Adjuvant Brachytherapy with Ruthenium-106 to Reduce the Risk of Recurrence of Conjunctival Melanoma after Excision.

Introduction: Local recurrence of conjunctival melanoma (CM) is common after excision. Local radiotherapy is an effective adjuvant treatment option, and brachytherapy with ruthenium-106 (106Ru) is one such option. Thus, herein, we aimed to describe our experience with and the clinical results of post-excision adjuvant 106Ru plaque brachytherapy in patients with CM. Methods: Nineteen patients (8 men and 11 women) received adjuvant brachytherapy with a 106Ru plaque after tumor excision. The mean adjuvant dose administered was 109 Gy (range, 80-134 Gy), and a depth of only 2.2 mm was targeted because the tumor had been excised. A full ophthalmological examination including visual acuity testing, slit-lamp examination, and indirect ophthalmoscopy was performed before therapy and at every postoperative follow-up. The mean follow-up period was 62 months (range, 2-144 months). Results: Three patients developed a recurrence in a nontreated area, at either the conjunctiva bulbi or the conjunctiva tarsi. None of the patients developed a recurrence in the treated area. The local control rate was 84% (16/19). Conclusion: 106Ru plaque brachytherapy is an effective adjuvant treatment to minimize the risk of local recurrence after excision of a CM. Patients have to be followed up regularly and carefully for the early detection of recurrence.

Impact of tumour volume and treatment delay on the outcome after linear accelerator-based fractionated stereotactic radiosurgery of uveal melanoma.

BACKGROUND/AIMS: Primary radiation therapy is used to treat malignant uveal melanoma (UM). We report our single-centre experience with fractionated radiosurgery (fSRS) with a linear accelerator (LINAC) after specific adaptation for small target volumes with HybridArc. METHODS: From October 2014 to January 2020, 101 patients referred to Dessau City Hospital with unilateral UM underwent fSRS with 50 Gy given in five fractions on five consecutive days. Primary endpoints were local tumour control, globe preservation, metastasis and death. Potential prognostic features were analysed. Kaplan-Meier analysis, Cox proportional hazards model and linear models were used for calculations. RESULTS: The median baseline tumour diameter was 10.0 mm (range, 3.0-20.0 mm), median tumour thickness 5.0 mm (range, 0.9-15.5 mm) and median gross tumour volume (GTV) 0.4 cm³ (range, 0.2-2.6 cm³). After a median follow-up of 32.0 months (range, 2.5-76.0 months), 7 patients (6.9%) underwent enucleation: 4 (4.0%) due to local recurrence and 3 (3.0%) due to radiation toxicities, and 6 patients (5.9%) revealed tumour persistence with a GTV exceeding 1.0 cm³. Of 20 patients (19.8%) who died, 8 (7.9%) were tumour-related deaths. Twelve patients (11.9%) suffered from distant metastasis. GTV showed an impact on all endpoints, and treatment delay was associated with reduced odds of eye preservation. CONCLUSION: LINAC-based fSRS with static conformal beams combined with dynamic conformal arcs and discrete intensity-modulated radiotherapy results in a high tumour control rate. The tumour volume is the most robust physical prognostic marker for local control and disease progression. Avoiding treatment delay improves outcomes.

Feasibility of aponeurectomy in combination with perioperative 192Ir high dose rate brachytherapy for Dupuytren's disease.

PURPOSE: Partial aponeurectomy (PA) is a standard procedure for Dupuytren's contracture (DC). Here we report a novel approach using surgery combined with perioperative high dose rate (192Ir-HDR) brachytherapy. METHODS AND PATIENTS: From March 2018 until February 2020, thirteen rays of 6 patients with Dupyutren's contractures underwent PA followed by HDR brachytherapy. After removal of fibrous tissue and mobilization of the tendons, one to three catheters per patient were placed intraoperatively. Immediately after surgery, a planning computer tomography with 3D-planning was performed. Then 10-12 Gy were given to 0-2 mm from the catheters' surface and the catheters were removed 6-12 h after brachytherapy. RESULTS: No complications were observed. The mean contractures were reduced from 55.4° (standard error SE 19.6) to 15.4° (SE 6.7; p < 0.01). One patient showed progressive fibrosis of a nontreated ray during follow-up. CONCLUSIONS: HDR brachytherapy in combination with surgery is feasible and harbors the potential for combined modality therapy to reduce relapse rates of advanced or relapsing DC. Controlled studies are warranted to investigate the role of bimodal therapy compared with PA alone.

Anti-cancer agent 3-bromopyruvate reduces growth of MPNST and inhibits metabolic pathways in a representative in-vitro model.

BACKGROUND: Anticancer compound 3-bromopyruvate (3-BrPA) suppresses cancer cell growth via targeting glycolytic and mitochondrial metabolism. The malignant peripheral nerve sheath tumor (MPNST), a very aggressive, therapy resistant, and Neurofibromatosis type 1 associated neoplasia, shows a high metabolic activity and affected patients may therefore benefit from 3-BrPA treatment. To elucidate the specific mode of action, we used a controlled cell model overexpressing proteasome activator (PA) 28, subsequently leading to p53 inactivation and oncogenic transformation and therefore reproducing an important pathway in MPNST and overall tumor pathogenesis. METHODS: Viability of MPNST cell lines S462, NSF1, and T265 in response to increasing doses (0-120 µM) of 3-BrPA was analyzed by CellTiter-Blue® assay. Additionally, we investigated viability, reactive oxygen species (ROS) production (dihydroethidium assay), nicotinamide adenine dinucleotide dehydrogenase activity (NADH-TR assay) and lactate production (lactate assay) in mouse B8 fibroblasts overexpressing PA28 in response to 3-BrPA application. For all experiments normal and nutrient deficient conditions were tested. MPNST cell lines were furthermore characterized immunohistochemically for Ki67, p53, bcl2, bcl6, cyclin D1, and p21. RESULTS: MPNST significantly responded dose dependent to 3-BrPA application, whereby S462 cells were most responsive. Human control cells showed a reduced sensitivity. In PA28 overexpressing cancer cell model 3-BrPA application harmed mitochondrial NADH dehydrogenase activity mildly and significantly failed to inhibit lactate production. PA28 overexpression was associated with a functional glycolysis as well as a partial resistance to stress provoked by nutrient deprivation. 3-BrPA treatment was not associated with an increase of ROS. Starvation sensitized MPNST to treatment. CONCLUSIONS: Aggressive MPNST cells are sensitive to 3-BrPA therapy in-vitro with and without starvation. In a PA28 overexpression cancer cell model leading to p53 inactivation, thereby reflecting a key molecular feature in human NF1 associated MPNST, known functions of 3-BrPA to block mitochondrial activity and glycolysis were reproduced, however oncogenic cells displayed a partial resistance. To conclude, 3-BrPA was sufficient to reduce NF1 associated MPNST viability potentially due inhibition of glycolysis which should lead to the initiation of further studies and promises a potential benefit for NF1 patients.

The superficially averaged dose gradient at the target volume's boundary: A two-dimensional formulation and solution of anisotropic dose gradient problems.

BACKGROUND AND PURPOSE: Dose conformity and steepness of dose fall-off at a target volume's boundary are important quality criteria in treatment planning to predict complication rates in normal tissue and critical structures. Several dose gradient measures are in use; ICRU Report 91 recommends one of two gradient metrics for reporting. All of the common gradient indices are one-dimensional, although dose gradient problems are at least two-dimensional and anisotropic. Four of ten investigated gradient indices show false characteristics on the mean value of the physical dose gradients. Anisotropic dose gradient measures can be the basis of clinical therapeutic decisions if tumours are surrounded by organs at risk with various tolerance dose values. To close this information gap, the author presents a mathematical description and solution of anisotropic dose gradient problems. MATERIALS AND METHODS: The new two-dimensional dose gradient measure is called the superficially averaged dose gradient (SADG). The particular informative content of the ten common dose gradient indices was assessed by classification and analysing their properties. The correlations between all of the dose gradient measures were investigated for linac-based stereotactic radiosurgery of 13 brain metastases. RESULTS: From all of the one-dimensional dose gradient indices, the approximated SADG* showed the best correlation on the SADG. Here, Pearson's correlation coefficient was 1.000 and the relative errors were in a range of -0.2 to 2.9%. Distributions of anisotropic dose gradients were graphically represented by dose gradient-solid angle histograms. CONCLUSIONS: Two-dimensional dose gradient measures such as the SADG are urgently required for lesions that are located in non-homogeneous normal tissue. The quality of each present and future dose gradient measure concerning the description of anisotropic dose gradient problems is now verifiable by use of the SADG. Through the SADG, the influences of collimation types on the dose fall-off at the target volume's boundary can be investigated. The algorithm for determining the SADG should be implemented in treatment planning systems to utilise the formalism for all users. The dose gradient indices recommended in ICRU Report 91 overestimate and underestimate physical dose gradients, respectively.

Stereotactic radiotherapy for choroidal melanomas by means of HybridArc™ : Physics and technique of linac-based photon beam therapy.

PURPOSE: Stereotactic radiotherapy (SRT) is suitable to treat ocular tumours. The optimal beam geometry for SRT, however, has not been defined. Here we evaluate a combination technique with dynamic conformal arcs (DCAs) and intensity-modulated static fields (IMRT), known as HybridArc™ (HA). METHODS: For the first consecutive 25 cases with choroidal melanomas with volumes of 0.02 to 1.18 cm3 treated with 50 Gy in five fractions, the results with respect to dose conformity, homogeneity, and dose distributions were summarised. To describe the dose distribution at the planning target volume (PTV) boundary, we defined a spatially averaged dose gradient (SADG) and compared it with Paddick's gradient index (GI). We made dosimetric comparisons between HA and other irradiation techniques. RESULTS: The PTVs ranged from 0.42 to 3.37 cm3. The conformity index (CI) was 1.25 ± 0.15, and the homogeneity index (HI) 0.08 ± 0.02. The SADG was (-3.5 ± 0.5) Gy/mm or (-7.0 ± 1.0) %/mm between the isodose levels 95 and 20%; local minima reached -11.5 Gy/mm or -22.9%/mm. The coefficient of determination for a nonlinear regression of GI on SADG was 0.072. After a median follow-up time of 19.6 months, local tumour control was 100% without any case of post-therapeutic enucleation. Two patients (8%) developed liver metastases. CONCLUSION: SRT of ocular tumours by HA is highly appropriate, and HA is superior to intensity-modulated arc therapy (IMAT) concerning dose reduction in organs at risk (OARs). The novel gradient measure SADG is more informative than Paddick's GI.

Optimizing radiosurgery with photons for ocular melanoma.

BACKGROUND AND PURPOSE: Photon radiotherapy has been established for the treatment of ocular melanoma (OM). Here we investigate the planning qualities of two different planning approaches, a combination of dynamic conformal arcs (DCA) complemented with multiple non-coplanar static intensity-modulated (IMRT) fields (DCA-IMRT), and volumetric modulated arc therapy (VMAT) in combination with automated planning (AP). MATERIALS AND METHODS: Thirteen consecutive patients treated for ocular melanoma with curative intent on a Linac-based radiosurgery system were analyzed. Fractionated stereotactic radiosurgery (fSRS) was applied using 50 Gy in 5 fractions using the combination of DCA-IMRT. Plans were reviewed and the thirteen cases were compared to plans obtained with optimized automated VMAT based on a set of 28 distinct patients treated with DCA-IMRT who were selected to generate the AP model for the prediction of dose volume constraints. RESULTS: Overall, plan quality of DCA-IMRT was superior to AP with VMAT. PTV coverage did not exceed 107% in any case treated with DCA-IMRT, compared to seven patients with VMAT. The median PTV covered by >95% was 98.3% (91.9%-99.7%) with DCA-IMRT, compared to 95.1% (91.5%-97.9%) (p < 0.01) with VMAT. The median mean dose delivered to the treated eye was 22.4 Gy (12.3 Gy-33.3 Gy) with DCA-IMRT compared to 27.2 Gy (15.5 Gy-33.7 Gy) (p < 0.01). Dose to the ipsilateral lacrimal gland and the ipsilateral optic nerve were comparable for DCA-IMRT and VMAT, however, the dose to the lens was lower with DCA-IMRT compared to VMAT. CONCLUSIONS: The combination of multiple arcs complemented with multiple IMRT fields sets the gold standard for fSRS of ocular melanoma for photon therapy.