Marco Hassler

Venous thromboembolism and survival in patients with high-grade glioma

Patients with malignancy, particularly patients with high-grade glioma (HGG; WHO grade III/IV), have an increased risk of venous thromboembolism (VTE). It has been suggested that VTE predicts survival in cancer patients. The aim of our study was to investigate the occurrence of symptomatic VTE and its impact on survival in patients with HGG. Consecutive patients (n = 63; 36 female, 27 male; median age, 58 years) who had neurosurgical intervention between October 2003 and December 2004 were followed after surgery until October 2005. Objectively confirmed VTE was recorded as an event. All patients had received thrombosis prophylaxis with low-molecular-weight heparin (LMWH) during the immediate postoperative period. Subsequently, 56 patients received radiochemotherapy, 6 radiotherapy, and 1 chemotherapy only. Patients were followed over a median time period of 348 days. Fifteen patients (24%) developed VTE. Pulmonary embolism was diagnosed in nine patients (60%) and was fatal twice. The cumulative probability of VTE was 21% after three months and 26% after 12 months. The highest frequency of VTE was observed in patients with biopsy and subtotal tumor resection (n = 37; multivariate hazard ratio, 3.58; 95% CI = 0.98-13.13; P = 0.054) compared with patients with total resection. Survival did not significantly differ among patients with and without VTE and was 53% after 12 months in both groups. Patients with HGG, particularly those with biopsy and subtotal resection, are at high risk to develop VTE postoperatively. Thrombosis was not associated with a significant reduction of survival.

Recurrent and metastatic clivus chordoma: systemic palliative therapy retards disease progression.

We report on a male patient with progressive and metastatic clivus chordoma treated over a period of 9 years by a multidisciplinary approach. Within the first 4 years, the patient underwent surgery four times. Thereafter, he received radiotherapy and subsequent chemotherapy. Stabilization of disease was achieved repeatedly for variable periods under local radiotherapy, systemic chemotherapy, immunomodulatory and anti-angiogenic therapy with isotretinoin and interferon-&agr;, followed by thalidomide. Due to the occurrence of brain and lung metastases 8 years after initial diagnosis, liposomal doxorubicin was added to thalidomide. At the last follow-up control the patient had stable disease, with no progression of the intracranial tumor and regression of pulmonary metastases. He is in a good physical, psychological and neurological condition with a Karnofsky score of 80. Our observations show that multimodal therapy including a systemic palliative approach is associated with long quiescent intervals in recurrent chordoma and with regression of its metastases. Use of substances with high efficacy on tumor tissue and low toxicity, allowing long-term administration, seems promising in similar situations.

Microvascularization and expression of VEGF and its receptors in recurring meningiomas: pathobiological data in favor of anti-angiogenic therapy approaches.

AIM We studied expression of molecules of the vascular endothelial growth factor (VEGF) pathway and its relation to vascularization, cell proliferation and patient outcome in recurring non-anaplastic meningioma. We studied 29 tumor specimens of 8 patients with recurring meningiomas and of 8 age- and gender-matched control patients with non-recurring meningiomas (including meningothelial, transitional, fibroblastic and atypical subtypes) using immunohistochemistry and in-situ hybridization. RESULTS VEGF protein, VEGF-mRNA, VEGF receptor (VEGFR)-1 mRNA, VEGFR-2 mRNA and hypoxia-inducible factor (HIF)-1-α protein were expressed in 27/29 (93%), 20/27 (74%), 9/27 (33.3%), 12/27 (44.4%) and 5/29 (17.2%) specimens, respectively. VEGFR- 2 mRNA expression was found in 6/8 tumors extracted at first operation in patients with recurring tumors and in none of the control cases (p = 0.007). Microvessel density (MVD) and Ki-67 index values were generally higher in meningiomas with expression of angiogenic factors. The association of high Ki-67 index values with VEGF-mRNA expression was significant (p = 0.04). Time to recurrence was shorter in patients with high MVD than in patients with low MVD (p = 0.027). CONCLUSIONS High MVD correlates with unfavorable prognosis in our series of recurring meningioma. VEGF and its receptors are frequently expressed in meningiomas and seem important for tumor growth and recurrence. Thus, anti-VEGF therapy in aggressive meningioma seems rational from a pathobiological point of view.

Retrospective analysis of re-irradiation in malignant glioma : a single-center experience

SummaryINTRODUCTION: Malignant gliomas are brain tumors deriving from the brains glia cells. Primary treatment comprises resection, irradiation and chemotherapy, but these tumors almost always recur. In this situation, palliative chemotherapy is relatively well established, but a second local treatment is sometimes possible. We evaluated the safety and efficacy of re-irradiation in patients with recurrent malignant glioma. PATIENTS AND METHODS: Twenty-two patients were treated with a second irradiation for recurrent or progressive glioma. Patients either received hypofractionated stereotactic treatment or conventionally fractionated conformal therapy, depending on tumor size. Wherever possible, a second resection was performed. Time to progression (TTP) and survival were estimated using the Kaplan–Meier product-limit method. RESULTS: Median age was 31 (8–77) years. Median TTP after onset of re-treatment was 4 (1–31) months. Median overall survival was 7 (1–46) months, and overall survival from primary diagnosis was 49 (7–136) months. Significantly longer TTP (P = 0.008) and overall survival (P = 0.005) were observed in re-resected patients than in those without a second surgical intervention. CONCLUSION: Re-irradiation in malignant glioma is a feasible and safe treatment option, and the benefit appears to be especially large in re-resected patients. To make a final conclusion possible, larger prospective trials are warranted.ZusammenfassungEINLEITUNG: Aktuelle Behandlungskonzepte für maligne Gliome umfassen neurochirurgische Resektion, Chemotherapie und Bestrahlung, ein Rezidiv oder Progress kann jedoch im Allgemeinen nicht verhindert werden. In dieser Situation ist eine palliative Chemotherapie relativ gut etabliert, in ausgewählten Patienten ist jedoch eine zweite lokale Behandlung möglich. Wir berichten unsere Erfahrung mit Zweitbestrahlungen bei Patienten mit progredienten malignen Gliomen. PATIENTEN UND METHODE: 22 Patienten wurden behandelt, in Abhängigkeit von der Tumorgröße wurde eine hypofraktionierte stereotaktische oder eine konventionell fraktionierte konformale Bestrahlung durchgeführt. Wenn möglich erfolgte vor der Zweitbestrahlung eine neuerliche neurochirurgische Resektion. Zeit zum Erkrankungsprogress (TTP) und Überleben wurden mittels der Kaplan–Meier-Schätzung ermittelt. ERGEBNISSE: Das mediane Alter der Patienten war 31 (8–77) Jahre. Mediane TTP nach Beginn der Zweitbestrahlung war 4 (1–31) Monate, medianes Überleben nach Zweitbestrahlung 7 (1–46) Monate und medianes Gesamtüberleben 49 (7–136) Monate. Eine signifikant längere TTP (P = 0,008) und ein signifikant längeres Überleben (P = 0,005) nach Zweitbehandlung zeigte sich bei den Patienten, bei denen auch eine zweite neurochirurgische Resektion möglich war. DISKUSSION: Eine Zweitbestrahlung bei malignen Gliomen ist eine relativ sichere und effektive Behandlungsmethode. Ein möglicher Vorteil dürfte vor allem für die Patienten bestehen, die für eine neuerliche Resektion in Frage kommen. Um eine endgültige Einschätzung zu ermöglichen, sind aber größere, randomisierte Studien nötig.

Frequent MGMT (06-methylguanine-DNA methyltransferase) hypermethylation in long-term survivors of glioblastoma: a single institution experience

Frequent MGMT (06-methylguanine-DNA methyltransferase) hypermethylation in long-term survivors of glioblastoma: a single institution experience Background. The aim of this retrospective study was to analyse the MGMT (06-methylguanine-DNA methyltransferase) promoter methylation status in long-term surviving (≥ 3 years) patients with glioblastoma multiforme (GBM). Methods. The methylation status of the MGMT promoter was determined by bisulfite modification of the DNA and subsequent methylation-specific polymerase-chain-reaction (MSP). DNA was extracted from routinely formalin-fixed and paraffin-embedded tumour tissue samples. Results. MSP yielded interpretable results in only 14 of 33 (42%) long-term surviving patients with GBM. A methylated band was seen in 3 of 14, methylated as well as unmethylated bands in 8 of 14 and an only unmethylated band in 3 of 14 patients, thus, yielding MGMT promoter methylation in 11 of 14 patients. The two groups of patients with methylated and unmethylated MGMT promoter status were too small to draw any firm statistical conclusions. Conclusions. Long-term surviving patients with GBM have very frequently intratumoural MGMT promoter methylation. This phenomenon discriminates long-term survivors from a non-selected group of patients with GBM. The standardization of the MSP for the determination of the MGMT promoter methylation status seems to be necessary in order to make this methodology a more reliable one.

Sorafenib for patients with pretreated recurrent or progressive high-grade glioma: a retrospective, single-institution study.

Therapeutic options for patients with pretreated advanced high-grade glioma (HGG) are limited. Sorafenib, a small molecule with multiple potential beneficial actions, appears particularly promising. We reviewed the outcomes of 30 patients with recurrent or progressive HGG treated with sorafenib within a named patient program. Overall, 16 patients suffered from recurrent or progressive glioblastoma multiforme and 14 patients had grade 3 gliomas. All but four patients had previously undergone surgical debulking; all but one patient had received previous standard multimodal treatment; and 18 patients (60%) had received more than one line of chemotherapy, in median three. Progression-free survival (PFS), defined as the time from initiation of sorafenib to treatment discontinuation because of tumor progression or death, was selected as the endpoint. The use of sorafenib resulted in a median PFS of 3 months [95% confidence interval (CI) 1.9–4.1 months] in patients with glioblastoma and of 3.1 months (95% CI 1.4–4.8 months) in patients with other HGG. The PFS-6 for the whole cohort was 23%. Sixteen patients reported adverse events, mostly moderate, with hypertension as the most frequently reported toxicity (seven patients). One patient died of cerebral bleeding (grade 5 toxicity). The overall survival after initiation of sorafenib was 6 months (95% CI 3.9–8.0 months) for patients with glioblastoma multiforme and 10 months (95% CI 3.1–16.9 months) for patients with HGG. In this retrospective analysis of heavily pretreated patients with HGG, sorafenib monotherapy was associated with tumor stabilization in a small subset of patients. The risk–benefit ratio was acceptable in the context of an apparent clinical benefit in patients with a fatal disease.

Cancer rehabilitation in Austria—aspects of Physical Medicine and Rehabilitation

SummaryIn Austria, cancer rehabilitation is an important issue in the management of cancer patients. Survival rates and survival time of cancer patients are increasing, and cancer rehabilitation is an important part in the treatment and care of cancer patients with the goal to improve functional status, quality of life, and (social) participation. Today, in Austria there are approximately 600 beds for inpatient rehabilitation. The field of outpatient rehabilitation will maybe be expanded after evaluating the existing pilot projects. Beside other specialities, the field of Physical Medicine and Rehabilitation (PM&R) plays an important role in cancer rehabilitation. In cancer rehabilitation, especially activating modalities from PM&R such as exercise are very important and well-accepted parts to improve functional status, quality of life, and participation of patients.ZusammenfassungDie onkologische Rehabilitation spielt im Management von Krebspatienten in Österreich eine wichtige Rolle. Bei steigenden Überlebensraten und -zeiten ist die onkologische Rehabilitation zur Verbesserung des funktionellen Status, der Lebensqualität und der (sozialen) Partizipation der Patienten wesentlich. Für die stationäre onkologische Rehabilitation gibt es in Österreich derzeit ungefähr 600 Betten. Die ambulante onkologische Rehabilitation könnte nach Evaluierung der bestehenden Pilotprojekte ausgerollt werden. Neben weiteren Fachdisziplinen spielt die Physikalische Medizin und Rehabilitation (PM&R) in der onkologischen Rehabilitation eine gewichtige Rolle. Hier sind insbesondere die aktivierenden Therapien, wie die Medizinische Trainingstherapie zur Verbesserung des funktionellen Status, der Lebensqualität und der Partizipation, wichtig und gut akzeptiert.

Case Report: Pregnancy in a patient with recurrent glioblastoma.

We report the case of a woman with relapsed glioblastoma multiforme (GBM) who recently gave birth. She announced her pregnancy shortly after the sixth cycle of a dense regimen of temozolomide, prescribed for treating the first recurrence of glioblastoma. Three years ago, in April 2008, she had undergone gross total resection of a glioblastoma multiforme in the postcentral region of the right hemisphere and had subsequently received treatment according to the actual standard therapy consisting of radiotherapy up to 60 Gy with concomitant and adjuvant temozolomide. The complete amount of temozolomide given before this pregnancy was 20.9 mg/m 2. Nevertheless, she delivered a 1890 g child by caesarean section in the 32/6 week of pregnancy. The child showed no anomalies and is developing normally under close surveillance by paediatricians.

Evaluation of diagnostic and treatment approaches towards acute dyspnea in a palliative care setting among medical students at the University of Vienna

ZusammenfassungGRUNDLAGEN: Bei Patienten mit fortgeschrittener Krebserkrankung ist Dyspnoe eines der häufigsten Symptome. Opioide zählen mit zur Standardtherapie. ZIEL: Ziel der Studie war, den Wissenstand von Studenten im 8. Semester über Diagnose und Therapiemaßnahmen von Dyspnoe zu evaluieren. METHODIK: Ein Fallbericht eines Patienten mit akuter Dyspnoe bei fortgeschrittenem Bronchialkarzinom wurde an Studenten verteilt mit der Bitte, diagnostische und therapeutische Optionen nach einem Rankingsystem anzugeben. ERGEBNISSE: 633 Medizinstudenten erhielten einen Fallbericht, dieser wurde von 423 vollständig ausgefüllt. Die häufigste diagnostische Maßnahme war die Messung der Sauerstoffsättigung mittels Pulsoxymeter (n = 388), gefolgt von Auskultation (n = 339). Die häufigste Behandlungsoption für Studenten war die Verabreichung von Sauerstoff (n = 393). Immerhin 138 Studenten schlugen die Verabreichung von Opioiden vor. SCHLUSSFOLGERUNGEN: Obwohl die Studenten über wenig praktische Erfahrung verfügten, schlugen 32,6% eine Behandlung mit Opioiden vor.SummaryBACKGROUND: Dyspnea is common in advanced cancer patients with opioids as first line treatment. OBJECTIVES: To evaluate the level of knowledge about diagnosis and treatment of dyspnea in palliative care patients among 4th year students. METHODS: A case report was distributed to the students describing acute dyspnea in a lung cancer patient. Students were asked to rank their diagnosis and treatment options by importance. RESULTS: 633 medical students in their 4th year attended a seminar about palliative care. Of these, 423 (77%) completed the case report. The most frequent diagnostic option was measuring patients oxygen saturation (n = 388), followed by auscultation (n = 339). As treatment options, students chose the delivery of oxygen (n = 393) as most important. The application of opioids was suggested by a total of 138 students. CONCLUSION: Although students did not have practical skills in treating advanced cancer patients with acute dyspnea, 32.6% would suggest an opioid as treatment option.