Olga Ésik

Malignant mucosal melanoma of the head and neck — a review

Mucosal melanomas comprise about 1% of all malignant melanomas and exhibit far more aggressive behaviour than that of skin melanomas: they are more inclined to metastatize into regional and distant sites or recur locally, regionally or in distant locations, resulting in a high rate of cause-specific death. Mucosal melanomas in the head and neck region account for half of all mucosal melanomas, occurring mainly in the upper respiratory tract, oral cavity and pharynx. They appear with equal gender distribution and with a peak incidence in the age range 60–80 years. In consequence of their hidden location, they are usually diagnosed in a locoregionally advanced clinical stage, with a rate of 5–48% of regional and 4–14% of distant dissemination. The typical therapeutic approach is surgery, postoperative irradiation and systemic therapy. Local control with either surgery or radiotherapy is frequently (60–70%) achieved, but the rates of local, regional and distant recurrences are high (50–90%, 20–60% and 30–70%, respectively). The reported 5-year actual survival rates are poor (17–48%), which is attributed mainly to a haematogenous dissemination. These characteristics demonstrate that identification of the precursor lesions and more effective local and systemic approaches are needed to improve the therapeutic results.

Multisegmented tangential breast fields: a rational way to treat breast cancer.

Purpose:Using three-dimensional conformal radiation therapy (3D-CRT) and multisegmented conformal radiation therapy (MS-CRT) for breast cancer treatment, the dose coverage of the planning target volume (PTV) and the radiation burden on the organs at risk (OARs) were evaluated.Material and Methods:3D-CRT and MS-CRT were planned for 436 unilateral breasts (217 left). All patients were treated with MS-CRT between 2005 and 2007. For PTV delineation and beam orientation, supportive structures were applied. The mean PTV was 1,130 cm3 (in ten patients > 2,200 cm3). Three-dimensional planning with weight-optimized medial and lateral open fields at a total dose of 50.4/1.8 Gy was followed by multisegmented planning with a reasonably high-dose-level dose cloud to define the medial subfield, and renewed optimization. This was repeated for the lateral subfield with a final optimization. For PTV coverage evaluation, the ICRU 50 was considered: the PTV portions receiving 95–107%, < 95% and > 107% of the prescribed dose (PTVD95– 107%, PTVD107%), and the PTV maximal dose (PTVDmax). To compare the OAR radiation burdens, the mean doses to the ipsi-/contralateral lung, contralateral breast, and whole heart were documented.Results:The multisegmented plans furnished significantly (p < 0.0001) better target coverage (PTVD95–107% 82.8% vs. 90.9%, PTVD107% 5.9% vs. 0.3% and PTVDmax 56.6 vs. 54.3 Gy). The mean OAR doses remained almost unchanged: ipsilateral lung 10.5 versus 10.4 Gy, contralateral lung 0.4 versus 0.4 Gy, contralateral breast 0.8 versus 0.8 Gy, and whole heart (for left-sided cancers) 4.8 versus 4.8 Gy. The subfields required a mean of 9.8 MU (monitor units), i.e., a mean total 7.6 MU increment. The planning took 10–20 min, and the delivery 5–10 min.Conclusion:MS-CRT is a good alternative to breast intensity-modulated radiation therapy (IMRT) and seems adequate for right-sided cancers, whereas left-sided cancers necessitate a longer follow-up of heart-related side effects before a final assessment.Ziel:Die Erfassung des Planungszielvolumens (PTV) und die Strahlenbelastung der Risikoorgane (OARs) bei dreidimensionaler konformaler Radiotherapie (3D-CRT) oder multisegmentaler konformaler Radiotherapie (MS-CRT) des Mammakarzinoms wurden ausgewertet.Material und Methodik:Dreidimensionale und multisegmentale konformale Bestrahlungspläne wurden für 436 unilaterale (217 linksseitige) Brüste erstellt. Zwischen 2005 und 2007 erhielten alle Patientinnen eine MS-CRT. Zur PTV-Konturierung und Feldausrichtung wurden Hilfsstrukturen angebracht. Das durchschnittliche PTV betrug 1 130 cm3 (bei zehn Patientinnen > 2 200 cm3). Im Anschluss an die dreidimensionale Planung mit optimal gewichteten medialen und lateralen Feldern bis zu einer Gesamtdosis 50,4/1,8 Gy erfolgte die multisegmentale Planung mit einer angemessen hohen Dosiswolke für das mediale Teilfeld und erneuter Optimierung. Dies wurde für das laterale Teilfeld wiederholt und abschließend optimiert. Bei der Beurteilung der PTV-Erfassung wurde der ICRU 50 berücksichtigt: die Anteile des PTV, die 95–107%, < 95% und > 107% der verordneten Dosis erhielten (PTVD95–107%, PTVD107%), sowie das Dosismaximum (PTVDmax). Zum Vergleich der Dosisbelastung der OARs wurden die Durchschnittsdosen der ipsi-/kontralateralen Lungen, der kontralateralen Brust und des Herzen dokumentiert.Ergebnisse:Die multisegmentale Planung erbrachte eine signifikant (p < 0,0001) bessere PTV-Erfassung (PTVD95–107% 82,8% vs. 90,9%, PTVD107% 5,9% vs. 0,3% und PTVDmax 56,6 vs. 54,3 Gy). Die durchschnittlichen OAR-Dosen blieben nahezu unverändert: ipsilaterale Lunge 10,5 versus 10,4 Gy, kontralaterale Lunge 0,4 versus 0,4 Gy, und kontralaterale Brust 0,8 versus 0,8 Gy, Herz (bei linksseitigem Brustkrebs) 4,8 versus 4,8 Gy. Für die Teilfelder wurden durchschnittlich 9,8 MU (Monitoreinheiten) benötigt, d.h. eine Gesamterhöhung um im Mittel 7,6 MU. Die Planungsprozedur dauerte 10–20 min und die Bestrahlung 5–10 min.Schlussfolgerung:Die MS-CRT stellt eine gute Alternative zur intensitätsmodulierten Radiotherapie (IMRT) der Brust dar und scheint sich vor allem bei rechtsseitigem Brustkrebs anzubieten, während bei Befall der linken Mamma aufgrund der kardialen Nebenwirkungen vor einer abschließenden Bewertung eine längere Nachbeobachtung erforderlich ist.

A Review on Radiogenic Lhermitte's Sign *

Radiation myelopathy is a rare, but extremely serious side-effect of radiotherapy. Recovery from radiation-induced motor sequelae is rare, whereas, the regeneration of sensory losses is relatively frequent. Among the sensory radiogenic injuries of the spinal cord, Lhermitte’s sign (LS) is most frequent. This review describes the clinical picture and diagnostic imaging signs of radiogenic LS. There have been only a few studies on large patient groups with radiogenic LS, demonstrating a rate of occurrence of 3.6–13%, relating mainly to mantle irradiation or the radiotherapy of head and neck tumors. These cases typically manifest themselves 3 months following radiotherapy and gradually disappear within 6 months. Only 3 LS cases have been described in the English literature with extraordinarily severe symptoms lasting for more than 1 year. MRI, a sensitive tool in the detection of demyelination, failed to reveal any pathological sign accompanying radiogenic LS. However, positron emission tomography demonstrated increased [18F]fluorodeoxyglucose accumulation and [15O]butanol perfusion, but a negligible [11C]methionine uptake in the irradiated spinal cord segments in patients with long-standing LS. These imaging data are suggestive of a close direct relationship between the regional perfusion and metabolism of the spinal cord, very much like the situation in the brain. We postulate that an altered, energy-demanding conduction along the demyelinated axons of patients with chronic radiogenic LS may explain the increased metabolism and perfusion.

Radiation myelopathy with partial functional recovery: PET evidence of long-term increased metabolic activity of the spinal cord

Postoperative telecobalt irradiation was performed with a biologically effective extrapolated response dose of 165 Gy2 delivered to the spinal cord of a papillary thyroid cancer patient. Incomplete cervical transection developed, followed by a gradual functional improvement, which is still continuing 8 years after radiotherapy. Between the 6th and 8th years of the clinical course, positron emission tomography investigations demonstrated an increased 18F-deoxyglucose accumulation and (15)O-butanol perfusion, but negligible 11C-methionine uptake in the irradiated spinal cord segment. We suggest that the increased metabolism and perfusion, and the lack of detectable protein synthesis may be related to the increased energy demands of action potential conduction, due to the higher than normal density of sodium channels along demyelinated axons displaying restored conduction.

Angiography effectively supports the diagnosis of hepatic metastases in medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) belongs in the group of neuroendocrine tumors with early lymphatic and hepatic dissemination. A high rate of undetectable metastases is hypothesized to be responsible for the frequent mismatch between the apparent relatively small tumor burden and the elevated plasma tumor marker level.

Total body irradiation before bone marrow transplantation : Technique and acute toxicity

Purpose: To evaluate the total body irradiation methods in the National Institute of Oncology between January 1984 and February 1998. Patients and Method: One hundred and twenty-four patients underwent total body irradiation prior to bone marrow transplantation in the last 15 years. A special cobalt unit has been used, the dose rate was 6 to 8 cGy/min in the midline of the abdomen. The source-midline distance (SMD) was 340 cm and the field size was 80 × 200 cm. The dose calculation was done on the basis of a tissue-phantom ratio curve measured in total body irradiation conditions and effective tissue thickness (ETT). Between 1984 and 1992 the beam direction was horizontal, the patients laid in lateral position. In 11 cases the total dose to the abdominal midline was 10 Gy, in 1 fraction. From 1986 the fractionation changed to 4 × 3 Gy in 4 days. With individual lung shielding the average lung dose was 8.5 Gy. In 44/124 cases the order of conditioning treatment was chemo-radiotherapy. Since 1992 vertical beams were used, and the patients (80/124) laid in prone/supine position. The fractionation remained the same but radio-chemotherapy regime has been used. Results: The irradiation in prone position proved to be safer than lateral because of smaller patient motion and it resulted in a more accurate positioning of lung shielding, too. In all cases, the acute side effects (headache, nausea, vomiting) were moderate. Using radio-chemotherapy the acute side effects during the total body irradiation were uncommon and well tolerable. Conclusion: Our technique with the large source-midline distance, vertical beam direction and the supine/prone position is stable, convenient and safe to produce homogeneous dose distribution and ensures accurate and reproducible lung shielding.Ziel: Evaluation der Methodik der Ganzkörperbestrahlung am National Institue of Oncology in Ungarn im Zeitraum zwischen Januar 1984 und Februar 1998. Patienten und Methoden: 124 Patienten wurden einer Ganzkörperbestrahlung vor Knochenmarktransplantation in den letzten 15 Jahren unterzogen. Eine spezielle Kobaltbestrahlungseinheit wurde verwendet. Die Dosisleistung in Körpermitte Abdomen betrug 6 bis 8 cGy/min. Der Abstand von der Quelle zur Körpermittellinie (SMD) betrug 340 cm, und die Feldgröße war 80 × 200 cm. Die Dosis wurde auf der Basis von Gewebe-Phantom-Verhältnissen, die unter Ganzkörperbestrahlungsbedingungen gemessen waren, und unter Berücksichtigung der effektiven Gewebedicke (ETT) berechnet. In den Jahren 1984 bis 1992 war die Strahlrichtung horizontal, und die Patienten waren seitlich gelagert. In elf Fällen wurde die Gesamtdosis von 10 Gy (Körpermittellinie Abdomen) in einer Fraktion appliziert. Ab 1986 wurde die Fraktionierung zu vier Fraktionen à 3 Gy an vier aufeinanderfolgenden Tagen abgeändert. Mit individueller Lungenabschirmung wurde die Lungendosis auf 8,5 Gy reduziert. In 24 von 124 Fällen war die Reihenfolge der Behandlung Chemotherapie-Strahlentherapie. Seit 1992 wird ein vertikaler Strahlengang benutzt, und die Patienten (80/124) werden in Bauch- und Rückenlage gelagert. Die Fraktionierung blieb unverändert, die Reihenfolge wurde jedoch in Strahlentherapie-Chemotherapie umgekehrt. Ergebnisse: Die Bestrahlung in liegender Position erwies sich als sicherer im Vergleich zur Seitenlage aufgrund geringerer Bewegung der Patienten und aufgrund einer exakteren Positionierung der Lungenabschirmung. In allen Fällen waren die akuten Nebenwirkungen (Kopfschmerzen, Übelkeit, Erbrechen) gering. Bei Strahlentherapie vor Chemotherapie waren die akuten Nebenwirkungen selten und gut toleriert. Schlußfolgerung: Unsere Bestrahlungstechnik mit großem Körpermittellinienabstand, vertikalem Strahlengang und Lagerung in Bauch- bzw. Rückenlage ist stabil, bequem und sicher, um eine homogene Dosisverteilung zu erreichen, und ermöglicht eine exakte und reproduzierbare Lungenabschirmung.

PET identifies transitional metabolic change in the spinal cord following a subthreshold dose of irradiation.

Positron emission tomographic (PET) investigations were performed to obtainin vivo information on symptomless radiation-induced pathological changes in the human spinal cord. PET investigations were carried out prior to radiotherapy and during the regular follow-up in an early hypopharyngeal cancer patient (the spinal cord was irradiated with a biologically effective dose of 80 Gy2), with [18F]fluorodeoxyglucose (FDG), [11C]methionine and [15O]butanol as tracers; radiosensitivity and electroneuronographic (ENG) studies were also performed. A very low background FDG accumulation (mean standardized uptake values, i.e. SUV: 0.84) was observed in the spinal cord before the initiation of radiotherapy. An increased FDG uptake was measured 2 months after the completion of radiotherapy (mean SUV: 1.69), followed by a fall-off, as measured 7 months later (mean SUV: 1.21). By 44 months after completion of irradiation, the FDG accumulation in the irradiated segments of the spinal cord had decreased to a level very close to the initial value (mean SUV: 1.11). The simultaneous [15O]butanol uptake results demonstrated a set of perfusion changes similar to those observed in connection with the FDG accumulation. The patient exhibited an extremely low [11C]methionine uptake within the irradiated and the nonirradiated spinal cord during the clinical course. She has not had any neurological symptoms, and the results of central ENG measurements before radiotherapy and 2 months following its completion proved normal. Radiobiological investigations did not reveal unequivocal signs of an increased radiosensitivity. A transitory increased spinal cord FDG uptake following radiotherapy may be related to the posttherapeutic mild inflammatory and regenerative processes. The normal [11C]methionine accumulation observed is strong evidence against intensive cell proliferation. The high degree of normalization of the temporarily increased FDG uptake of the irradiated spinal cord segments by 44 months is in good agreement with the results of monkey studies, which demonstrated a nearly complete recovery from radiation-induced spinal cord injury.

Local tumour irradiation enhances the anti-tumour effect of a double-suicide gene therapy system in a murine glioma model.

Gliomas are invasive malignant tumours with poor prognosis. Combination of gene directed enzyme pro‐drug therapy with existing treatment modalities might open new therapeutic potentials.

Increased Metabolic Activity in the Spinal Cord of Patients with Long-Standing Lhermitte’s Sign

Purpose:To investigate the pathophysiology of the radiation-induced, chronic Lhermitte’s sign (LS) on the basis of long-standing case histories with partial functional recovery.Patients and Methods:As radiotherapy in two nasopharyngeal cancer patients, a biologically effective dose (BED) of 103.8 Gy2 (case 1) and 94.8 Gy2 (case 2) was delivered to the cervical spinal cord. Neurologic signs relating to the irradiated spinal cord segments developed after 2 months (case 1) and 5 years (case 2), with radiation-induced damage equivalent to grade 3 (case 1) and grade 2 (case 2) toxicity (Common Toxicity Criteria, Version 2.0). The clinical status improved to grade 2 (case 1) and grade 1 (case 2). Positron emission tomography (PET) and fibroblast clonogen assay were applied 25 and 7 years postirradiation, respectively, to characterize this rare clinical picture.Results:PET demonstrated increased [18F]fluorodeoxyglucose (FDG) accumulation and [15O]butanol perfusion, but negligible [11C]methionine uptake in the irradiated spinal cord segments in both patients. In clonogenic assays, fibroblasts from case 1 displayed much higher radiation sensitivity than in healthy controls, while in case 2 the fibroblasts sensitivity was normal.Conclusions:These data suggests a close direct relationship between regional perfusion and metabolism of the spinal cord, similarly as in the brain. The postirradiation recovery may be related to energy-demanding conduction, explaining the increased metabolism and perfusion. The increased radiosensitivity and higher spinal cord BED may have contributed to the more severe sequelae in case 1.Ziel:Untersuchung der Pathophysiologie des strahleninduzierten chronischen Lhermitte-Zeichens auf der Basis der Langzeitbeobachtung von zwei Patienten mit partieller funktioneller Erholung.Patienten und Methodik:Bei zwei Patienten mit Nasopharynxkarzinom wurde die Halswirbelsäule mit einer biologisch effektiven Dosis (BED) von 103,8 Gy2 (Patient 1) bzw. 94,8 Gy2 (Patient 2) bestrahlt. Neurologische Symptome, die auf die bestrahlten Segmente des Zervikalmarks zurückzuführen waren, traten nach 2 Monaten (Patient 1) bzw. nach 5 Jahren (Patient 2) auf, wobei die strahleninduzierte Schädigung einer Grad-3- (Patient 1) bzw. Grad-2-Toxizität (Patient 2) entsprach (Common Toxicity Criteria, Version 2.0). Der klinische Status ging auf Grad 2 (Patient 1) bzw. Grad 1 (Patient 2) zurück. Positronenemissionstomographie (PET) und der Fibroblastenklonogenitätsassay wurden 25 bzw. 7 Jahre nach der Strahlentherapie eingesetzt, um dieses seltene Krankheitsbild zu charakterisieren.Ergebnisse:Im PET zeigten sich bei beiden Patienten eine erhöhte [18F-]Fluorodesoxyglucose-(FDG-)Aufnahme und [15O-] Butanol-Perfusion, jedoch eine vernachlässigbar geringe [11C-]Methionin-Aufnahme in den bestrahlten Segmenten. In den Klonogenitätsassays hatten die Fibroblasten des Patienten 1 eine höhere Strahlungsempfindlichkeit als bei gesunden Kontrollen, während die Fibroblastensensitivität bei Patient 2 normal war.Schlussfolgerungen:Diese Befunde sprechen für eine—ähnlich wie im Gehirn—enge direkte Beziehung zwischen regionaler Perfusion und Metabolismus des Rückenmarks. Die Erholung nach der Strahlentherapie dürfte mit Energie verbrauchenden Prozessen einhergehen, was die Steigerung von Metabolismus und Perfusion erklärt. Die erhöhte Strahlenempfindlichkeit und die höhere BED am Rückenmark können zu den gravierenderen Folgeerscheinungen bei Patient 1 beigetragen haben.

Autopsy verifies demyelination and lack of vascular damage in partially reversible radiation myelopathy

Study design: Case report of recovering radiation myelopathy.Objective: To present autopsy and functional imaging findings on a unique case of slowly recovering radiation myelopathy with the aim of the clarification of the underlying mechanism.Patient: The cervical spinal cord and the distal part of the medulla oblongata of a 36-year-old thyroid cancer patient had been incorrectly irradiated with a total dose of 61 Gy and a fraction size of 3.4 Gy (J Neurol Sci 1999; 163:39–43), resulting in incomplete cervical transection with a 5-month latency period following the termination of radiotherapy. This was followed by a 9.5-year spontaneous improvement until her demise, during which the check-ups were supplemented by positron emission tomography (PET) investigations; these indicated increased [18F]deoxyglucose and [15O]butanol uptakes, but a diminished [11C]methionine accumulation by the irradiated spinal cord segment.Results: Autopsy revealed demyelination (with axonal loss) and neuronal damage in the cervical spinal cord and the distal part of the medulla oblongata. In the same region, only minimal vascular injury (thickening of some of the capillary walls) was detected, but not cell proliferation or chronic inflammation. Bilateral, secondary pyramidal tract degeneration caudal to the irradiated segment was observed. The PET and autopsy findings, although separated by 2 years, are consistent.Conclusions: The pathological state of the spinal cord revealed by the autopsy is concordant with the incomplete cervical transection, implying that the functional recovery is supported by a process that probably differs from the restoration of the mechanism destroyed by the radiotherapy. For the restoration of the function, we suggest an altered conduction mechanism of the action potential, involving an increased number of sodium channels along the demyelinated segments of the injured axons, which is fully congruent with the PET findings.