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Biomedical subjects

H Kostron

Publications and source records attributed to H Kostron.

At least 19 recordsLinked to original sources

Basic fibroblast growth factor isoforms promote axonal elongation and branching of adult sensory neurons in vitro.

Synthesis of the multifunctional cytokine basic fibroblast growth factor (FGF-2) is up-regulated after sciatic nerve lesion. In this study, the effects of low and high molecular weight FGF-2 isoforms on axonal elongation and branching of dissociated rat sensory neurons derived from adult lumbar dorsal root ganglia were investigated. These neurons express FGF receptor (FGFR) type I in the cytoplasmic/membrane compartment and in nuclear speckles. FGF-2 isoforms increase the number of axonal branches in cultures obtained from control rats, but do not promote axonal elongation. In response to a preconditioning lesion, i.e. transection of the sciatic nerve 1 week before culture, the axonal length of ipsilateral lumbar sensory neurons increases two-fold when compared with non-lesioned control rats, and this response is significantly enhanced by FGF-2 isoforms but not by nerve growth factor (NGF). Neurons dissociated from ganglia located contralaterally to the lesion exhibit a smaller increase in axon elongation (30%). The stimulating effects of FGF-2 isoforms on axon growth are fully blocked, and the enhanced regeneration of prelesioned neurons is reduced by the FGFR inhibitor SU5402 suggesting an involvement of endogenous FGF signaling in response to a lesion. The present data support a direct neurotrophic role of the 18 kD and 23 kD FGF-2 isoforms on adult axonal regeneration which may be of therapeutic value in the treatment of peripheral nerve lesions. Furthermore, evidence is provided for an enhanced regenerative capacity not only of preaxotomized neurons but also of homonymous non-axotomized neurons.

Animals↗

mTHPC-mediated photodynamic diagnosis of malignant brain tumors.

Radical tumor resection is the basis for the prolonged survival of patients suffering from malignant brain tumors such as glioblastoma multiforme. We have carried out a phase-II study involving 22 patients with malignant brain tumors to assess the feasibility and the effectiveness of the combination of intraoperative photodynamic diagnosis and fluorescence-guided resection (FGR) mediated by the second-generation photosensitizer meta-tetrahydroxyphenylchlorin (mTHPC). In addition, intraoperative photodynamic therapy (PDT) was performed. Several commercially available fluorescence diagnostic systems were investigated for their applicability in clinical practice. We have adapted and optimized a diagnostic system that includes a surgical microscope, an excitation light source (filtered to 370-440 nm), a video camera detection system and a spectrometer for clear identification of the mTHPC fluorescence emission at 652 nm. Especially in regions of faint fluorescence, it turned out to be essential to maximize the spectral information by optimizing and matching the spectral properties of all components, such as excitation source, camera and color filters. To sum up, on the basis of 138 tissue samples derived from 22 tumor specimens, we have been able to achieve a sensitivity of 87.9% and a specificity of 95.7%. This study demonstrates that mTHPC-mediated intraoperative FGR followed by PDT is a highly promising concept in improving the radicality of tumor resection combined with a therapeutic approach.

Adult↗

Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas.

Glial cell line-derived neurotrophic factor (GDNF), a sequence-related factor of the transforming growth factor-beta family, has been identified as a potent neurotrophic factor for a variety of neuronal cell populations. At present, it is still unknown whether human gliomas in vivo are also capable of producing GDNF. We studied the expression of GDNF in 14 human glioblastomas, 1 gliosarcoma and 5 astrocytomas. Using an enzyme-linked immunosorbent assay, the amount of GDNF was quantified in human gliomas and compared to GDNF-expression in C6 glioma cells, mouse fibroblasts and normal human and rat brain. Mean concentration of GDNF in gliomas was 937 +/- 140 pg GDNF/g tissue (n = 20). C6 cells revealed the highest expression levels of 2,837 +/- 813 pg/g, whereas mouse 3T3 fibroblasts showed no detectable GDNF protein. Mean GDNF tissue levels in normal human and rat brain were significantly lower. Using reverse transcriptase-polymerase chain reaction, GDNF mRNA was detected in human gliomas and in rat C6 cells. Immunohistochemistry revealed strong GDNF- and GDNF receptor-alpha 1-expressing tumor cells in human glioma tissue. These results show that glial tumors, even in the most dedifferentiated form of glioblastoma, express GDNF at concentrations up to five times higher compared to normal human brain. This overexpression of GDNF may be of biological relevance for proliferation of glial tumors in humans.

Adult↗

Vascular endothelial growth factor (VEGF) is elevated in brain tumor cysts and correlates with tumor progression.

Vascular endothelial growth factor (VEGF), a key regulatory protein in neoangiogenesis, is strongly expressed in a variety of primary brain tumors, particularly malignant gliomas. In previous studies, high levels of VEGF were also reported in tumor cysts of glioblastomas. Using an ELISA method we measured the concentration of VEGF in matched samples of aspiration fluid from tumor cysts and serum. Samples were collected from 14 patients with primary brain tumors of various histology (six glioblastomas, one protoplasmatic astrocytoma, two pilocytic astrocytomas, one ependymoma, one meningioma, and three craniopharyngiomas) and two patients with solitary cystic brain metastases from adenocarcinomas of the lung. Aspiration fluids of tumor cysts from all patients revealed high VEGF levels ranging between 882 and 1,263,000 pg/ml, which were 2 to more than 2,000 times higher than the corresponding serum levels. Maximum VEGF levels were detectable in cyst fluids from recurrent glioblastoma. Serum VEGF levels ranged between 125 and 716 pg/ml and did not differ from serum levels in 145 healthy volunteers. In a single patient with metastatic lung cancer the concentration of VEGF in serum and cyst fluid was determined during disease progression. During 60 days of follow-up VEGF concentrations in the cyst fluid collected by puncture of an Ommaya reservoir increased 650-fold, while serum levels remained rather constant. These findings indicate that immunoreactive VEGF is produced at the tumor site and abundantly released into the cyst fluid of primary and metastatic brain tumors. Interestingly, this abundant local release is not reflected in serum VEGF levels, even in the case of very high VEGF concentrations in tumor cysts. Thus, VEGF may be biologically relevant for the formation of tumor cysts in brain tumors and correlates with local disease progression.

Adolescent↗

Photodynamic therapy for recurrent gynecologic malignancy: a report on 4 cases.

4 patients with recurrent gynecological malignancy were treated photodynamically, 4 d after sensitisation with intravenous meso-tetra(hydroxyphenyl)-chlorin (m-THPC) at a dose of 0.15 mg/kg bodyweight (total dose ranged from 12-15 mg). Light at 652 nm was derived from a KTP-Dye laser (Diasonic) and delivered superficially at a total light dose of 20 J/cm2 (power density of 100 mW/sec). Within 24 h necrosis occurred which was restricted to the tumor area. There was serious bleeding occurred in 1 patient. All tumors responded to PDT, however woundhealing was significantly delayed and survival times were disappointingly short.

Adenocarcinoma↗

Uptake and kinetics of 14C-labelled meta-tetrahydroxyphenylchlorin and 5-aminolaevulinic acid in the C6 rat glioma model.

Meta-tetrahydroxyphenylchlorin (m-THPC) and 5-aminolaevulinic acid (5-ALA) are two second-generation photosensitizers which are currently under investigation for photodynamic therapy (PDT) and photodynamic diagnosis (PDD). So far, the experience with these photosensitizers for use within brain tumours is limited. We examined the distribution and retention of 14C-labelled m-THPC and [14C]5-ALA in the rat C6 glioma brain tumour model. After intraperitoneal injection of m-THPC (71,909 d.p.m. microl(-1); 0.16 mg ml(-1) m-THPC; 0.3 mg kg(-1)), the following activities were found after 36 h: brain tumour 223,664 d.p.m. g(-1), brain contralateral to the tumour side 2567 d.p.m. g(-1), liver 369,959 d.p.m. g(-1) and skin 55,197 d.p.m. g(-1); 100,000 d.p.m. corresponding to 0.22 microg of m-THPC. After 7 days, the concentration of m-THPC decreased to 76,277 d.p.m. g(-1) in tumour and 635 d.p.m. g(-1) in brain. The radioactivity after intravenous administration of [14C]5-ALA (23,079 d.p.m. microl(-1); 40 mg ml(-1); 120 mg kg(-1)) increased within 15 min (59,634 d.p.m. g(-1) in tumour, 17,427 d.p.m. g(-1) in brain); after 8 h only a small amount (3653 d.p.m. g(-1) in tumour) remained. Brain adjacent to the tumour was also found to have a higher uptake of 5-ALA. This study provides basic information for the use of m-THPC and 5-ALA in brain tumours. Because of the different pharmacokinetic and toxicological profile, we recommend m-THPC for PDT and 5-ALA for PDD. Clinical trials now have to prove the superior phototoxic properties of these second-generation photosensitizers.

Aminolevulinic Acid↗

Transcutaneous pressure-adjustable valves and magnetic resonance imaging: an ex vivo examination of the Codman-Medos programmable valve and the Sophy adjustable pressure valve.

OBJECTIVE: We investigated the compatibility of magnetically adjustable cerebrospinal fluid valves with clinical magnetic resonance imaging. Torque acting on the valves, subjective sensations of valve-carrying volunteers, extension of artifacts on acquired images, changes in valve pressure setting, and accurate valve function after repeated exposure to the magnetic field were tested. METHODS: Two externally adjustable differential pressure valves, i.e., the Codman-Medos programmable valve (Medos S.A., Le Locle, Switzerland) (n = 5) and the Sophy programmable pressure valve (Sophysa, Orsay, France) (Model SP3, n = 4; Model SU8, n = 3; and Model SM8, n = 2) were exposed to the magnetic fields of 1.5-T clinical scanners. Ferromagnetic properties were investigated according to an established protocol. Subjective sensations during positioning and scanning and image artifacts were investigated using standard clinical imaging protocols. Changes in opening pressure setting during repeated magnetic field exposure were examined using valves affixed to a dummy. RESULTS: Deflection forces measured 117 dynes in the Medos valve, and 2439 (Model SP3), 2172 (Model SU8) and 1914 (Model SM8) dynes in the Sophy valves. Torque during positioning and during imaging was reported for the Sophy valves. Distortion of the magnetic field with artifacts on acquired images ranged 6 x 6 x 12 cm around the Sophy valve and 4 x 4 x 4 cm around the Medos valves. Artifact extension increased with longer TE times on T2-weighted images and when using gradient-echo sequences. The pressure setting of the Medos valves did not change in 31 of 88 tests. Below 170 mm H2O, the maximal disadjustment was 60 mm H2O in each direction. Minor changes of the pressure setting were observed at 50 and 30 mm H2O. In 11 of 15 tests at 200 mm H2O, the setting after magnetic field exposure was below 30 mm H2O. One Medos valve could no longer be programmed after being exposed four times to the static magnetic field. Sophy valves remained at or changed to "high" in 68 of 81 tests and to "low" in 9. All Sophy valves exhibited paramagnetic behavior after the tests. All remained programmable. Observed changes always occurred within the safety area of the magnet. CONCLUSION: Subjective disturbances resulting from paramagnetic valve behavior are absent in Medos valves and are minor in Sophy valves. Image artifacts require careful planning of valve position. Artifacts observed in magnetic resonance imaging are less disturbing than those observed in computed tomography. Medos valves are more stable regarding disadjustment than are Sophy valves. Radiological control of valve setting after exposure to the magnetic field is mandatory in both. The 0.5-mT safety line encircling the area that patients with pacemakers should not enter is a useful safety borderline for patients with pressure-adjustable valves. Failure of the programming mechanism of one Medos valve after several exposures to the magnetic field requires clarification.

Artifacts↗

Photodynamic therapy in neurosurgery: a review.

Photodynamic therapy (PDT) has been investigated extensively, both experimentally and clinically, as an adjunctive treatment in the neuro-oncological field. It is based on the more selective accumulation of a photosensitizer in malignant than normal tissue with low systemic toxicity. Subsequent light activation induces photo-oxidation, followed by selective tumour destruction via vascular and direct cellular mechanisms. Malignant brain tumours carry a lethal prognosis with a median survival of 15 months despite surgery, radiotherapy and chemotherapy. PDT is therefore a logical therapeutic concept for brain tumours infiltrating into normal brain. In this review, all the available data on patients treated with haematoporphyrin derivative-mediated PDT are critically analysed. Over 310 patients have been reported in the literature suffering from primary or recurrent malignant brain tumours which were treated with PDT following tumour resection in open clinical phase I/II trials. This number includes 58 patients treated at our own institution. Variations in the treatment protocols make evaluation scientifically difficult; however, there is a clear trend of increased median survival after surgical resection and one single photodynamic treatment. PDT is generally well tolerated and side effects consist of moderate increased intracranial pressure and prolonged skin sensitivity to direct sunlight. The current available data indicate that PDT is a safe treatment, which is well tolerated by the patients and yields an improvement in survival of those with malignant brain tumours. Conclusive information can be expected from controlled clinical trials which are currently being designed. The results raise the hope that PDT will be a valuable addition to the armamentarium for the treatment of cerebral malignancies.

Biopsy↗

Unusual adverse reaction in a patient sensitized with Photosan 3.

Serious side effects of photodynamic therapy (PDT) are rare (A.L. Abramson, M.J. Shikowitz, V.M. Mullooly, Clinical effects of photodynamic therapy on recurrent laryngeal papillomas, Arch. Otolaryngology Head Neck Surg., 118 (1992) 25-29; A.L. Abramson, M.J. Shikowitz, Clinical exacerbation of systemic lupus erythematosus after photodynamic therapy of laryngotracheal papillomatosis, Laser Surg. Med., 13 (1993) 677-679). The most frequent side effects of PDT are hypersensitive skin reactions, local edema, nausea, a metallic taste and liver-toxicity (J. Feyh, E. Kastenbauer, Treatment of laryngeal papillomatosis with photodynamic laser therapy, Laryngorhinootologie, 71 (1992) 190-192; J. Feyh, R. Gutmann, A. Leunig, Die Photodynamische Therapie im Bereich der Hals-, Nasen-, Ohrenheilkunde Laryngorhinootologie, 72(6) (1993) 273-78; M.S. Kavuru, A.C. Mekta, Treatment of recurrent respiratory papillomatosis, N. Engl. J. Med., 326 (1992) 204-205; B.L. Wenig, D.M. Kurtzmann, Photodynamic therapy in the treatment of squamous cell carcinomas of the head and neck, Arch. Otolaryngol Head Neck Surg., 116 (1990) 1267-1270). In this case a patient (aged 57 years) suffering from a recurrent larynx papillomatosis was treated with PDT. He was sensitized with Photosan 3 (DHE) 2.5 mg kg-1 body weight, 24 h prior to photoradiation. As a light source, an argon dye laser, operating at a wavelength of 630 nm was used, coupled with a cylindrical light applicator. After treatment the patient was admitted to an intensive care unit for 24 h. 3 h after photoradiation, general urticarial wheals arose, as well as tachycardia and a decrease in blood pressure followed by all the signs of serious anaphylaxis. 1.5 h after treatment with adrenaline and cortisone and stabilization of the cardiac and circulatory situation no more skin lesions were visible.

Anaphylaxis↗

Electromotive diffusion (EMD) and photodynamic therapy with delta-aminolaevulinic acid (delta-ALA) for superficial bladder cancer.

Recent reports have shown that topical application of delta-aminolaevulinic acid (delta-ALA) can be used for the photodynamic diagnosis and therapy of superficial bladder tumours. Electromotive diffusion (EMD) increases the cellular uptake of polar substances. In six patients with biopsy-proven recurrent carcinoma in situ of the bladder after Bacillus Calmette-Guérin (BCG) treatment, 100 cm3 of a 0.5% delta-ALA solution at pH approximately 6 was instilled into the bladder. With a special Foley catheter containing a stainless steel electrode, EMD, with a 15 mA, pulsed current, positive polarity at the catheter, was created for 20 min in the sedated patient. Thereafter a laser fibre with a spheric diffuser was inserted into the bladder over a cystoscope. The bladder surface was irradiated at a wavelength of 632 nm with 350 mW s-1 (total dose, 30-50 J cm-2). Follow-up consisted of a cystoscopy and biopsy after 6 weeks and cystoscopy and cytology every 3 months thereafter. The whole procedure was well tolerated. Currently, five patients are tumour free after a follow-up of 10-16 months. One patient has recurred after 10 months with a Ta G3 superficial tumour at the bladder neck which was resected. In a transwell cell culture model, we investigated the effect of delta-ALA treatment with and without application of EMD. In this in vitro system, application of an electric field showed only a small increase in delta-ALA uptake compared with uptake by passive diffusion.

Aged↗

Therapy of glioblastoma multiforme: a cumulative experience of 10 years.

PURPOSE: Comparison of the effect of different therapeutic modalities on survival time of patients with glioblastoma multiforme operated on during the last decade (1980-1990). PATIENTS AND METHODS: The records of 157 consecutive patients with the histological diagnosis of glioblastoma multiforme were analysed for survival with respect to age of patients, extent of surgery, influence of re-operation and adjuvant postoperative treatment. The latter included fractionated radiotherapy, chemotherapy (BCNU. CCNU with Vincristine) and photodynamic therapy (PDT). RESULTS: Analysis of variance showed a significant effect for survival after macroscopically radical surgery (p = 0.005), postoperative radiotherapy (p < 0.001), chemotherapy (p < 0.01). Low age (p < 0.05) and a postoperative Karnofsky performance score (KPS) > or = 60 (p < 0.001) had a positive influence: the site of tumour and pre-operative presence of seizures had no significant influence (p > 0.1) on survival time. CONCLUSION: We conclude that the current adequate management of glioblastoma multiforme should include surgical resection followed by adjuvant treatment such as radiotherapy and chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

Treatment of patients with severe head injury by triamcinolone: a prospective, controlled multicenter clinical trial of 396 cases.

The present studies were conducted to test whether the outcome of severe head injury is improved by early administration of the synthetic corticosteroid triamcinolone. In a prospective, double-blind, multicenter clinical trial, 396 patients with severe head injury were randomized to a steroid group (n = 187) receiving 200 mg triamcinolone acetonide (Volon A soluble) i.v. within 4 h after trauma, followed by 3 x 40 mg/day i.v. for 4 days, and 3 x 20 mg/day i.v. for a further 4 days, and a placebo group (n = 209) receiving injections which did not contain any active drug. The placebo group was subjected to the same standard treatment procedures. Clinical features were not different between the groups upon admission to hospital. Subdural hematoma, epidural hematoma, and focal supratentorial contusion were among the most frequent diagnoses. The result of treatment with triamcinolone was assessed at discharge from the hospital and at 1 year after trauma, using the Glasgow Outcome Scale. Differences in favor of steroid treatment could be detected with regard to the patients' condition at discharge (P = 0.0634). More patients with steroids had a good recovery (49.2% vs 40.7%), and fewer died (16.0% vs 21.5%). Differences in outcome were even more pronounced (P < 0.0145) in patients with a focal lesion and a Glasgow Coma Score on admission of < 8 (n = 93). In this group, 34.8% of the patients made a good recovery, as against 21.3% of the placebo group; mortality was also lower in the verum group (19.6% vs 38.3%). The results indicate that a major subgroup of patients with severe head injury benefits from early administration of triamcinolone. Efficacy of the treatment can be expected, in particular, in patients with a focal cerebral lesion and a Glasgow Coma Score of < 8 on admission. Administration of steroids beginning at the scene of an accident would therefore be beneficial in these cases.

Adolescent↗

[Photodynamic therapy in patients with recurrent gynecologic cancers].

Patients with recurrent gynaecological carcinomas have a poor prognosis, with a survival of a few months. Three patients with a recurrent vulva carcinoma, one patient with a recurrent cervical carcinoma, one patient with a recurrent endometrial carcinoma, and one patient with a recurrent breast carcinoma underwent PDT after parenteral or topical sensitisation with Photosan 3. From these patients, two of them showed a complete response with no evidence of disease for 32 and 29 months. One patient responded partially with two recurrences, which were treated twice after tropical sensitisation, living now 21 months. The remaining three patients showed partial response and died 3 to 8 months after PDT. The energy applied was derived from an argon-dye-laser ranging between 225 and 750 joule/cm2. Photosan 3 was given intravenously at a dose of 2.5 mg/kg body weight and was tolerated without any allergic reaction. The response rate in three of six patients in recurrent gynaecological malignancies encourages us to pursue PDT in gynaecological disease.

Aged↗

[Tractotomy and partial nucleotomy as a form of therapy in refractory pain of the trigeminal nerve and cancer pain in the head and neck area].

Persistent trigeminal neuralgia, herpes zoster neuralgia of the first division of the trigeminal nerve and pain caused by cancer situated in the head and neck pose frustrating problems for patients and physicians. Tractotomy and/or partial vertical nucleotomy of the subnucleus caudalis nervi trigemini offers a logical approach to the treatment of such pain, since these structures contain fibres of the Vth nerve, as well as the somatosensory fibres of the VIIth, IXth and Xth nerve. Tactile and some thermal sensitivity of the face is preserved and anaesthesia dolorosa and keratitis neuroparalytica is avoided. Over the past 30 years 370 patients with therapy-refractory trigeminal pain, pain due to cancer of the head and neck and herpes zoster trigeminal pain were treated by means of tractotomy (personal series of V. Grunert), including 30 patients who underwent partial vertical nucleotomy. The mean age of the patients was 68 years (range 54-84 years). The mortality in this series was 0.9% (4 patients; one operative mortality due to air embolism, one postoperative cardiac failure following myocardial infarction and two intracerebral haematomas). 60% of the patients with persistent trigeminal neuralgia were pain-free and 28% improved, whereas 12% were unchanged or suffered from recurrent pain. Of the patients with cancer who complained of pain derived from the Vth, VIIth, IXth and Xth nerve, 40% demonstrated marked pain relief and 60% showed no improvement. Tractotomy and partial vertical nucleotomy offer a valuable method in experienced hands for relieving pain where other methods have failed.

Aged↗

Photodynamic treatment of malignant brain tumors.

30 patients with primary or recurrent malignant brain tumors (9 primary, 18 recurrent malignant gliomas, 1 malignant meningioma, 2 melanomas) were treated altogether 37 times by photodynamic therapy (PDT) whether after intravenous, intraarterial or direct intratumoral sensitisation by hematoporphyrin (HPD) after conventional surgical removal of the tumor mass. The light was produced by an Argon pumped dye laser at doses varying from 40-220 J/cm2. A single dose of radiation of 4 Gy was administered to 18 patients immediately after PDT. The 9 patients with primary glioblastomas received in addition a full course of radiation therapy. The histological specimens taken during PDT demonstrated tumor necrosis, with oedema of normal brain tissue adjacent to the tumorbed. The median survival of patients with multiple recurrences and various radio- and chemotherapeutic modalities was 6 months (range 4-13 months). 9 patients with primary manifestation of a glioblastoma had a median survival of 19 months (0.5-29 months). Increased phototoxicity of the skin was the only side effect of PDT and did not reduce the quality of life of the patients.

Adult↗

[Steroid receptors and atypical histology as prognostic parameters in meningioma].

Cytosolic oestrogen and progesterone receptors (ER and PR) were determined in 58 primary and 13 recurrent meningiomas and related to their histological and clinical features. ER levels were low or not detectable (range 0-34 fmol/mg prot., median 0 fmol), whereas considerable amounts of PR were found in 69% of primary tumours (range 0-583 fmol/mg prot., median 72 fmol) and in 5/5 long-term recurrences (range 69-505 fmol/mg prot., median 143). Eight tumours recurred within a short-term period (less than 5 years) with a low PR expression (range 0-34 fmol/mg prot., median 0 fmol) and all presented raised cellularity and mitotic rate ("atypical" meningioma) or criteria of definitely malignant meningioma. The primary tumours of the short-term recurrences were not available for receptor analysis; however, they also were either "atypical" or anaplastic meningiomas. Long-term recurrences never displayed other than classical histology. From our results we conclude that polymorphy, as well as a lack of PR are strong indicators for short-term recurrence.

Brain↗

[Intraoperative radiotherapy of brain gliomas].

11 patients with recurrent brain tumours underwent intraoperative radiotherapy (IORT) at a dosage of 15-25 Gy of fast electrons (17-20 MEV). IORT allows a higher dose of irradiation to be delivered to a well-defined target than is possible with external radiation, in anticipation of favourable results. However, tumour growth was not influenced in 7 out of the 11 patients and these patients died between 2 and 10 months following IORT. The remaining four patients are living still up to 15 months postoperatively. Due to the inhomogeneity of our patients no definitive conclusions can be drawn. However, well-defined tumours which can be radically excised are definitely more suitable for IORT than large, infiltrating tumours.

Adult↗