Christoph Meisner

Noninvasive detection and evaluation of atherosclerotic coronary plaques with multislice computed tomography

OBJECTIVES The aim of the present study was to evaluate the accuracy in determining coronary lesion configuration by multislice computed tomography (MSCT). The results were compared with the findings of intracoronary ultrasound (ICUS). BACKGROUND The risk of acute coronary syndromes caused by plaque disruption and thrombosis depends on plaque composition rather than stenosis severity. Thus, the reliable noninvasive assessment of plaque configuration would constitute an important step forward for risk stratification in patients with known or suspected coronary artery disease. Just recently, MSCT scanners became available for general purpose scanning. Due to improved spatial and temporal resolution, this new technology holds promise to allow for differentiation of coronary lesion configuration. METHODS The ICUS and MSCT scans (Somatom Volume Zoom, Siemens, Forchheim, Germany) were performed in 15 patients. Plaque composition was analyzed according to ICUS (plaque echogenity: soft, intermediate, calcified) and MSCT criteria (plaque density expressed by Hounsfield units [HU]). RESULTS Thirty-four plaques were analyzed. With ICUS, the plaques were classified as soft (n = 12), intermediate (n = 5) and calcified (n = 17). Using MSCT, soft plaques had a density of 14 +/- 26 HU (range -42 to +47 HU), intermediate plaques of 91 +/- 21 HU (61 to 112 HU) and calcified plaques of 419 +/- 194 HU (126 to 736 HU). Nonparametric Kruskal-Wallis test revealed a significant difference of plaque density among the three groups (p < 0.0001). CONCLUSIONS Our results indicate that coronary lesion configuration might be correctly differentiated by MSCT. Since also rupture-prone soft plaques can be detected by MSCT, this noninvasive method might become an important diagnostic tool for risk stratification in the near future.

Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial

BACKGROUND Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. METHODS Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m(2) temozolomide, given on days 1-7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6-7 weeks in 30 fractions of 1·8-2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241. FINDINGS Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3-10·2) in the temozolomide group versus 9·6 months (8·2-10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84-1·42, p(non-inferiority)=0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2-4·1] vs 4·7 [4·2-5·2]; HR 1·15, 95% CI 0·92-1·43, p(non-inferiority)=0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0-10·0]; HR 0·62, 95% CI 0·42-0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5-11·7] vs 4·6 [4·2-5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0-3·5] vs 4·6 months [3·7-6·3]). The most frequent grade 3-4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). INTERPRETATION Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. FUNDING Merck Sharp & Dohme.

Clinical studyNoninvasive detection and evaluation of atherosclerotic coronary plaques with multislice computed tomography1

OBJECTIVES The aim of the present study was to evaluate the accuracy in determining coronary lesion configuration by multislice computed tomography (MSCT). The results were compared with the findings of intracoronary ultrasound (ICUS). BACKGROUND The risk of acute coronary syndromes caused by plaque disruption and thrombosis depends on plaque composition rather than stenosis severity. Thus, the reliable noninvasive assessment of plaque configuration would constitute an important step forward for risk stratification in patients with known or suspected coronary artery disease. Just recently, MSCT scanners became available for general purpose scanning. Due to improved spatial and temporal resolution, this new technology holds promise to allow for differentiation of coronary lesion configuration. METHODS The ICUS and MSCT scans (Somatom Volume Zoom, Siemens, Forchheim, Germany) were performed in 15 patients. Plaque composition was analyzed according to ICUS (plaque echogenity: soft, intermediate, calcified) and MSCT criteria (plaque density expressed by Hounsfield units [HU]). RESULTS Thirty-four plaques were analyzed. With ICUS, the plaques were classified as soft (n = 12), intermediate (n = 5) and calcified (n = 17). Using MSCT, soft plaques had a density of 14 +/- 26 HU (range -42 to +47 HU), intermediate plaques of 91 +/- 21 HU (61 to 112 HU) and calcified plaques of 419 +/- 194 HU (126 to 736 HU). Nonparametric Kruskal-Wallis test revealed a significant difference of plaque density among the three groups (p < 0.0001). CONCLUSIONS Our results indicate that coronary lesion configuration might be correctly differentiated by MSCT. Since also rupture-prone soft plaques can be detected by MSCT, this noninvasive method might become an important diagnostic tool for risk stratification in the near future.

Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study

BACKGROUND Cutaneous squamous-cell carcinomas (SCC) are among the most common cancers capable of metastasis. Current Tumour Node Metastasis (TNM) staging includes horizontal tumour size, involvement of extradermal structures, and degree of differentiation. The aim of this study was to prospectively analyse the key factors predicting metastasis and local recurrence in cutaneous SCC. METHODS We assessed prospectively investigated potential risk factors for metastasis or local recurrence of SCC, previously suggested by retrospective studies and small case series, in 615 white patients. Between Jan 1, 1990, and Dec 31, 2001, all patients underwent surgery for cutaneous SCC with complete histological examination of the three-dimensional excision margins (3D-histology) in one centre. Univariate and multivariate analysis included tumour thickness, horizontal size, body site, histological differentiation, desmoplastic growth, history of multiple SCC, and immunosuppression. Primary endpoints were time to metastasis and time to local recurrence, defined as the time from date of diagnosis of the primary tumour to the date of diagnosis of metastasis or local recurrence, respectively. FINDINGS 653 patients were enrolled in the study. 38 patients were lost to follow-up leaving 615 assessable patients (median age 73 years [range 27-98]). During a median follow-up period of 43 months (range 1-165), 26 (4%) of 615 patients developed metastases and 20 patients developed local recurrence (3%). Tumours 2.0 mm or less in thickness did not metastasise. Metastases occurred in 12 (4%) of 318 tumours between 2.1 mm and 6.0 mm in thickness, and in 14 (16%) of 90 tumours with a thickness greater than 6.0 mm. On multivariate analysis, key prognostic factors for metastasis were increased tumour thickness (hazard ratio 4.79 [95% CI 2.22-10.36]; p<0.0001), immunosuppression (4.32 [1.62-11.52]; p=0.0035), localisation at the ear (3.61 [1.51-8.67]; p=0.0040), and increased horizontal size (2.22 [1.18-4.15]; p=0.0128). The risk of local recurrence depended on increased tumour thickness (6.03 [2.71-13.43]; p<0.0001) and desmoplasia (16.11 [6.57-39.49]; p<0.0001). INTERPRETATION Only SCC greater than 2.0 mm in thickness are associated with a significant risk of metastasis. Tumours greater than 6.0 mm are associated with a high risk of metastasis and local recurrence. Desmoplastic growth is an independent risk factor for local recurrence. Studies should assess the role of follow-up visits and sentinel-lymph-node biopsy in high-risk patients.

Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the german prospective randomized trial hit ’91

Purpose: The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT ’91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy. Methods and Materials: Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine (“Philadelphia protocol”). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose). Results: During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4–62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70 ± 0.08; for patients with residual disease: 0.72 ±0.06; without residual disease: 0.68 ± 0.09; M0: 0.72 ± 0.04; M1: 0.65 ± 0.12; and M2/3: 0.30 ± 0.15. For all randomized patients without M2/3 disease: 0.65± 0.05 (arm I) and 0.78 ± 0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60 ± 0.13 and 0.64 ± 0.14, respectively, but patients between 6 and 18 years: 0.62 ± 0.09 and 0.84 ± 0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03). Conclusions: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.

Noninvasive determination of endothelium-mediated vasodilation as a screening test for coronary artery disease: Pilot study to assess the predictive value in comparison with angina pectoris, exercise electrocardiography, and myocardial perfusion imaging

BACKGROUND Peripheral endothelial dysfunction (ED) quantified by the determination of flow-mediated dilation (FMD%) of the brachial artery with the use of high-resolution ultrasound is an early marker of atherosclerosis. Although a positive correlation with coronary artery disease (CAD) has been reported, the unanswered clinical question is the validity of FMD% as a screening test in patients with clinical suspicion of CAD. Thus the aim of this study was to determine the predictive value of FMD% compared with angina pectoris, exercise electrocardiography, and myocardial perfusion imaging. METHODS AND RESULTS In this pilot study, we measured ED in 122 patients scheduled for coronary angiography by using high-resolution ultrasound (13 MHz). We defined ED as FMD% </=4.5%. The presence of CAD was defined as angiographically detectable atherosclerotic vessel alterations of any degree. Exercise electrocardiography and myocardial perfusion imaging had been performed on an outpatient basis. Statistical analysis was conducted by analysis of variance and Mantel-Haenszel chi-square test. Patients with CAD (n = 101) had a significantly lower FMD% than patients without CAD (n = 21; 3.7% +/- 4.1% vs 7.01% +/- 3.5%, P <.001). A sensitivity of 71%, a specificity of 81% with a positive predictive value of 0.95 (72 of 76), and a negative predictive value of 0.41 (17 of 46) was calculated. In comparison to angina pectoris (sensitivity 95%, specificity 47.6%), exercise electrocardiography (sensitivity 82.4%, specificity 57.1%) and myocardial perfusion imaging (sensitivity in our study group 100%) had the best specificity, and a high sensitivity for FMD% was found. CONCLUSIONS The determination of ED was found to be a sensitive and specific screening test to predict the presence of CAD. Because this is a noninvasive, nonradioactive, and cost-effective approach, it warrants further evaluation to determine its value in daily clinical practice as an additional screening test in the diagnosis of CAD.

Radiation Therapy for Intracranial Germinoma: Results of the German Cooperative Prospective Trials MAKEI 83/86/89

PURPOSE A multicenter prospective trial was conducted (Maligue Keimzelltümoren [MAKEI] 83/86/89) to assess outcome in intracranial germinoma after treatment with radiotherapy alone at reduced doses. PATIENTS AND METHODS Between 1983 and 1993, 60 patients with histologically (n = 58) or cytologically (n = 2) confirmed germinoma were enrolled onto the study. Patients received radiotherapy alone (craniospinal axis/local boost). In the MAKEI 83/86 study (involving 11 patients), the dose to the craniospinal axis was 36 Gy and the dose to the tumor region was 14 Gy. In the MAKEI 89 study (involving 49 patients), doses were 30 and 15 Gy, respectively. RESULTS Median patient age was 13 years (range, 6 to 31 years). Complete remission was achieved in all patients. The estimated (Kaplan-Meier) 5-year relapse-free survival rate was 91.0% +/- 3.9% at a mean follow-up of 59.5 months (range, 3 to 180 months); the estimated overall survival rate was 93.7% +/- 3.6%. Relapse occurred in five patients 10 to 33 months (mean, 18.4 months) after diagnosis (one patient developed a spinal canal metastasis and underwent salvage radiotherapy and chemotherapy; four patients had metastases outside the CNS and underwent salvage chemotherapy alone). Four patients died: one died from disease, two died from therapy-related complications, and one committed suicide. Acute complications with long-lasting sequelae were tumor or surgery related (three cases of blindness, six of reduced vision, two of hemiparesis). Psychosocial development was normal in the majority of patients. CONCLUSION Radiotherapy directed toward the craniospinal axis or tumor site alone at decreased dose levels is effective. To reduce the risk of late side effects, further attempts to decrease total doses are justified. In cases of recurrent disease, chemotherapy administered outside the CNS is the treatment of choice.

German Cancer Society Neuro‐Oncology Working Group NOA‐03 multicenter trial of single‐agent high‐dose methotrexate for primary central nervous system lymphoma

The prospective multicenter NOA‐03 trial, conducted by the Neuro‐Oncology Working Group (NOA) of the German Cancer Society, was initiated to define the feasibility and efficacy of single‐agent high‐dose methotrexate therapy without concomitant radiotherapy in immunocompetent patients with primary central nervous system lymphoma. Thirty‐seven patients (median age, 60 years) received 179 biweekly courses of 8g/m2 methotrexate. Response was assessed after 3 and 6 courses. We had planned to enter 105 patients into the trial. Since fewer than the projected 18 of 37 patients achieved a complete response after an intermediate analysis, the trial was closed. In intention‐to‐treat analysis, 11 of 37 patients (29.7%) achieved complete response, whereas 14 of 37 patients (37.8%) were found to have progressive disease. The median relapse‐free survival among complete response patients was 13.7 months. Multivariate logistic regression analysis revealed that corticosteroid application during the first methotrexate course was associated with complete response. The regimen was well tolerated, but, unlike previously reported results, the activity of high‐dose methotrexate was only moderate.

Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in childhood: results of the german prospective trials hit 88/89 and hit 91

PURPOSE To evaluate the outcome in children with anaplastic ependymomas after surgery, irradiation, and chemotherapy; and to identify prognostic factors for survival. METHODS AND MATERIALS Fifty-five children (n = 27 girls, 28 boys; median age at diagnosis, 6.2 years) with newly diagnosed anaplastic ependymomas were treated in the multicenter, prospective trials HIT 88/89 and HIT 91. Macroscopic complete resection was achieved in 28 patients; 27 patients underwent incomplete resection. All patients received chemotherapy before (n = 40) or after irradiation (n = 15). The irradiation volume encompassed either the neuraxis followed by a boost to the primary tumor site (n = 40) or the tumor region only (n = 13). No radiotherapy was administered in two patients. RESULTS Median follow-up was 38 months. The overall survival rate at 3 years after surgery was 75.6%. Disease progression occurred in 25 children with local progression occurring in 20. The median time to disease progression was 45 months. The only significant prognostic factor was the extent of resection (estimated progression-free survival [EPFS] after 3 years was 83.3% after complete resection and 38.5% after incomplete resection) and the presence of metastases at the time of diagnosis (0% vs. 65.8% 3-year EPFS in localized tumors). Age, sex, tumor site, mode of chemotherapy, and irradiation volume did not influence survival. CONCLUSIONS Treatment centers should be meticulous about surgery and diagnostic workup. Because the primary tumor region is the predominant site of failure it is important to intensify local treatment. Dose escalation by hyperfractionation or stereotactic radiotherapy might be a promising approach in macroscopically residual disease. The role of adjuvant chemotherapy requires further study.

Radiotherapy for Stages IIA/B Testicular Seminoma: Final Report of a Prospective Multicenter Clinical Trial

PURPOSE A prospective multicenter trial was initiated to evaluate the role of modern radiotherapy with reduced treatment portals for stage IIA and IIB testicular seminoma. PATIENTS AND METHODS Patients with stages IIA/B disease (Royal Marsden classification) were assessable for the trial. Staging comprised computed tomography of the chest, abdomen, and pelvis as well as analysis of tumor markers alpha-fetoprotein and beta human chorionic gonadotropin. Linac-based radiotherapy was delivered to para-aortic and high ipsilateral iliac lymph nodes. The total doses were 30 Gy for stage IIA and 36 Gy for stage IIB disease. RESULTS Between April 1991 and March 1994, 94 patients were enrolled for the trial by 30 participating centers throughout Germany. Seven patients were lost to follow-up. Median time to follow-up of 87 assessable patients was 70 months. There were 66 stage IIA and 21 stage IIB patients. One mediastinal and one field-edge relapse were observed in the stage IIA group. In the stage IIB group, there was one mediastinal and one mediastinal/pulmonary relapse. All patients were treated with a salvage regimen of platinum-based chemotherapy. Actuarial relapse-free survival at 6 years was 95.3% (95% confidence interval [CI], 88.9% to 100%) and 88.9% (95% CI, 74.4% to 100%) for stage IIA and IIB groups, respectively. Maximum acute side effects were 8% grade 3 nausea for stage IIA and 10% grade 3 nausea and diarrhea for stage IIB groups. No late toxicity was observed. CONCLUSION Radiotherapy for stages IIA/B seminoma with reduced portals yields excellent tumor control at a low rate of acute toxicity and no late toxicity, which supports the role of radiotherapy as the first treatment choice for these patients.