Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial.

BACKGROUND: Approvals of cancer therapeutics are primarily disease entity specific. Current molecular diagnostic approaches frequently identify actionable alterations in rare cancers or rare subtypes of common cancers for which the corresponding treatments are not approved and unavailable within clinical trials due to entity-related eligibility criteria. Access may be negotiated with health insurances. However, approval rates vary, and critical information required for a scientific evaluation of treatment-associated risks and benefits is not systematically collected. Thus clinical trials with optimized patient selection and comprehensive molecular characterization are essential for translating experimental treatments into standard care. PATIENTS AND METHODS: Continuous ReAssessment with Flexible ExTension in Rare Malignancies (CRAFT) is an open-label phase II trial for adults with pretreated, locally advanced, or metastatic solid tumors. Based on the evaluation by a molecular tumor board, patients are assigned to combinations of six molecularly targeted agents and a programmed death-ligand 1 (PD-L1) antagonist within seven study arms focusing on (i) BRAF V600 mutations; (ii) ERBB2 amplification and/or overexpression, activating ERBB2 mutations; (iii) ALK rearrangements, activating ALK mutations; (iv and v) activating PIK3CA and AKT mutations, other aberrations predicting increased PI3K-AKT pathway activity; (vi) aberrations predicting increased RAF-MEK-ERK pathway activity; (vii) high tumor mutational burden and other alterations predicting sensitivity to PD-L1 inhibition. The primary endpoint is the disease control rate (DCR) at week 16; secondary and exploratory endpoints include the progression-free survival ratio, overall survival, and patient-reported outcomes. Using Simon's optimal two-stage design, 14 patients are accrued for each study arm. If three or fewer patients achieve disease control, the study arm is stopped. Otherwise, 11 additional patients are accrued. If the DCR exceeds 7 of 25 patients, the null hypothesis is rejected for the respective study arm. CONCLUSIONS: CRAFT was activated in October 2021 and will recruit at 10 centers in Germany. TRIAL REGISTRATION NUMBERS: EudraCT: 2019-003192-18; ClinicalTrials.gov: NCT04551521.

High tumour mutational burden and EGFR/MAPK pathway activation are therapeutic targets in metastatic porocarcinoma.

BACKGROUND: Eccrine porocarcinoma (EPC) is a rare skin cancer arising from the eccrine sweat glands. Due to the lack of effective therapies, metastasis is associated with a high mortality rate. OBJECTIVES: To investigate the drivers of EPC progression. METHODS: We carried out genomic and transcriptomic profiling of metastatic EPC (mEPC), validation of the observed alterations in an EPC patient-derived cell line, confirmation of relevant observations in a large patient cohort of 30 tumour tissues, and successful treatment of a patient with mEPC under the identified treatment regimens. RESULTS: mEPC was characterized by a high tumour mutational burden (TMB) with an ultraviolet signature, widespread copy number alterations and gene expression changes that affected cancer-relevant cellular processes such as cell cycle regulation and proliferation, including a pathogenic TP53 (tumour protein 53) mutation, a copy number deletion in the CDKN2A (cyclin dependent kinase inhibitor 2A) region and a CTNND1/PAK1 [catenin delta 1/p21 (RAC1) activated kinase 1] gene fusion. The overexpression of EGFR (epidermal growth factor receptor), PAK1 and MAP2K1 (mitogen-activated protein kinase kinase 1; also known as MEK1) genes translated into strong protein expression and respective pathway activation in the tumour tissue. Furthermore, a patient-derived cell line was sensitive to EGFR and MEK inhibition, confirming the functional relevance of the pathway activation. Immunohistochemistry analyses in a large patient cohort showed the relevance of the observed changes to the pathogenesis of EPC. Our results indicate that mEPC should respond to immune or kinase inhibitor therapy. Indeed, the advanced disease of our index patient was controlled by EGFR-directed therapy and immune checkpoint inhibition for more than 2 years. CONCLUSIONS: Molecular profiling demonstrated high TMB and EGFR/MAPK pathway activation to be novel therapeutic targets in mEPC.

Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma.

Background: Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. We here aimed to identify actionable genetic alterations in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy. Patients and methods: We used whole-exome and transcriptome sequencing to identify a KIT exon 11 mutation (c.1733_1735del, p.D579del) as potentially druggable target in this patient and carried out cancer hotspot panel sequencing to detect secondary resistance-conferring mutations in KIT. Furthermore, as a step towards clinical exploitation of the recently described signatures of mutational processes in cancer genomes, we established and applied a novel bioinformatics algorithm that enables supervised analysis of the mutational catalogs of individual tumors. Results: Molecularly guided treatment with imatinib in analogy to the management of gastrointestinal stromal tumor (GIST) resulted in a dramatic and durable response with remission of nearly all tumor manifestations, indicating a dominant driver function of mutant KIT in this tumor. KIT dependency was further validated by a secondary KIT exon 17 mutation (c.2459_2462delATTCinsG, p.D820_S821delinsG) that was detected upon tumor progression after 10 months of imatinib treatment and provided a rationale for salvage therapy with regorafenib, which has activity against KIT exon 11/17 mutant GIST. Conclusions: These observations highlight the potential of unbiased genomic profiling for uncovering the vulnerabilities of individual malignancies, particularly in rare and unclassifiable tumors, and underscore that KIT exon 11 mutations represent tractable therapeutic targets across different histologies.

Cooperation of BRAF(F595L) and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling.

Activating BRAF mutations, in particular V600E/K, drive many cancers and are considered mutually exclusive with mutant RAS, whereas inactivating BRAF mutations in the D(594)F(595)G(596) motif cooperate with RAS via paradoxical MEK/ERK activation. Due to the increasing use of comprehensive tumor genomic profiling, many non-V600 BRAF mutations are being detected whose functional consequences and therapeutic actionability are often unknown. We investigated an atypical BRAF mutation, F595L, which was identified along with mutant HRAS in histiocytic sarcoma and also occurs in epithelial cancers, melanoma and neuroblastoma, and determined its interaction with mutant RAS. Unlike other DFG motif mutants, BRAF(F595L) is a gain-of-function variant with intermediate activity that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling, which is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from patients and cell lines show that BRAF(F595L), as well as other intermediate-activity BRAF mutations, frequently coincide with mutant RAS in various cancers. These data define a distinct class of activating BRAF mutations, extend the spectrum of patients with systemic histiocytoses and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway and underscore the value of comprehensive genomic testing for uncovering the vulnerabilities of individual tumors.

Repetitive elements in imprinted genes.

Genomic imprinting in mammals results in mono-allelic expression of about 80 genes depending on the parental origin of the alleles. Though the epigenetic mechanisms underlying imprinting are rather clear, little is known about the genetic basis for these epigenetic mechanisms. It is still rather enigmatic which sequence features discriminate imprinted from non-imprinted genes/regions and why and how certain sequence elements are recognized and differentially marked in the germlines. It seems likely that specific DNA elements serve as signatures that guide the necessary epigenetic modification machineries to the imprinted regions. Inter- and intraspecific comparative genomic studies suggest that the unusual occurrence and distribution of various types of repetitive elements within imprinted regions may represent such genomic imprinting signatures. In this review we summarize the various observations made and discuss them in light of experimental data.

Course of brain shift during microsurgical resection of supratentorial cerebral lesions: limits of conventional neuronavigation.

BACKGROUND: The authors have conducted a prospective study to evaluate the amount and course of brain shift during microsurgical removal of supratentorial cerebral lesions, and to assess factors which potentially influence these shifts. METHOD: In 61 patients the displacement of 2-3 cortical landmarks on the cerebral surface was dynamically quantified during surgery, i.e. during dissection of the tumour at the estimated half-time of surgery, and at the end of microsurgical removal of the cerebral lesion using the neuronavigation system EasyGuide Neuro. In 14 of these patients the displacement of a subcortical landmark was additionally analysed. Age of the patients, preoperative midline shift, location of the lesion, lesion volume, depth of the lesion below the cortical surface, presence or absence of oedema, and size of the craniotomy were analysed for potential influence on the amount of brain shift. Correlations were analysed for all patients together and for the subgroups of vault meningiomas (n=10), gliomas (n=30), and nonglial intra-axial lesions (n=21). FINDINGS: The mean displacement of the cortical landmarks ranged between 0.8 and 14.3 mm (mean: 6.1 mm, standard deviation: 3.4 mm) during surgery (10-210 minutes [mean: 50.7 minutes, standard deviation: 34.5 minutes] after dura opening) and between 2.4 and 15.2 mm (mean: 6.6 mm, standard deviation: 3.2 mm) at the end of microsurgical removal of the tumourous cerebral lesions (20-375 minutes [mean: 107.2 minutes, standard deviation: 65.6 minutes] after dura opening). Significant correlations (p<0.01) for the entire patient group were found between brain shift and tumour volume, midline shift, and size of the craniotomy, respectively. For the subgroup of vault meningiomas a significant correlation (p<0.01) between brain shift and patient age was found. For the subgroup of gliomas a significant correlation (p<0.01) between brain shift and tumour volume, midline shift and size of the craniotomy, respectively, was found. For the subgroup of nonglial intra-axial lesions a significant correlation (p<0.01) between brain shift and midline shift and between brain shift and size of the craniotomy was found. The quantity of shared common variance ranged between 10-50%. Performing a discriminant analysis, lesion volume was the only certain factor influencing brain shift intra-operatively as well as at the end of lesion removal. 58.5% of the extent of brain shift could be correctly classified by the tumour volume as the only discriminating variable during dissection of the tumour and at the end of surgery. Comparing superficial with subcortical brain shift over the same time period, a mean superficial shift of 4.6 mm (1.6-10.8 mm, standard deviation: 2.8 mm) and a mean subcortical shift of 3.5 mm (1.0-7.7 mm, standard deviation: 2.3 mm) was found. A highly significant Spearman correlation (Rho:.97, p<0.001) between superficial and subcortical brain shift emerged. Shifting of superficial landmarks exceeded shifting of subcortical structures in all patients. CONCLUSIONS: The data demonstrate the dynamics of brain shift and the limits of conventional neuronavigation and add additional support for the unavoidable inaccuracy of contemporary neuronavigational systems once the cranium is opened. Brain shift leads to a significant loss of reliability of neuronavigation systems during microsurgical removal of intracranial lesions and there are differences of the course and the amount of brain shift in relation to special subgroups of supratentorial cerebral lesions. However, because of the heterogeneous nature of lesions neurosurgeons have to remove, the modest quantity of shared common variance, and the differences between superficial and subcortical brain shift, it seems unlikely that the amount and course of brain shift become exactly predictable pre-operatively. Only an intra-operative update of image data should have the capacity to overcome this fundamental problem of modern neuronavigation.

Prognostic factors for patients with microsurgically resected brain metastases.

BACKGROUND: With the advent of new therapies for metastatic carcinoma to the brain, patterns of intracranial disease and factors influencing survival become important considerations when examining treatment options. This study was conducted at a single institution to determine prognostic factors for tumor response and patient survival after microsurgical resection of brain metastases. PATIENTS AND METHODS: 187 consecutive patients who underwent microsurgical resection of brain metastases between July 1989 and September 1996 were retrospectively reviewed and statistically analyzed. The primary cancers included lung cancer (85), gastrointestinal cancer (20), renal cell cancer (19), breast cancer (17), malignant melanoma (8) and 38 cases of various other carcinomas or of unknown primary site. 111 patients received whole-brain radiation therapy (WBRT) with a mean dose of 32 Gy after tumor resection. The influence of number, size, and localization of brain metastases as well as histology of the primary tumor, preoperative performance status, presence of extracranial systemic disease, time course and adjuvant radiation therapy were statistically evaluated (uni- and multivariate) as prognostic factors for survival. RESULTS: Early postoperative Karnofsky score was improved in 59%, unchanged in 32% and worse in 9% of patients. Median survival time (MST) was 9.8 months (range 1 day-5.3 years). The most important parameter showing a significant influence on survival time was the histology of the primary tumor, with prediction of a bad outcome especially for patients with metastases from renal-cell cancer and malignant melanomas. Patients with breast cancer showed longer survival than patients with other primary cancers. Furthermore, survival varied significantly depending on location of brain metastases, performance status at time of craniotomy and duration of symptoms. None of the other studied variables gained prognostic significance. CONCLUSION: Microsurgical resection of one or more brain metastases followed by WBRT still is a useful and efficient treatment in a carefully selected patient group to prolong median survival and improve or stabilize the performance status. Among the factors determining the survival times in this patient group, histology of the primary tumor is most important, together with preoperative Karnofsky score, location of metastasis and preoperative duration of symptoms.

Quality of life in patients with traumatic brain injury-basic issues, assessment and recommendations.

INTRODUCTION: Traumatic brain injuries (TBI) are one of the most common consequences of traffic accidents. Patients with mild, moderate or severe brain injuries suffer from physical, cognitive, behavioral, emotional and social problems. Most of these problems have been a long standing focus amongst practitioners and researchers. Only recently a development has started that took interest in the quality of life outcome of TBI patients. The international members of this consensus meeting reviewed the literature on Quality of Life assessment after TBI and discussed the applicability of different measurements to this specific patient group. TIME POINTS: During the acute phase (T1; < 3 month after trauma) QoL it is difficult to assess due to the reduced consciousness of TBI patients. In the phase of rehabilitation (T2; < one year after trauma) and in the post-rehabilitation phase (T3) repeated assessment of QoL is recommended. INSTRUMENTS: Several generic and disease-specific instruments possibly relevant to TBI patients or specifically developed for this group were assessed according to the existing evidence in the literature. Criteria for the evaluation of these instruments were: feasibility, specificity, validity, comprehensiveness, international availability, existence of norms, and psychometric quality. The cognitive impairment and the existential dimension were not sufficiently considered in most of the reviewed instruments. GROUP CONSENSUS: The family's and relatives' view of the patient's QoL should not be used as a proxy but provides an additional source of information in the acute phase. At T2 and T3, assessment of the patient's quality of life should include a generic as well as a disease specific instrument. Among the generic instruments the SF-36, the EuroQol and the WHO-QoL should be considered. The literature about specific instruments for patients with TBI like the EBIC is scarce. Therefore, the group could hardly give an empirically based recommendation. The need for further investigation on QoL instruments in TBI patients is strongly emphasized.

[The significance of health related quality of life for the evaluation of interventional measures in patients with COPD]. / Die Bedeutung der gesundheitsbezogenen Lebensqualität für die Bewertung interventioneller Massnahmen bei Patienten mit COPD.

Health related quality of life (HRQOL) is an important criterion for the evaluation of rehabilitation measures in patients with chronic obstructive pulmonary disease (COPD). The present paper reviews the current literature about the effects of pulmonary rehabilitation on the HRQOL of patients with COPD. The aim is to summarize critically methods, results and unanswered issues of the present research on the effects of pulmonary rehabilitation on HRQOL. The rehabilitation of patients suffering of COPD is mainly based on six types of interventions: 1. long-term oxygen therapy (LTO), 2. pharmacological management, 3. surgical therapy (bilateral reduction of lung volume), 4. physical therapy, 5. nutritional therapy (special diets), and 6. psycho-social interventions (e.g. psychotherapy, training and education). Thirty-one studies could be included in which HRQOL served as an outcome criterion for the rehabilitation of COPD patients. In 14 (45%) studies exclusively a disease-specific measure for the assessment of HRQOL was employed, while in 12 (39%) studies a generic instrument was applied. In the remaining five (16%) studies two ore more measures were used, whereas four of them combined a generic and a disease-specific method. The St. Georges Respiratory Questionnaire (SGRQ) und the Chronic Respiratory Disease Questionnaire (CRDQ) belonged to the group of the specific instruments, while among the generic measures the Sickness Impact Profile (SIP), the Nottingham Health Profile (NHP), the SF-36 and the Quality of Well-Being Scale (QWB) were most frequently used in COPD patients. The surgical bilateral reduction of lung volume, pharmacological therapy, upper extremities muscle training and psychological measures as single interventions proved to have persistent positive effects on the HRQOL. Several rehabilitation programs, composed of a wide variety of different interventions were effective in terms of HRQOL. On the other hand, at follow-up, the short-term positive effects had decreased in two of the three studies, where the rehabilitation took place exclusively in an inpatient setting. However, in three of four programs implemented in an outpatient setting, a persistent positive effect on HRQOL could be demonstrated. In conclusion from the as of yet available findings, we suggest for future studies to use only such measures of HRQOL which have been tested psychometrically in patients with COPD and to combine disease-specific and generic measures. In order to achieve lasting positive effects of rehabilitation on HRQOL, outpatient settings or ambulatory refreshment sessions following rehabilitation on an inpatient basis should be preferred.

Health-related quality of life after aneurysmal subarachnoid hemorrhage: impacts of bleeding severity, computerized tomography findings, surgery, vasospasm, and neurological grade.

OBJECT: Based on the results of earlier studies it is agreed that the significance of aneurysm location and surgery for neuropsychological impairments after subarachnoid hemorrhage (SAH) is secondary to the effects of the bleeding itself. Therefore, the present study was performed to evaluate whether bleeding, acute clinical course, and surgery have persistent effects on health-related quality of life (QOL) after SAH. METHODS: A series of 116 patients was examined for 4 to 5 years (mean 52.2 months) after aneurysmal SAH by means of a QOL questionnaire. Eighty-six patients (74.1%) had undergone surgery early (< or = 72 hours post-SAH). There were 77 women (66.4%) and 39 men (33.6%) in the study group, and the mean age of the patients was 50.3+/-13.3 years (range 30-69 years). Patients who had undergone surgery for a left-sided middle cerebral artery (MCA) aneurysm complained of significantly more impairments in social contact, communication, and cognition than those treated for a right-sided MCA aneurysm. No other effects of aneurysm location (including the anterior communicating artery) emerged. Multiple aneurysms, intraoperative aneurysm rupture, and partial resection of the gyrus rectus had no adverse effects on later daily life. Only temporary clipping was associated with increased complaints in some QOL areas. Disturbances of the circulation of cerebrospinal fluid and the presence of intraventricular hemorrhage led to more impairments in daily life. Specific effects of the anatomical pattern of the bleeding could be identified, but no adverse effects of vasospasm were found. Multivariate analyses revealed, in particular, that patient age and admission neurological status (Hunt and Hess grade) are substantial predictors of the psychosocial sequelae of SAH. CONCLUSIONS: In contrast to the mild effects of aneurysm surgery, patient's age, initial neurological state on admission, and the bleeding pattern substantially influence late QOL after SAH.

Influence of intraventricular hemorrhage on outcome after rupture of intracranial aneurysm.

This study was performed to analyze the effect of intraventricular hemorrhage (IVH) on 14-day mortality, outcome at 6 months, and the occurrence of chronic hydrocephalus in patients with aneurysmal subarachnoid hemorrhage. Clinical grade of subarachnoid hemorrhage and the distribution of extravasated blood were evaluated in 219 patients with ruptured aneurysms. Computed tomographic scans performed within 72 h of hemorrhage were analyzed to determine the severity of intraventricular and subarachnoid hemorrhage and the volume of intracerebral hematomas. Outcome at 6 months was assessed using the Glasgow Outcome Scale. Intraventricular hemorrhage extension occurred in 109 of the 219 patients studied. Fourteen-day mortality increased from 7.3% in patients without IVH to 14.1% in those with moderate IVH (IVH score 1-6) and to 41.7% in those with more severe IVH (IVH score > 6). The corresponding figures for unfavorable outcome at 6 months are 19.8%, 30.5%, and 66.7%, respectively. According to logistic regression analyses, the severity of IVH was an independent predictor of mortality and functional outcome. The clinical outcome after aneurysm rupture is at least in part determined by the severity of IVH. Knowledge of the effect of IVH may help guide physicians in the care of patients with aneurysmal bleeding.

[Background and first results about methodological characteristics of the Aachen Life Quality Inventory]. / Grundlagen und erste Ergebnisse zur methodischen Eignung des Aachener Lebensqualitätsinventars.

Health-related quality of life has become an important criterion for assessing disease impact and treatment outcome. Therefore, we developed a questionnaire called Aachen Life Quality Inventory (ALQI) for the use in neurosurgical patients with brain damage. The ALQI is derived from the German version of the Sickness Impact Profile (SIP). The 117 items are formulated on a concrete behavioral level covering the following dimensions of health-related quality of life: 1. activation; 2. mobility; 3. house-work; 4. social contact; 5. family relations; 6. ambulation; 7. work; 8. free-time activities; 9. autonomy; 10. communication; 11. cognitive capacity. As in the SIP, a summary score of total impairment (ALQI Total score), a summary score covering the psycho-social dimension (ALQI Psycho-social score) and a summary score covering aspects of physical functioning (ALQI Physical score) can be calculated. The ALQI consists of a self-rating and a parallel proxy-rating version. The ALQI was validated and psychometrically verified using the data of as yet 231 neurosurgical patients with brain damage of mixed etiology (subarachnoid hemorrhage, closed-head injury, benign brain tumors). Internal consistency (Cronbach's Alpha) ranged from.68 to.91 for the subscales, while it was.97 for the whole instrument,.94 for the psycho-social and.93 for the physical score. The internal consistency for the subscales of the proxy-rating version of the ALQI ranged between.77 and.92, while it was.97 for the whole inventory and.94 for the psycho-social and the physical scores, respectively. Examination of construct validity revealed substantial correlations with a wide range of relevant neurological, neurosurgical and neuropsychological parameters. Beyond other findings, substantial associations emerged with several neuropsychological tests (r =.30 to r =.50), the Glasgow Outcome Scale (r =.39; p <.00) and in patients after subarachnoid hemorrhage with the Hunt& Hess grading (r =.28; p <.001). According to these results, the ALQI promises to become a valid and reliable means for assessing quality of life in patients with brain damage. Nevertheless, further analyses using larger patient samples and with particular emphasis on the investigation of the retest-reliability and the prognostic validity are called for in the future.

Health-related quality of life, psychological adjustment and compliance to treatment in patients on domiciliary liquid oxygen.

The purpose of this study was to investigate the effects of two different aspects of compliance with liquid oxygen (LOX) therapy on quality of life and to explore possible pulmonary and psychosocial concomitants. The study sample consisted of 57 oxygen-dependent patients with chronic obstructive pulmonary disease under LOX therapy. Compliance was defined as continuous oxygen use as prescribed and also as readiness to use LOX outdoors. The study design encompassed three major measuring points, the first of which was an initial assessment, the second 3 months later and the third follow-up after 14 months. Furthermore, during the course of the study, two telephone interviews were conducted. The psychosocial variables studied included quality of life, psychological adjustment and two different aspects of compliance with LOX therapy. Seven (12%) patients used LOX less than prescribed and 13 (23%) refused to use LOX away from home. Those patients who used LOX insufficiently had a significantly lower life-satisfaction than those who were compliant (p = 0.02). The discriminance analysis included several psychosocial variables discriminating between both groups, allowing the correct classification of 85% of the patients who used LOX as prescribed and 83% of the noncompliant patients (p = 0.01). At follow-up, the data of 25 patients were available. Of these, five refused outdoor LOX use. Their quality of life was significantly worse in almost all areas examined as compared to the outdoor LOX-users (p < 0.05, respectively). Compliance is an essential prerequisite for the beneficial effects of liquid oxygen on quality of life. Because psychological factors influence adherence to liquid oxygen therapy, patients should receive individual psychological counselling and training before transfer to liquid oxygen therapy.

Analysis of the dormancy-inducible narK2 promoter in Mycobacterium bovis BCG.

Upon depletion of oxygen, the obligate aerobe mycobacteria switch from growth to a state of non-replicating persistence or dormancy. Here, we report the first functional analysis of a dormancy-dependent mycobacterial promoter in Mycobacterium bovis BCG. Promoter probing using a 'lacZ reporter detected a dormancy-inducible promoter activity upstream of the coding sequence for the putative nitrite extrusion protein NarK2. Primer extension analysis mapped a transcriptional start point 47 bp upstream of the narK2 start codon. Deletion analysis revealed that the sequence -222 to -133 bp upstream from the transcriptional start point was required for basal and dormancy-inducible reporter expression. The sequence +1 to +47 downstream of the transcriptional start point had a strong inhibitory effect on the level of dormancy-induced beta-galactosidase activity. The identification of apparent activating and inhibiting regions suggests that the narK2 promoter is at least under dual control.

Virtual pointer projection of the central sulcus to the outside of the skull using frameless neuronavigation -- accuracy and applications.

BACKGROUND: The purpose of this prospective study was to localize the central sulcus by frameless neuronavigation and to project this anatomical structure to the outside of the skull on the skin. This method was analyzed in respect to its practicability, accuracy, and potential applications. METHOD: In 27 patients investigated (28 unaffected hemispheres), the central sulcus was virtually projected to the outside of the skull using frameless neuronavigation and a virtual pointer elongation of 15 or 20 mm. The following parameters were measured on the scalp: 1. the distance between the bregma and the midline junction of the central sulcus, and 2. the angle between the central sulcus and the midline. These dada were compared with measurements based on the original axial MR images of these patients. Finally, a laboratory phantom study was designed in analogy to a patient's examination for estimation of the overall accuracy of the neuronavigation system in the experimental setup used in this study. FINDINGS: Virtual pointer projection of the central sulcus to the outside of the skull using frameless neuronavigation was found to be easily possible. The distance between the bregma and the midline junction of the central sulcus amounted to a mean of 55 mm on the left and 56 mm on the right. The angle between the central sulcus and the midline reached a mean of 63 degrees on the left and 60 degrees on the right. These data confirmed results of other studies with no frameless neuronavigation devices. The phantom study revealed a mean overall inaccuracy of 0.9 mm at a virtual pointer elongation of 15 mm. At a virtual pointer elongation of 20 mm, the mean overall inaccuracy of our study was 1.1 mm. These results correspond to the inaccuracy of frame based stereotaxy. INTERPRETATION: It is easily possible, valid, and reliable to virtually project the central sulcus to the outside of the skull with an acceptably low inaccuracy using frameless neuronavigation. This is important for research studies that correlate and integrate different functional imaging methods with the aid of frameless neuronavigation.