Rolf Fimmers

Mammography, Breast Ultrasound, and Magnetic Resonance Imaging for Surveillance of Women at High Familial Risk for Breast Cancer

PURPOSE To compare the effectiveness of mammography, breast ultrasound, and magnetic resonance imaging (MRI) for surveillance of women at increased familial risk for breast cancer (lifetime risk of 20% or more). PATIENTS AND METHODS We conducted a surveillance cohort study of 529 asymptomatic women who, based on their family history and/or mutational analysis, were suspected or proven to carry a breast cancer susceptibility gene (BRCA). A total of 1,542 annual surveillance rounds were completed with a mean follow-up of 5.3 years. Diagnostic accuracies of the three imaging modalities used alone or in different combinations were compared. RESULTS Forty-three breast cancers were identified in the total cohort (34 invasive, nine ductal carcinoma-in-situ). Overall sensitivity of diagnostic imaging was 93% (40 of 43 breast cancers); overall node-positive rate was 16%, and one interval cancer occurred (one of 43 cancers, or 2%). In the analysis by modality, sensitivity was low for mammography (33%) and ultrasound (40%) or the combination of both (49%). MRI offered a significantly higher sensitivity (91%). The sensitivity of mammography in the higher risk groups was 25%, compared with 100% for MRI. Specificity of MRI (97.2%) was equivalent to that of mammography (96.8%). CONCLUSION Mammography alone, and also mammography combined with breast ultrasound, seems insufficient for early diagnosis of breast cancer in women who are at increased familial risk with or without documented BRCA mutation. If MRI is used for surveillance, diagnosis of intraductal and invasive familial or hereditary cancer is achieved with a significantly higher sensitivity and at a more favorable stage.

Primary Central Nervous System Lymphoma: Results of a Pilot and Phase II Study of Systemic and Intraventricular Chemotherapy With Deferred Radiotherapy

PURPOSE To evaluate response rate, response duration, overall survival (OS), and toxicity in primary CNS lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. PATIENTS AND METHODS From September 1995 to July 2001, 65 consecutive patients with PCNSL (median age, 62 years) were enrolled onto a pilot and phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX; cycles 1, 2, 4, and 5) and cytarabine (ARA-C; cycles 3 and 6)-based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ARA-C. RESULTS Sixty-one of 65 patients were assessable for response. Of these, 37 patients (61%) achieved complete response, six (10%) achieved partial response, and 12 (19%) progressed under therapy. Six (9%) of 65 patients died because of treatment-related complications. Follow-up is 0 to 87 months (median, 26 months). The Kaplan-Meier estimates for median time to treatment failure (TTF) and median OS were 21 months and 50 months, respectively. For patients older than 60 years, median survival was 34 months, and the median TTF was 15 months. In patients younger than 61 years, median survival and median TTF have not been reached yet; the 5-year survival fraction is 75%. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 12 patients (19%), and permanent cognitive dysfunction possibly as a result of treatment occurred in only two patients (3%). CONCLUSION Primary chemotherapy based on high-dose MTX and ARA-C is highly efficient in PCNSL. Response rate and response duration in this series are comparable to the response rates and durations reported after combined radiotherapy and chemotherapy. Neurotoxicity was infrequent.

Silent and apparent cerebral embolism after retrograde catheterisation of the aortic valve in valvular stenosis: a prospective, randomised study

BACKGROUND In most patients, severity of valvular aortic stenosis can be accurately assessed non-invasively by echocardiography. However, retrograde catheterisation of the aortic valve is often undertaken. This procedure has a potential risk of neurological complications, with an unknown incidence of clinically silent embolism. We aimed to establish the frequency of clinically apparent and silent cerebral embolism after this procedure. METHODS We prospectively randomised 152 consecutive patients with valvular aortic stenosis at a German university hospital to receive either cardiac catheterisation with (n=101) or without (n=51) passage through the aortic valve. Patients underwent cranial MRI and neurological assessment within 48 h before and after the procedure to assess cerebral embolism. Controls were 32 patients without valvular aortic stenosis who underwent coronary angiography and laevocardiography. FINDINGS 22 of 101 patients (22%) who underwent retrograde catheterisation of the aortic valve had focal diffusion-imaging abnormalities in a pattern consistent with acute cerebral embolic events after the procedure; three of these patients (3%) had clinically apparent neurological deficits. By contrast, none of the patients without passage of the valve, or any of the controls, had evidence of cerebral embolism as assessed by MRI. INTERPRETATION Patients with valvular aortic stenosis who undergo retrograde catheterisation of the aortic valve have a substantial risk of clinically apparent cerebral embolism, and frequently have silent ischaemic brain lesions. Patients should be informed about these risks, and this procedure should be used only in patients with unclear echocardiographical findings when additional information is necessary for clinical management.

The Spectrum of Long-term Epilepsy–associated Tumors: Long-term Seizure and Tumor Outcome and Neurosurgical Aspects

Summary:  Purpose: To describe the histologic spectrum and clinical characteristics of patients with neuroepithelial tumors and drug‐resistant epilepsy and to analyze clinical data and treatment related to seizure outcome and survival.

Risk and Fate of Cerebral Embolism After Transfemoral Aortic Valve Implantation : A Prospective Pilot Study With Diffusion-Weighted Magnetic Resonance Imaging

OBJECTIVES The aim of this study was prospective investigation of silent and clinically apparent cerebral embolic events and neurological impairment after transfemoral aortic valve implantation (TAVI). BACKGROUND TAVI is a novel therapeutic approach for multimorbid patients with severe aortic stenosis. We investigated peri-interventional cerebral embolism with diffusion-weighted magnetic resonance imaging (DW-MRI) and its relationship to clinical and serologic parameters of brain injury. METHODS Cerebral DW-MRI was performed before, directly, and 3 months after TAVI with the current third-generation self-expanding CoreValve (Medtronic, Minneapolis, Minnesota) prosthesis. At the timepoints of the serial MRI studies, focal neurological impairment was assessed according to the National Institutes of Health Stroke Scale (NIHSS), and serum concentration of neuron-specific enolase (NSE), a marker of the volume of brain tissue involved in an ischemic event, were determined. RESULTS Thirty patients were enrolled; 22 completed the imaging protocol. Three patients (10%) had new neurological findings after TAVI, of whom only 1 (3.6%) had a permanent neurological impairment. Of the 22 TAVI patients with complete imaging data, 16 (72.7%) had 75 new cerebral lesions after TAVI presumed to be embolic. The NIHSS and NSE were not correlated with DW-MRI lesions. CONCLUSIONS The incidence of clinically silent peri-interventional cerebral embolic lesions after TAVI is high. However, in this cohort of 30 patients, the incidence of persistent neurological impairment was low. (Incidence and Severity of Silent and Apparent Cerebral Embolism After Conventional and Minimal-invasive Transfemoral Aortic Valve Replacement; NCT00883285).

Risk Factors for Relapse in Clinical Stage I Nonseminomatous Testicular Germ Cell Tumors: Results of the German Testicular Cancer Study Group Trial

PURPOSE To prospectively assess potential risk factors for relapse in clinical stage I nonseminomatous germ cell tumors of the testis (CS I NSGCT). PATIENTS AND METHODS From September 1996 to May 2002, 200 patients with CS I NSGCT were prospectively assigned to retroperitoneal lymph node dissection (RPLND), and risk factor assessment was performed within a multicenter protocol. One hundred sixty-five patients had an adequate minimum follow-up of 12 months (mean, 34.5 months) or had pathologic stage II. RESULTS Pathologic stage II disease was found in 27.9% of patients. Only 0.6% of patients relapsed in the retroperitoneum after confirmation of pathologic stage I disease. With reference pathology, vascular invasion (VI) was most predictive of stage in multifactorial analysis (accuracy, 65.1%). However, the positive predictive value (PPV) of VI to predict patients who have metastatic disease or relapse during follow-up was only 52.7%. With absent VI, low-risk patients had a negative predictive value (NPV) of 76.9%. With a combination of several risk factors, the PPV increased to 63.6% and the negative predictive value increased to 86.5%. CONCLUSION Even with an optimal combination of prognostic factors and reference pathology, more than one third of patients predicted to have pathologic stage II or relapse during follow-up will not harbor metastatic disease and, therefore, would be overtreated with adjuvant therapy. However, patients at low risk may be predicted at an 86.5% level, and thus, surveillance in highly compliant patients would be a valuable option. For high-risk patients, further reduction of adjuvant treatment is necessary.

Supratentorial gangliogliomas: histopathologic grading and tumor recurrence in 184 patients with a median follow-up of 8 years.

Supratentorial gangliogliomas (GGs) are rare tumors of the central nervous system and are commonly associated with chronic seizures. To date, only case reports and small series of patients with short‐term follow‐up have been available for the assessment of the potential of GGs to recur and progress.

Parametric and Nonparametric Multipoint Linkage Analysis with Imprinting and Two-Locus–Trait Models: Application to Mite Sensitization

We present two extensions to linkage analysis for genetically complex traits. The first extension allows investigators to perform parametric (LOD-score) analysis of traits caused by imprinted genes-that is, of traits showing a parent-of-origin effect. By specification of two heterozygote penetrance parameters, paternal and maternal origin of the mutation can be treated differently in terms of probability of expression of the trait. Therefore, a single-disease-locus-imprinting model includes four penetrances instead of only three. In the second extension, parametric and nonparametric linkage analysis with two trait loci is formulated for a multimarker setting, optionally taking imprinting into account. We have implemented both methods into the program GENEHUNTER. The new tools, GENEHUNTER-IMPRINTING and GENEHUNTER-TWOLOCUS, were applied to human family data for sensitization to mite allergens. The data set comprises pedigrees from England, Germany, Italy, and Portugal. With single-disease-locus-imprinting MOD-score analysis, we find several regions that show at least suggestive evidence for linkage. Most prominently, a maximum LOD score of 4.76 is obtained near D8S511, for the English population, when a model that implies complete maternal imprinting is used. Parametric two-trait-locus analysis yields a maximum LOD score of 6.09 for the German population, occurring exactly at D4S430 and D18S452. The heterogeneity model specified for analysis alludes to complete maternal imprinting at both disease loci. Altogether, our results suggest that the two novel formulations of linkage analysis provide valuable tools for genetic mapping of multifactorial traits.

Endometrial receptivity in an in vitro fertilization program as assessed by spiral artery blood flow, endometrial thickness, endometrial volume, and uterine artery blood flow

OBJECTIVE To investigate the role of sonographic parameters in assessing endometrial receptivity in an in vitro fertilization (IVF) program. DESIGN Prospective clinical study. SETTING University setting. PATIENT(S) One hundred thirty-five patients in our IVF program, selected prospectively on the day of oocyte retrieval. INTERVENTION(S) Transvaginal ultrasound examination was performed before oocyte collection. MAIN OUTCOME MEASURE(S) Association between implantation rate and spiral artery blood flow (primary outcome measure) and between implantation rate and endometrial measurements as well as uterine artery blood flow (secondary outcome measures). RESULT(S) Overall implantation rate was 23.7% per cycle. Subendometrial blood flow was detected in 113 (83.7%) cases, with pregnancy occurring in 21.2%. Mean spiral artery pulsatility index values were 1.12 +/- 0.28 and 1.21 +/- 0.27 for nonconception and conception cycles, respectively. Nondetectable spiral artery blood flow was not associated with a lower implantation rate. Neither endometrial thickness nor endometrial volume was correlated with the likelihood of successful implantation. Minimum endometrial thickness and volume associated with pregnancy were 6.9 mm and 1.59 mL, respectively. CONCLUSION(S) Neither Doppler sonography of the spiral or uterine arteries nor measurement of the endometrial thickness or volume allowed a reliable prediction of subsequent IVF outcome.

Oligodendroglial tumors: refinement of candidate regions on chromosome arm 1p and correlation of 1p/19q status with survival.

Loss of heterozygosity (LOH) on the chromosome arms 1p and 19q is frequent in oligodendroglial tumors and has been correlated with chemosensitivity and good prognosis in anaplastic oligodendrogliomas. The oligodendroglioma‐associated tumor suppressor genes on 1p and 19q are as yet unknown. To narrow down candidate regions on 1p, we investigated oligodendroglial tumors from 89 patients for LOH at up to 30 polymorphic loci on 1p. In addition, all tumors were studied for LOH at 7 loci on 19q. Combined LOH on 1p and 19q was detected in 20 (83%) of 24 oligodendrogliomas, 15 (63%) of 24 anaplastic oligodendrogliomas, 10 (56%) of 18 oligoastrocytomas, and 12 (52%) of 23 anaplastic oligoastrocytomas. Five tumors demonstrated partial deletions on 1p, which allowed to define 3 distinct candidate regions at 1 p36.31 ‐pter distal to D1S2633, 1p36.22‐p36.31 between D1S489 and D1S2642, and 1p34.2‐p36.1 between D1S2743 and D1S482, respectively. No partial deletions were detected on 19q. Combined LOH on 1p and 19q was associated with prolonged time to progression (TTP), longer overall survival (OS), and a higher 5‐year survival rate. Depending on the presence or absence of combined LOH on 1p and 19q, patients with anaplastic oligodendroglial tumors treated with adjuvant radio‐ and/or chemotherapy showed a median TTP of 86 months versus 39 months, a median OS of 91 months versus 46 months, and a 5‐year survival rate of 80% versus 36%, respectively. Similarly, LOH on 1p and 19q was associated with longer survival in patients with low‐grade oligodendroglial tumors (TTP: 57 months versus 47 months; OS: 172 months versus 105 months; 5‐year survival rate: 92% versus 70%). Thus, our results refine the location of putative oligodendroglioma suppressor genes on 1p and support the significance of LOH on 1p and 19q as a favorable prognostic marker.