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.

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.

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.

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.

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.

Host vector system for high-level expression and purification of recombinant, enzymatically active alanine dehydrogenase of Mycobacterium tuberculosis.

The 40-kDa antigen of M. tuberculosis, which is an alanine dehydrogenase, is a species-specific antigen that is potentially useful for strain identification. Large quantities of the purified protein are required for immunological, as well as for detailed biochemical and structural, characterization. The AlaDH gene was cloned by PCR from H37Rv (virulent) and H37Ra (partially attenuated) strains of M. tuberculosis, and their DNA sequence was determined. A host-vector system suitable for the production of sufficient quantities of the recombinant AlaDH antigen was developed. The AlaDH gene was expressed under the control of strong, transcriptional (bacteriophage pLpR) and translational (atpE) signals. High-level expression of soluble AlaDH was obtained using the recombinant E. coli K-12 strain CAG629 [pMSK12], which is deficient in Lon protease and the heat-shock response. A simple two-step procedure for the rapid purification of the recombinant protein was developed. The protein was purified to near homogeneity, and the purified AlaDH showed a specific enzyme activity comparable to the native protein isolated from M. tuberculosis. In addition, the product showed an expected amino acid sequence and reacted strongly to the 40-kDa (AlaDH)-specific mAb HBT-10. Furthermore, the epitope of the mAb HBT-10 was mapped to a 12-amino-acid region. Contrary to the published results, we show that the AlaDH and the PNT (pyridine nucleotide transhydrogenase) of M. tuberculosis do not share common epitopes reacting to the species-specific mAb HBT-10. The availability of highly purified AlaDH should now enable a detailed biochemical and structural characterization of this important enzyme of M. tuberculosis.

Molecular genetic characterisation of whiB3, a mycobacterial homologue of a Streptomyces sporulation factor.

WhiB is an essential sporulation factor in Streptomyces coelicolor. We report here the molecular genetic characterisation of whiB3, a whiB-like gene in the nonspore-forming Mycobacterium smegmatis mc(2)155. M. smegmatis whiB3 encodes a 96-amino-acid protein with 81% similarity to its M. tuberculosis counterpart identified in the genome project, and 35% similarity to S. coelicolor WhiB. In both mycobacteria, whiB3 is flanked by the same upstream gene, Rv3415c, and appears to be monocistronic. Promoter probe analyses suggest that the whiB3 gene is expressed constitutively. Disruption of whiB3 did not affect growth or the dormancy response of M. smegmatis.

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.

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.

Up-regulation of narX, encoding a putative 'fused nitrate reductase' in anaerobic dormant Mycobacterium bovis BCG.

Mycobacterium tuberculosis and its closely related but non-pathogenic relative M. bovis Bacille Calmette-Guèrin (BCG) have the capability to adapt to anaerobiosis by shifting down from aerobic growth to a state of non-replicating persistence or dormancy. Here, we report the results of a comparative Northern analysis of 23 genes identified in the tubercle bacillus genome project that might play a role in the energy metabolism under anaerobic conditions. The expression of a majority of the genes was found to be down-regulated in the dormant BCG culture. However, the mRNA level for narX, a putative 'fused nitrate reductase' not found in other bacteria, was strongly up-regulated in anaerobic dormant bacilli. narX is the first transcriptionally induced gene in anaerobic dormant mycobacteria and might be a useful marker for monitoring the dormancy response in infected animals.

Increased alanine dehydrogenase activity during dormancy in Mycobacterium smegmatis.

The aerobic fast-growing Mycobacterium smegmatis has, like its slow-growing pathogenic counterpart M. tuberculosis, the capability to adapt to anaerobiosis by shifting down to a drug resistant dormant state. Here, we report the identification of the first enzyme, L-alanine dehydrogenase, whose specific activity is increased during dormancy development in M. smegmatis. This mycobacterial enzyme activity was previously identified as the 40-kDa antigen in M. tuberculosis and shows a preference for the reductive amination of pyruvate to alanine at physiological pH. The determination of the temporal profile of alanine dehydrogenase activity during dormancy development showed that the activity stayed at a low baseline level during the initial aerobic exponential growth phase (0.7 mU mg-1 min-1). After termination of aerobic growth, alanine dehydrogenase activity increased rapidly 5-fold. As oxygen becomes more and more limiting, the enzyme activity declined until it reached a level about two-third that of the peak value. The strong induction immediately after deflection from aerobic growth suggests that alanine might be required for the adaptation from aerobic growth to anaerobic dormancy. As alanine synthesis is coupled to NADH oxidation, we propose that the induction of alanine dehydrogenase activity might also support the maintenance of the NAD pool when oxygen as a terminal electron acceptor becomes limiting.

Which neuropsychological deficits are hidden behind a good outcome (Glasgow = I) after aneurysmal subarachnoid hemorrhage?

A series of 31 patients with good neurological 6-month outcomes (Glasgow Outcome Scale = I) was examined with a battery of cognitive tests 1 to 5 years after aneurysmal subarachnoid hemorrhage (SAH) and early operation. The results showed a marked disability in 28 to 62% of these patients in the subtests of a complex choice reaction task. Short-term memory was impaired in 53% of the patients neuropsychologically examined, whereas 21% of them had a reduced long-term memory. Concentration was impaired in 7 to 16% of the SAH patients. Also, 10% of the patients rated Glasgow Outcome Scale = I had an indication for an aphasic language disturbance. Multivariate analysis proved significant harmful effects of the severity of the bleeding seen on computed tomographic scan (Fisher scale) on information processing and word-finding capacity. Patients who were older at the time of the SAH were significantly more disturbed in concentration, short-term memory, and information-processing capacity at follow-up. It can be concluded from these results that a good neurological outcome (Glasgow Outcome Scale = I) does not exclude persisting neuropsychological deficits. Therefore, the value of the clinical use of the Glasgow Outcome Scale is limited. As a consequence, a differentiated neuropsychological examination is proposed to evaluate the exact outcome of SAH patients.

Cognitive deficits in the acute stage after subarachnoid hemorrhage.

OBJECTIVE: In spite of fundamentally improved medical management of subarachnoid hemorrhage (SAH), many patients remain mentally impaired. However, the causes of these disturbances are unclear. The present study was performed to elucidate the significance of the hemorrhage itself and related events in the neuropsychological performance of patients in the acute stage after SAH. METHODS: A series of 51 patients were examined, by means of a battery of cognitive tests, 1 to 13 days (mean, 5.9 d) after SAH. Thirty-three patients had experienced ruptured aneurysms, and 18 had sustained SAH of unknown origin. Furthermore, 25 patients who had undergone surgical treatment (a mean of 5.0 d earlier) of prolapsed lumbar discs served as a control group. RESULTS: The cognitive deficits of the patients after aneurysmal SAH proved to be comparable to those after spontaneous SAH of unknown origin, with the single exception of a significantly worse (P = 0.003) concentration capacity in the surgically treated group. The severity of SAH in computed tomographic scans correlated (up to r = 0.57, P < 0.001) with poor performance on tests of memory, concentration, divided attention, and perseveration. Frontal intracerebral hemorrhage led to significantly more errors in an aphasia screening test (P < 0.001) and a test of perseveration (P < 0.001). If acute hydrocephalus was present, the patients exhibited worse long-term memory (P < 0.001), showed slower reaction times (P = 0.01), and made more errors in the perseveration test (P = 0.004). Patients with intraventricular blood performed at significantly lower levels in the concentration (P = 0.001), divided attention (P = 0.01), long-term memory (P < 0.001), and perseveration (P = 0.003) tests. CONCLUSION: The results emphasize that the severity of SAH (Fisher score) is the most important factor related to cognitive dysfunction, but frontal hematoma, intraventricular hemorrhage, and acute hydrocephalus were also associated with cognitive deficits, compared with patients with SAH without these findings.

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.

[The "false-positive polyp" during contrast examination of the colon (author's transl)]. / Der "falsch-positive polyp" in Kolonkontrasteinlauf.

44 cases of false-positive radiological diagnosis of colonic polyps are reviewed with regard to cause, frequency, distribution and radiological criteria. Most common causes are scybala and air bubbles (77%) and effects of overlapping and projection (19%). Due to extensive folding of the colon misinterpretations are frequently seen in the sigmoid and in the area of both flexures; the folding allows overlapping of mucosal structures and trapping of bowel contents. The validity of roentgen signs in polyp diagnosis and the limits of colonoscopy are discussed. Diagnostic reliability may be improved by optimal technique of examination and standardized proceeding.

[Co-existence of fibrous bone dysplasia and familial intestinal polyposis]. / Koexistenz von fibröser Knochendysplasie und familiärer intestinaler Polyposis.

The aetiology of fibrous bone dysplasia is unknown. Combinations with endocrine and non-endocrine diseases are recognised. The co-existence of polyostotic fibrous dysplasia with Peutz-Jeghers syndrome has not been previously described. A patient is now reported who had both these diseases. They have in common a benign proliferative tendency in various organs, but the common denominator is unknown. The basic relationship between the conditions requires further observation and study.

[Primary duodenal carcinoma. Clinico-radiologic study]. / Das primäre Duodenalkarzinom. Eine klinisch-radiologische Studie.

Primary carcinoma of the duodenum represents about 0.35% of all gastrointestinal carcinomas and is thus a rare disease. The radiological diagnosis of a duodenal origin is made more difficult by the close proximity of the pancreas, biliary system, right kidney and transverse colon. Histologically, duodenal malignant tumours are usually adenocarcinomas. Between 1973 and 1983, eight patients with primary duodenal carcinomas were diagnosed at the University of Tübingen. Average age of the patients was 67 years. There was no sex difference. Average survival was 3.3 years.

[Preoperative T-staging of prostatic carcinoma: endorectal magnetic resonance tomography compared with other imaging and clinical methods]. / Präoperatives T-Staging des Prostatakarzinoms: Endorektale Magnetresonanztomographie im Vergleich zu anderen bildgebenden und klinischen Methoden.

PURPOSE: The diagnostic value of endorectal magnetic resonance imaging (MRI) in comparison to clinical information and other imaging modalities was analysed in order to define the most accurate preoperative staging method. METHODS: 54 patients with biopsy proven prostate carcinoma, who underwent subsequent prostatectomy, were examined with an endorectal surface coil. The results were compared to body coil MRI, digital rectal examination and prostate specific antigen levels. In 37 patients, results of endorectal ultrasound were available. RESULTS: Staging accuracy, sensitivity and specificity of endorectal coil MRI were 83.3%. For body coil MRI, staging accuracy was 59.2%, sensitivity 43.3% and specificity 82.6%, for transrectal ultrasound 59.5%, 36.4% and 91.7% and for the digital rectal examination 55.6%, 26.7% and 91.7%, respectively. Staging accuracy of endorectal MRI was significantly (p < 0.05) superior to that of the other imaging modalities. CONCLUSION: Endorectal coil MRI allows reliable distinction between localised and advanced tumour stages and is superior to other imaging techniques in this regard. It can thus be recommended for staging in patients with prostate carcinoma.

Cognition and quality of life in patients after transcallosal microsurgery for midline tumors.

OBJECTIVE: The transcallosal route has been propagated as a safe approach to midline tumors. The present study was performed in order to elucidate the neurobehavioral late sequelae in patients after transcallosal microsurgery on near-midline tumors. EXPERIMENTAL DESIGN: The present study was performed retrospectively with a delay between surgery and follow-up examination ranging from 2 to 36 months (mean 10.2 months). SETTING: The study was performed in the Department of Neurosurgery, University Hospital of the University of Technology (RWTH) Aachen, Germany. PATIENTS: A consecutive series of 18 patients treated for an intracranial lesion by transcallosal surgery was included into the study. The patients had to be not younger than 16 and not older than 67 years. The age mean was 38.9 years (range 16 to 65 years). INTERVENTIONS: The surgical approach was performed along the falx cerebi under microneurosurgical conditions with direct use of the microscope after opening the dura. MEASURES: Beyond neurological examinations, the patients were submitted to an extensive neuropsychological testing battery. Furthermore, quality of life was examined by means of a questionnaire. RESULTS: Surgery was performed without persistent new neurological deficits. Cognitive deficits were found in short- and long-term memory, motor fine-coordination, reaction time, divided attention and fronto-cortical capacity. The quality of life was particularly impaired in the area of cognitive capacity in daily life. These findings could be related to the duration of preoperative symptoms and to the tumor location. CONCLUSIONS: The deficits found cannot be explained by surgical damage to the corpus callosum itself. Rather, they seem to correspond to an extra-callosal pathology. Further studies with a prospective evaluation of larger patient samples are called for in the future.