Rochester, 4·4% in Marshfield); swabs were collected from 208 subjects. The cumulative ARI incidence for the entire 3-month period was 52% in Rochester [95% confidence interval (CI) 42-63] and 35% in Marshfield (95% CI 28-42). A specific virus was identified in 39% of specimens: human coronavirus (13% of samples), rhinovirus (12%), RSV (7%), influenza virus (4%), human metapneumovirus (4%), and adenovirus (1%). Only 39/200 (20%) had a healthcare visit (2/9 individuals with influenza). ARI incidence was ~5% per week during winter.

Systematic reviews and quality assessment of patient-reported outcome measures for physical function in comparative effectiveness studies regarding acute postoperative pain after total knee arthroplasty-Do we need to start all over again?

BACKGROUND AND OBJECTIVE: Recently, a consensus process specified a core outcome set (COS) of domains to be assessed in each comparative effectiveness research and clinical practice related to acute postoperative pain. Physical function (PF) was one of these domains. The aim of this review was to investigate which patient-reported outcome measures (PROMs) are used to assess PF after total knee arthroplasty (TKA) in clinical trials and if they fulfil basic requirements for a COS of PROMs based on their psychometric properties. METHODS: A systematic review of randomized controlled trials and observational studies based on a search in MEDLINE, EMBASE and CENTRAL was undertaken. PROMs and performance measures were extracted and investigated, including evaluation of psychometric properties of PROMs based on COSMIN recommendations. RESULTS: From initially 2896 identified records, 479 studies were included in the qualitative synthesis. Only 87 of these trials (18%) assessed PF using PROMs, whereas especially performance outcome measures were used in 470 studies (98%). Application of the 'COSMIN Risk-of-Bias-Box 1' to 13 of the 14 identified PROMs resulted in insufficient content validity of the included PROMs regarding the target population based on the inauguration or development articles. CONCLUSION: Our data indicate that a patient-centred postoperative assessment of PF in pain-related clinical trials early after TKA is not common, even though patient-reported assessment is widely recommended. In addition, none of the applied PROMs shows content validity based on their inauguration or development articles for the assessment of postoperative pain-related PF after TKA. SIGNIFICANCE: A systematic search for patient-reported outcome measures assessing postoperative, pain-related physical function after total knee arthroplasty in clinical trials and assessment of their content validity revealed none that fulfilled requirements based on COSMIN recommendations.

Galatheoidea are not monophyletic - molecular and morphological phylogeny of the squat lobsters (Decapoda: Anomura) with recognition of a new superfamily.

The monophyletic status of the squat lobster superfamily Galatheoidea has come under increasing doubt by studies using evidence as diverse as larval and adult somatic morphology, sperm ultrastructure, and molecular data. Here we synthesize phylogenetic data from these diverse strands, with the addition of new molecular and morphological data to examine the phylogeny of the squat lobsters and assess the status of the Galatheoidea. A total of 64 species from 16 of the 17 currently recognised anomuran families are included. Results support previous work pointing towards polyphyly in the superfamily Galatheoidea and Paguroidea, specifically, suggesting independent origins of the Galatheidae+Porcellanidae and the Chirostylidae+Kiwaidae. Morphological characters are selected that support clades resolved in the combined analysis and the taxonomic status of Galatheoidea sensu lato is revised. Results indicate that Chirostylidae are more closely related to an assemblage including Aegloidea, Lomisoidea and Paguroidea than to the remaining Galatheoidea and are referred to the superfamily Chirostyloidea to include the Chirostylidae and Kiwaidae. A considerable amount of research highlighting morphological differences supporting this split is discussed. The Galatheoidea sensu stricto is restricted to the families Galatheidae and Porcellanidae, and diagnoses for both Chirostyloidea and Galatheoidea are provided. Present results highlight the need for a detailed revision of a number of taxa, challenge some currently used morphological synapomorphies, and emphasise the need for integrated studies with wide taxon sampling and multiple data sources to resolve complex phylogenetic questions.

Assessing quality of life in long-term survivors after ¹²5I brachytherapy for low-grade glioma in childhood.

Quality of life (QOL) is important for the survivors of malignancies. We investigated health-related QOL in 51 patients treated with iodine-125 (¹²5I) brachytherapy for childhood low-grade gliomas. Instruments included a questionnaire on life situation, German versions of PEDQOL (8-18 years), EORTC QLQ-30 and head and neck module H&N-35 (>18 years), strength and difficulties questionnaire, "Fertigkeitsskala Münster Heidelberg", and an adapted Rankin score. The time lapsed since ¹²5I-brachytherapy was 134 months (median, range: 29-293 months). 57% of the patients were over 18 years of age, 34% were 11-17 years old and 8% were younger. 14 had undergone other treatments after ¹²5I brachytherapy. Over half of the >18 year olds reported residual problems; 68% were disabled, 38% to a severe degree. Many of the young adults still lived with their parents and 17% were jobless. 43% of the children/adolescents needed rehabilitative treatment, 20% visited special schools and 71% were disabled, 33% severely. The patients and their caregivers rated their QOL as not different from that of the normal population. However, many QOL dimensions correlated to the severity of disability. Comparison of QOL outcomes between different treatment measures would require a prospective study controlling for the most important factors of influence.

Development and national consensus finding on patient-centred high stakes communication skills assessments for the Swiss Federal Licensing Examination in Medicine.

OBJECTIVE: To describe and evaluate a consensus finding and expert validation process for the development of patient-centred communication assessments for a national Licensing Exam in Medicine. METHODS: A multi-professional team of clinicians and experts in communication, assessment and role-play developed communication assessments for the Swiss Federal Licensing Examination. The six-month process, informed by a preceding national needs-assessment, an expert symposium and a critical literature review covered the application of patient-centred communication frameworks, the development of assessment guides, concrete assessments and pilot-tests. The participants evaluated the process. RESULTS: The multiple-step consensus process, based on expert validation of the medical and communication content, led to six high-stakes patient-centred communication OSCE-assessments. The process evaluation revealed areas of challenge such as calibrating rating-scales and case difficulty to the graduates' competencies and integrating differing opinions. Main success factors were attributed to the outcome-oriented process and the multi-professional exchange of expertise. A model for developing high stakes patient-centred communication OSCE-assessments was derived. CONCLUSIONS: Consensus finding was facilitated by using well-established communication frameworks, by ensuring outcome-orientated knowledge exchange among multi-professional experts, and collaborative validation of content through experts. PRACTICE IMPLICATIONS: We propose developing high-stakes communication assessments in a multi-professional expert consensus and provide a conceptual model.

Effects of Immunization With the Soil-Derived Bacterium Mycobacterium vaccae on Stress Coping Behaviors and Cognitive Performance in a "Two Hit" Stressor Model.

Previous studies demonstrate that Mycobacterium vaccae NCTC 11659 (M. vaccae), a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, is a potentially useful countermeasure against negative outcomes to stressors. Here we used male C57BL/6NCrl mice to determine if repeated immunization with M. vaccae is an effective countermeasure in a "two hit" stress exposure model of chronic disruption of rhythms (CDR) followed by acute social defeat (SD). On day -28, mice received implants of biotelemetric recording devices to monitor 24-h rhythms of locomotor activity. Mice were subsequently treated with a heat-killed preparation of M. vaccae (0.1 mg, administered subcutaneously on days -21, -14, -7, and 27) or borate-buffered saline vehicle. Mice were then exposed to 8 consecutive weeks of either stable normal 12:12 h light:dark (LD) conditions or CDR, consisting of 12-h reversals of the LD cycle every 7 days (days 0-56). Finally, mice were exposed to either a 10-min SD or a home cage control condition on day 54. All mice were exposed to object location memory testing 24 h following SD. The gut microbiome and metabolome were assessed in fecal samples collected on days -1, 48, and 62 using 16S rRNA gene sequence and LC-MS/MS spectral data, respectively; the plasma metabolome was additionally measured on day 64. Among mice exposed to normal LD conditions, immunization with M. vaccae induced a shift toward a more proactive behavioral coping response to SD as measured by increases in scouting and avoiding an approaching male CD-1 aggressor, and decreases in submissive upright defensive postures. In the object location memory test, exposure to SD increased cognitive function in CDR mice previously immunized with M. vaccae. Immunization with M. vaccae stabilized the gut microbiome, attenuating CDR-induced reductions in alpha diversity and decreasing within-group measures of beta diversity. Immunization with M. vaccae also increased the relative abundance of 1-heptadecanoyl-sn-glycero-3-phosphocholine, a lysophospholipid, in plasma. Together, these data support the hypothesis that immunization with M. vaccae stabilizes the gut microbiome, induces a shift toward a more proactive response to stress exposure, and promotes stress resilience.

Effects of maternal separation on serotonergic systems in the dorsal and median raphe nuclei of adult male Tph2-deficient mice.

Previous studies have highlighted interactions between serotonergic systems and adverse early life experience as important gene x environment determinants of risk of stress-related psychiatric disorders. Evidence suggests that mice deficient in Tph2, the rate-limiting enzyme for brain serotonin synthesis, display disruptions in behavioral phenotypes relevant to stress-related psychiatric disorders. The aim of this study was to determine how maternal separation in wild-type, heterozygous, and Tph2 knockout mice affects mRNA expression of serotonin-related genes. Serotonergic genes studied included Tph2, the high-affinity, low-capacity, sodium-dependent serotonin transporter (Slc6a4), the serotonin type 1a receptor (Htr1a), and the corticosterone-sensitive, low-affinity, high-capacity sodium-independent serotonin transporter, organic cation transporter 3 (Slc22a3). Furthermore, we studied corticotropin-releasing hormone receptors 1 (Crhr1) and 2 (Crhr2), which play important roles in controlling serotonergic neuronal activity. For this study, offspring of Tph2 heterozygous dams were exposed to daily maternal separation for the first two weeks of life. Adult, male wild-type, heterozygous, and homozygous offspring were subsequently used for molecular analysis. Maternal separation differentially altered serotonergic gene expression in a genotype- and topographically-specific manner. For example, maternal separation increased Slc6a4 mRNA expression in the dorsal part of the dorsal raphe nucleus in Tph2 heterozygous mice, but not in wild-type or knockout mice. Overall, these data are consistent with the hypothesis that gene x environment interactions, including serotonergic genes and adverse early life experience, play an important role in vulnerability to stress-related psychiatric disorders.

Tumor-related prognostic factors for remission of brain metastases after radiotherapy.

PURPOSE: To study CT determined response to external beam radiotherapy as well as influence of tumor-related factors, especially of tumor volume, on remission and to evaluate whether particular subgroups of metastases are controlled by low-dose radiotherapy. METHODS AND MATERIALS: Contrast-enhanced CT scans before and after radiotherapy were analyzed. INCLUSION CRITERIA: brain metastases treated with whole-brain radiotherapy (10 fractions of 3 Gy over 2 weeks) since 1983; no additional treatment, for example, surgery or chemotherapy; at least one follow-up CT. Three hundred thirty-six metastases from 108 patients were evaluated with regard to their volume, extent of necrosis, histology of primary tumor, and interval between radiotherapy and follow-up CT. All parameters were correlated with best local result and progression-free survival by uni- and multivariate tests. Volume-response curves were calculated. RESULTS: In univariate analysis local result was significantly influenced by each of the four parameters mentioned above. Complete remission was observed in 37% of metastases from small-cell carcinoma, 35% of those from breast cancer, 25% of those from squamous-cell carcinoma, and 14% of those from nonbreast adenocarcinoma. The rate was 52% for metastases <0.5 cm3 and 0% for those >10 cm3. In multivariate analysis, small volume and no necrosis were the most important prognostic factors for complete remission. Progression-free survival was influenced by best local result. CONCLUSION: With radiotherapy to a total dose of 30 Gy even small metastases had a complete remission rate of 52% only. Therefore, patients should be treated with locally more effective dose and fractionation schedules when local control is the aim. However, partial remission rate was remarkable even for large and necrotic metastases. This should be considered when palliation is the aim of treatment.

A palliative accelerated irradiation regimen for advanced non-small-cell lung cancer vs. conventionally fractionated 60 GY: results of a randomized equivalence study.

PURPOSE: Radiation oncologists are often faced with patients with advanced non-small-cell lung cancer (NSCLC), who are not suitable candidates for state-of-the-art radical treatment, but who also are not judged to have a very short life expectancy. Some physicians treat these patients palliatively, whereas others advocate more intensive treatment. To find out if there is a substantial difference in outcome between these approaches, we performed a randomized prospective study. METHODS AND MATERIALS: Between 1994 and 1998, 152 eligible patients with advanced NSCLC Stage III (n = 121) or minimal Stage IV (n = 31) were randomized to receive conventionally fractionated (cf; A: 60 Gy, 6 weeks, n = 79) or short-term treatment (PAIR; B: 32 Gy, 2 Gy b.i.d.; n = 73) of tumor and mediastinum. RESULTS: One-year survival rate for all patients was 37% with no significant difference between the two treatment arms (A: 36%; B: 38%; p = 0.76). As far as can be judged from limited data available, palliation was adequate and similar for the two treatment arms. Apart from expected differences in the time course of esophagitis, acute side effects were moderate and equally distributed. No severe late effects were observed. CONCLUSIONS: In the present randomized trial, survival and available data on palliation were not different after cf to 60 Gy compared to the palliative PAIR regimen. Therefore, for patients who are not suitable for radical treatment approaches, the prescription of a palliative short-term irradiation appears preferable compared to cf over several weeks.

Relation between local result and total dose of radiotherapy for brain metastases.

PURPOSE: Some studies published recently focused on the improvement of the treatment results of patients with brain metastases who underwent radiation therapy. They evaluated survival as a measure for the expected improvement, but failed to demonstrate a significant benefit from an increased total dose of radiotherapy. This study was targeted to investigate the effect of dose escalation with a different endpoint, the local response. METHODS AND MATERIALS: As a first step, a retrospective analysis of 164 patients treated with a standard regimen of 10 x 3 Gy was performed to find factors correlating with the local result. All patients were systematically followed and underwent regular computed tomography (CT) examinations of the brain after irradiation. The second step was to compare, with respect to local control and survival, 39 patients treated with a total dose of 40-60 Gy with 39 patients treated with the standard regimen selected by means of a matched cohort pairs method. RESULTS: The retrospective analysis showed a dependence of the local result after irradiation on three parameters: diameter of brain metastases, primary tumor, and tumor histology. Small-cell and adenocarcinoma were found to be more radiosensitive than squamous-cell carcinoma. The highest radiosensitivity was found in breast cancer metastases. The matching procedure was performed with respect to those parameters and also the number of brain metastases and total cerebral tumor volume. The resulting groups were absolutely equivalent and differed only with regard to the total dose applied. The local response (complete or partial remission) was 48-52% after 30 Gy vs. 77% after 40-60 Gy (p < or = 0.05). Survival was not significantly different. A further analysis of the dose-response relationships showed the tendency of control probability to increase with total dose. CONCLUSION: This study suggests that there is a rationale for dose escalation in the treatment of brain metastases with radiotherapy, when local control is the aim. However, it seems questionable whether an improvement in survival results.

Prognostic factors in brain metastases: should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes?

PURPOSE: To determine whether or not Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) derived prognostic classes for patients with brain metastases are generally applicable and can be recommended as rational strategy for patient selection for future clinical trials. Inclusion of time to non-CNS death as additional endpoint besides death from any cause might result in further valuable information, as survival limitation due to uncontrolled extracranial disease can be explored. METHODS: We performed a retrospective analysis of prognostic factors for survival and time to non-CNS death in 528 patients treated at a single institution with radiotherapy or surgery plus radiotherapy for brain metastases. For this purpose, patients were divided into groups with Karnofsky performance status (KPS) <70% and KPS > or =70%, as proposed by the RTOG. RESULTS: Median overall survival was 2.9 months (2.0 months for patients with KPS <70% and 3.6 months for patients with KPS > or =70%, p < 0.001). We did not find other variables splitting patients with KPS <70% in different prognostic groups. However, advanced age, multiple brain metastases, presence of extracranial metastases, and uncontrolled primary tumor each predicted shorter survival in patients with KPS > or =70%. When grouped into the original RTOG RPA classes, our data set split into three subgroups with different prognosis and median survival times of 10.5, 3.5, and 2 months, respectively (p < 0.05). Only 3% of patients fell into the most favorable group. Median time to non-CNS death was 4.1 months (12.9 months in RPA class I, 4.9 months in RPA class II, and 3.8 months in RPA class III, respectively, p > 0.05 for RPA class II versus III). However, it was 8.5 months in RPA class II patients with controlled primary tumor, which was found to be the only prognostic factor for time to non-CNS death in patients with KPS > or =70%. In patients with KPS <70%, no statistically significant prognostic factors were identified for this endpoint. CONCLUSIONS: Despite some differences, this analysis essentially confirmed the value of RPA-derived prognostic classes, as published by the RTOG, when survival was chosen as endpoint. RPA class I patients seem to be most likely to profit from aggressive treatment strategies and should be included in appropriate clinical trials. However, their number appears to be very limited. Considering time to non-CNS death, our results suggest that certain patients in RPA class II also might benefit from increased local control of brain metastases.

Rapid course radiation therapy vs. more standard treatment: a randomized trial for bone metastases.

PURPOSE: In a prospective randomized trial we examined whether radiotherapy of painful bone metastases can be shortened using larger single doses without impairing effectivity. METHODS AND MATERIALS: One hundred patients with painful bone metastases having no prior surgical intervention or treatment with x-ray therapy and had a median follow-up of 12 months were analyzed. The primary tumor was located in the breast in 43%, in the lung in 24%, and in the prostate in 14%. The most frequent sites of metastases were the pelvis (31%), the vertebral column (30%), and the ribs (20%). Further percentages of sites were: lower extremity 11%, upper extremity 6%, and skull 2%. Fifty-one patients received a short course radiotherapy with a total dose of 20 Gy in 1 week (daily dose 4 Gy), and 49 patients received 30 Gy in 3 weeks (daily dose 2 Gy). RESULTS: There were no significant differences in frequency, duration of pain relief, improvement of mobility, recalcification, frequency of pathologic fractures nor survival. There was a light trend favoring 30 Gy in frequency of pain relief and recalcification. Survival was mostly influenced by primary tumor site, Karnofsky performance status, and possibly by the response to radiotherapy (pain relief). CONCLUSIONS: Because of the very short life expectancy of patients with metastatic bone disease, we now use 20 Gy in 1 week as our standard to reduce hospital stay.

18F-deoxyglucose positron emission tomography (FDG-PET) for the planning of radiotherapy in lung cancer: high impact in patients with atelectasis.

PURPOSE: 18F-deoxyglucose positron emission tomography (FDG-PET) is increasingly applied in the staging of lung cancer (LC). This study analyzes the potential contribution of PET in radiotherapy planning for LC with special respect to tumor-associated atelectasis. METHODS AND MATERIALS: Thirty-four patients with histologically confirmed LC, who had been examined by PET during pretreatment staging, were included. All were irradiated after CT-based therapy planning with anterior/posterior (AP) portals encompassing the primary tumor and the mediastinum (CT portals, CP). The result of the PET examination was unknown in treatment planning. In retrospect, a PET portal (PP) was delineated and compared with the CP. RESULTS: In 12/34 cases, the shape and/or size of the portals were changed, primarily (n = 10) the size of the fields was reduced. The median area of CP was 182 cm2 versus 167 cm2 of PP. Seventeen of 34 patients had dys- or atelectasis caused by a central primary tumor. In these cases, differences between CP and PP were significantly more frequent than in the other patients (8/17 vs. 3/17, p = 0.03). CONCLUSION: In this retrospective analysis, the information provided by FDG-PET would have contributed to a substantial reduction of the size of radiotherapy portals. This applies particularly for patients with tumor-associated dys- or atelectasis.

Multivariate logistic analysis of dose-effect relationship and latency of radiomyelopathy after hyperfractionated and conventionally fractionated radiotherapy in animal experiments.

PURPOSE: We examined in rats whether the radiation tolerance of spinal cord is enhanced by using hyperfractionated radiotherapy compared to a conventional schedule. Higher tolerable doses to the spinal cord would allow dose escalation to the tumor and thus possibly lead to higher cure rates, especially in tumors with high cell proliferation. METHODS AND MATERIALS: Cervical spinal cord of 276 healthy rats was irradiated over 6 weeks hyperfractionally with single doses ranging from 0.75-2.5 Gy up to total doses ranging from 45-150 Gy (60 fractions) and conventionally with single doses of 1.5-4.0 Gy up to total doses of 45-120 Gy (30 fractions). The rats were examined neurologically and sacrificed when paralysis of the hind legs occurred. After fixation, spinal cord was removed and examined histologically. Dose-effect relationship and latency from the beginning of radiotherapy to the onset of paralysis were computed and analyzed using a multivariate logistic regression model. RESULTS: The model fitted the observed data excellently. There were highly significant effects both for the dose level and for the treatment regimen. Latency analysis showed earlier and more intense acute side effects after hyperfractionation but radiomyelopathy occurred markedly later. CONCLUSIONS: The sparing effect of hyperfractionation on spinal cord as predicted by radiobiologists could be confirmed in our experiments. Thus, it seems possible to escalate tumor doses using hyperfractionation without enhanced risk to spinal cord but with higher probability of tumor cure.

Neutron and neutron-boost irradiation of soft tissue sarcomas: a 4.5 year analysis of 139 patients.

A 4.5 year analysis of neutron and neutron-boost therapy is presented for 139 patients with soft tissue sarcomas. The actuarial survival rate of all patients is 64.3%, the disease-free survival rate is 61.6%. Significant differences in local control rates were found as a function of tumour stage (100% for T1, 72% for T2 and 46% for T3; p: 0.018) and as a function of the presence (50.5%) or absence of clinical evidence of tumour at the time of irradiation (76%; p: 0.002). The corresponding actuarial survival rates are 90.1% for T1 tumours, 78.5% for T2 tumours and 51.2% for T3 tumours, and on the other hand, 50.5% for patients with gross tumour and 76% for patients with no clinical evidence of tumour. A rather high morbidity rate (31/111, i.e. 28%) was observed after full neutron treatment. In order to reduce this complication rate, a combination of photons and a neutron boost was adopted. On 28 patients treated up to now, only two severe complications were observed. The effectiveness of this treatment regimen is presently being evaluated in a prospective European Organization for Research on Treatment of Cancer (EORTC) trial.

Accelerated radiotherapy for brain metastases.

BACKGROUND AND PURPOSE: Two novel fractionation schedules for whole-brain irradiation were applied to patients with brain metastases. Both schedules were aimed at reduction of treatment time, whereby tumour control should be increasing with the application of a higher total dose (schedule 2). MATERIALS AND METHODS: We applied 2 x 2.5 Gy/day to a total dose of 30 Gy (schedule 1) or 2 x 1.8 Gy/day to a total dose of 50.4 Gy (schedule 2). The interval between daily fractions was 6 h. Treatment was interrupted on weekends. The 30 Gy schedule was also used in adjuvant treatment for resected brain metastases. We compared the results of 15 patients who underwent the 50.4 Gy schedule and 47 patients who were treated up to 30 Gy with those of a historical patient group, treated with one daily fraction of 3 Gy up to 30 Gy (n = 283). RESULTS: Local result, clinical course and survival were similar for the 30 Gy groups, whereby prognostic factors were equally distributed. Despite a favourable patient selection no therapeutic gain was seen for the 50.4 Gy group. Patients treated with the accelerated 30 Gy schedule had a significantly worse progression-free survival and a higher rate of late radiation toxicity than the historical group. In contrast, no severe acute toxicity was observed. CONCLUSIONS: Considering progression-free survival and late toxicity, the accelerated 30 Gy schedule can not be recommended without hesitation. Radiotherapy with a higher total dose (50.4 Gy) showed no advantage.