Benefit of delayed primary excision in rhabdomyosarcoma: A report from the Children's Oncology Group.

BACKGROUND: Most children with intermediate-risk rhabdomyosarcoma (RMS) have gross disease (group III) at the initiation of chemotherapy. Delayed primary excision (DPE) after induction chemotherapy allows for a reduction in adjuvant radiation dose, but with the risk of potential surgical morbidity. The objectives of this study were to compare outcomes in children with group III RMS who did and did not undergo DPE and to assess surgical morbidity. METHODS: The study included 369 patients who had clinical group III RMS at sites amenable to DPE from intermediate-risk Children's Oncology Group studies D9803 (encouraged DPE) and ARST0531 (discouraged DPE). RESULTS: The primary tumor site was bladder/prostate (136 patients; 37%), extremity (97 patients; 26%), trunk (24 patients; 7%), retroperitoneum (91 patients; 25%), or intrathoracic/perineum/perianal (21 patients; 6%). In total, 112 patients (53.9%) underwent DPE in D9803, and 26 patients (16.2%) underwent DPE in ARST0531 (P < .001), with loss of vital organ or function in 30 of 138 patients (22%). DPE allowed for a reduced radiation dose in 110 of 135 patients (81%; 51% were reduced to 36 Gy, and 30% were reduced to 42 Gy). Patients who underwent DPE had improved unadjusted overall survival (P = .013). In adjusted regression analysis, the risk of death (hazard ratio, 0.71; 95% CI 0.43-1.16) was similar for patients who did and did not undergo DPE and was improved for the subset of patients who had tumors of the trunk and retroperitoneum (hazard ratio, 0.44; 95% CI, 0.20-0.97). CONCLUSIONS: Children with group III RMS have equivalent or improved outcomes with DPE and can receive a decreased radiation dose for definitive local control. The choice of local control modality should weigh the potential morbidity of surgery versus that of higher dose irradiation.

Clinically relevant radioresistant rhabdomyosarcoma cell lines: functional, molecular and immune-related characterization.

BACKGROUND: The probability of local tumor control after radiotherapy (RT) remains still miserably poor in pediatric rhabdomyosarcoma (RMS). Thus, understanding the molecular mechanisms responsible of tumor relapse is essential to identify personalized RT-based strategies. Contrary to what has been done so far, a correct characterization of cellular radioresistance should be performed comparing radioresistant and radiosensitive cells with the same isogenic background. METHODS: Clinically relevant radioresistant (RR) embryonal (RD) and alveolar (RH30) RMS cell lines have been developed by irradiating them with clinical-like hypo-fractionated schedule. RMS-RR cells were compared to parental isogenic counterpart (RMS-PR) and studied following the radiobiological concept of the "6Rs", which stand for repair, redistribution, repopulation, reoxygenation, intrinsic radioresistance and radio-immuno-biology. RESULTS: RMS-RR cell lines, characterized by a more aggressive and in vitro pro-metastatic phenotype, showed a higher ability to i) detoxify from reactive oxygen species; ii) repair DNA damage by differently activating non-homologous end joining and homologous recombination pathways; iii) counteract RT-induced G2/M cell cycle arrest by re-starting growth and repopulating after irradiation; iv) express cancer stem-like profile. Bioinformatic analyses, performed to assess the role of 41 cytokines after RT exposure and their network interactions, suggested TGF-ß, MIF, CCL2, CXCL5, CXCL8 and CXCL12 as master regulators of cancer immune escape in RMS tumors. CONCLUSIONS: These results suggest that RMS could sustain intrinsic and acquire radioresistance by different mechanisms and indicate potential targets for future combined radiosensitizing strategies.

Patterns of failure and toxicity profile following proton beam therapy for pediatric bladder and prostate rhabdomyosarcoma.

PURPOSE/OBJECTIVE(S): Bladder and prostate are unfavorable sites for rhabdomyosarcoma (B/P-RMS), and represent a challenging location for radiotherapy. MATERIALS/METHODS: Nineteen patients with B/P-RMS were enrolled on a prospective registry protocol (2008-2017) and treated with chemotherapy, proton beam therapy (PBT), and surgical resection (n = 8; 42%). Emphasis was given to treatment technique, disease-related outcomes, and toxicity associated with PBT. RESULTS: The majority of patients had bladder RMS (74%) of embryonal histology (95%), Group III (68%), and intermediate-risk disease by Children's Oncology Group (COG) risk stratification (89%). Seven patients (37%) had primary tumors >5 cm in size. All patients were treated according to COG protocols. With a median follow-up of 66.2 months, 5-year overall survival (OS) and progression-free survival (PFS) were 76%. Four patients (21%) experienced disease relapse, all presenting with local failure. The 5-year local control (LC) rate was 76%. Tumor size predicted LC, with 5-year LC for patients with >5 cm tumors being 43% versus 100% for those with ≤5 cm tumors (P = .006). Univariate analysis demonstrated an effect of tumor size on OS (tumor >5 cm, hazard ratio [HR] 17.7, P = .049) and PFS (HR 17.7, P = .049). Acute grade 2 toxicity was observed in two patients (11%, transient proctitis). Late grade 2+ toxicity was observed in three patients (16%; n = 1 grade 2 skeletal deformity; n = 3 transient grade 2 urinary incontinence; one patient experienced both). CONCLUSIONS: PBT for B/P-RMS affords promising disease-related outcomes with an acceptable toxicity profile. Higher local failure rates were observed for larger tumors, supporting dose-escalation components of ongoing RMS clinical trials.

45 Gy is not sufficient radiotherapy dose for Group III orbital embryonal rhabdomyosarcoma after less than complete response to 12 weeks of ARST0331 chemotherapy: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

BACKGROUND: Recent Children's Oncology Group (COG) trials tested the efficacy of reduced therapy in an effort to lessen late effects compared to the Intergroup Rhabdomyosarcoma Study (IRS) IV regimen with associated hematologic and hepatic toxicity, and infertility. Here, we analyze the efficacy of 45 Gray (Gy) local radiotherapy (RT) in patients with Group III orbital embryonal rhabdomyosarcoma (ERMS) enrolled on the COG low-risk study ARST0331. PROCEDURE: Sixty-two patients with Group III orbital ERMS were treated on ARST0331 with four cycles of vincristine (VCR), dactinomycin (DACT), and cyclophosphamide (CPM; VAC, total cumulative CPM dose 4.8 g/m2 ) followed by four cycles of VCR and DACT over 22 weeks. Forty-five Gray of radiation was administered in 25 fractions beginning at week 13 of therapy. RESULTS: Fifty-three patients were evaluable for this response analysis; seven had missing week 12 response evaluation data and two had progressive disease prior to starting RT. Median follow-up was 7.8 years. None of the 15 patients with radiographic complete response (CR) compared to 6 of the 38 patients with

Pencil Beam Scanning Proton Therapy for Pediatric Parameningeal Rhabdomyosarcomas: Clinical Outcome of Patients Treated at the Paul Scherrer Institute.

BACKGROUND: Parameningeal rhabdomyosarcomas (PM-RMSs) represent approximately 25% of all rhabdomyosarcoma (RMS) cases. These tumors are associated with early recurrence and poor prognosis. This study assessed the clinical outcome and late toxicity of pencil beam scanning (PBS) proton therapy (PT) in the treatment of children with PM-RMS. PROCEDURES: Thirty-nine children with PM-RMS received neoadjuvant chemotherapy followed by PBS-PT at the Paul Scherrer Institute, with concomitant chemotherapy. The median age was 5.8 years (range, 1.2-16.1). Due to young age, 25 patients (64%) required general anesthesia during PT. The median time from the start of chemotherapy to PT was 13 weeks (range, 3-23 weeks). Median prescription dose was 54 Gy (relative biologic effectiveness, RBE). RESULTS: With a mean follow-up of 41 months (range, 9-106 months), 10 patients failed. The actuarial 5-year progression-free survival (PFS) was 72% (95% CI, 67-94%) and the 5-year overall survival was 73% (95% CI, 69-96%). On univariate analysis, a delay in the initiation of PT (>13 weeks) was a significant detrimental factor for PFS. Three (8%) patients presented with grade 3 radiation-induced toxicity. The estimated actuarial 5-year toxicity ≥grade 3 free survival was 95% (95% CI, 94-96%). CONCLUSIONS: Our data contribute to the growing body of evidence demonstrating the safety and effectiveness of PT for pediatric patients with PM-RMS. These preliminary results are encouraging and in line with other combined proton-photon and photons series; observed toxicity was acceptable.

Radiation therapy may increase metastatic potential in alveolar rhabdomyosarcoma.

BACKGROUND: We previously determined that radiation could be safely administered using a mouse-flank in vivo model to both alveolar (Rh30) and embryonal (Rh18) rhabdomyosarcoma xenografts. Mice from both tumor lines in this experiment developed metastases, an event not previously described with these models. We sought to determine if radiation-induced changes in gene expression underlie an increase in the metastatic behavior of these tumor models. PROCEDURE: Parental Rh18 and Rh30 xenografts, as well as tumor that recurred locally after radiotherapy (Rh18RT and Rh30RT), were grown subcutaneously in the flanks of SCID mice and then subjected to either fractionated radiotherapy or survival surgery alone. Metastasis formation was monitored and recorded. Gene expression profiling was also performed on RNA extracted from parental, recurrent, and metastatic tissue of both tumor lines. RESULTS: Rh30 and Rh30RT xenografts demonstrated metastases only if they were exposed to fractionated radiotherapy, whereas Rh18 and Rh18RT xenografts experienced significantly fewer metastatic events when treated with fractionated radiotherapy compared to survival surgery alone. Mean time to metastasis formation was 40 days in the recurrent tumors and 73 days in the parental xenografts. Gene expression profiling noted clustering of Rh30 recurrent and metastatic tissue that was independent of the parental Rh30 tissue. Rh18RT xenografts lost radiosensitivity compared to parental Rh18. CONCLUSION: Radiation therapy can significantly decrease the formation of metastases in radio-sensitive tumors (Rh18) and may induce a more pro-metastatic phenotype in radio-resistant lines (Rh30).

Rare embryonal rhabdomyosarcoma of external acoustic canal: a case report and literature review.

Embryonal rhabdomyosarcoma of external ear canal is very rare, even in the pediatric population. We report an embryonal rhabdomyosarcoma of external acoustic canal, occurring in a 12-year-old Chinese girl who presented with left ear canal mass. Wide local excision of the mass was done under local anesthesia. Histopathological examination revealed the diagnosis. She then underwent 20 cycles of radiotherapy. CECT scan post treatment showed clearance of tumor cell. Now, patient is disease free for 5 years. We believe that early diagnosis followed by complete resection of the tumor with clear margin and radiotherapy improves the prognosis of the disease.

A 16-Year-Old Girl with Sinonasal Cutaneous Fistula Following Excision and Radiotherapy for Rhabdomyosarcoma Requiring Reconstructive Surgery Using an Expanded Forehead Flap.

BACKGROUND Sinonasal rhabdomyosarcoma (RMS) is a rare malignancy in children and adolescents. It is aggressive and locally invasive, and can require local postoperative radiotherapy. This report presents the case of a 16-year-old girl with a sinonasal-cutaneous fistula following excision and radiotherapy for rhabdomyosarcoma, which required reconstructive surgery using an expanded forehead flap. CASE REPORT We report the case of a16-year-old girl who was referred to our clinic with sinonasal-cutaneous fistula. Prior to presentation at our department, she presented with bilateral intermittent nasal congestion 3 years ago. At a local hospital, orbital computed tomography and nasal endoscopic biopsy revealed an embryonal rhabdomyosarcoma (ERMS). One month later, skull base tumor resection, nasal cavity and sinus tumor resection, and low-temperature plasma ablation were performed at a local hospital. Two weeks after the operation, the patient received intensity-modulated radiation therapy for a total of 50 Gy. Chemotherapy started 15 days after radiotherapy, using a vincristine, dactinomycin, and cyclophosphamide (VAC) regimen. Approximately 1 month later, an ulcer appeared at the nasal root and the lesion gradually expanded. The patient was referred to our hospital due to the defect. Firstly, a tissue expander was implanted at the forehead for 7 months. Then, the skin around the defect was trimmed and forehead flap was separated to repair the lining and external skin. The flap survived well 1-year after the operation. CONCLUSIONS This report highlights the challenges of post-radiation reconstructive surgery and describes how an expanded forehead flap can achieve an acceptable cosmetic outcome in a patient with a sinonasal-cutaneous fistula.

Which Patients With Rhabdomyosarcoma Need Radiotherapy? Analysis of the Radiotherapy Strategies of the CWS-96 and CWS-2002P Studies and SoTiSaR Registry.

PURPOSE: To analyze and compare the indications, doses, and application methods of radiotherapy (RT) and their influence on prognosis of patients with localized rhabdomyosarcoma (RMS). METHODS: One thousand four hundred seventy patients with localized RMS 21 years and younger entered on CWS-96, CWS-2002P, and SoTiSaR were eligible for the analysis. The median follow-up was 6.5 years (IQR, 3.3-9.5). RESULTS: The 5-year event-free survival (EFS) and local control survival (LCS) for 910 (62%) irradiated versus nonirradiated patients were 71% versus 69% and 78% versus 73% (P = .03), respectively. Ninety-five percent of patients in IRS I (90% embryonal RMS [eRMS]) were nonirradiated (EFS, 87%). Irradiated patients with IRS II had improved LCS (91% v 80%; P = .01) and EFS (not significant). In IRS III, EFS and LCS were significantly better for RT patients: 71% versus 56% (P = 3.1e-06) and 76% versus 61% (P = 4.1e-07). Patients with tumors in the head and neck region (orbita, parameningeal, and nonparameningeal) and in other sites had significantly better EFS and LCS and in parameningeal also overall survival (OS). The efficacy of low RT doses of 32 Gy (hyperfractionated, accelerated RT [HART]) and 36 and 41.4 Gy (conventional fractionated RT [CFRT]) in the favorable groups and higher doses of 44.8 Gy (HART) and 50.4 and 55.4 Gy (CFRT) in the unfavorable groups was comparable. Proton RT was used predominantly in head/neck-parameningeal (HN-PM) tumors, with similar EFS and LCS to photon RT. CONCLUSION: RT can be omitted in patients with IRS I eRMS. RT improves LCS and EFS in IRS II and III. RT improves OS in patients with HN-PM, with proton RT comparable with photon RT. Doses of 32 Gy (HART) or 36 and 41.4 Gy (CFRT) had comparable efficacy in patients with favorable risk profiles and 44.8 Gy (HART) or 50.4 and 55.8 Gy (CFRT) in the unfavorable groups.

[Rhabdomyosarcoma in middle to old-aged patients: analysis of clinicopathological features and prognosis in 76 cases].

OBJECTIVE: Albeit rare, rhabdomyosarcoma (RMS) may occur in middle to old-aged adults. The purpose of this study was to investigate the clinicopathological characteristics and prognosis of RMS in patients ≥ 40 years of age. METHODS: The clinical, pathological and immunohistochemical profiles of the 76 cases were reviewed, and the outcomes were analyzed. RESULTS: There were 46 males and 30 females with a median age of 55 years. Sixty cases occurred in somatic soft tissues, including extremities (n = 25), head and neck (n = 19) and trunk (n = 16). Sixteen developed in the internal organs with predilection for the urogenital tract. Histologically, 38 cases (50.0%) were of embryonal RMS (ERMS) subtype, 29 cases (38.2%) of pleomorphic RMS (PRMS), 7 cases (9.2%) of poorly-differentiated RMS (PdRMS), and 2 cases (2.6%) of alveolar RMS (ARMS). Immunohistiochemically, the tumor cells showed diffuse staining of desmin (68/68, 100%), with a variable expression of myogenin (30/43, 69.8%), MyoD1 (33/51, 64.7%) and MSA (29/40, 72.5%). The therapy data available in 54 cases showed that three inoperable cases were treated with chemotherapy and radiotherapy, 51 cases underwent local excision, including 10 cases with chemotherapy, 9 cases with radiotherapy, 8 cases with chemotherapy and radiotherapy after surgery, and the remaining 24 cases were not administrered with postoperative adjuvant therapy. The follow-up data available in 54 cases showed that 22 patients were alive with unresectable or recurrent/disease and 32 patients were alive with no evidence of disease. The median disease-free and overall survivals were 6.0 months and 7.0 months, respectively. Twenty-seven patients exhibited progression of disease with recurrence in 8 cases and metastasis in 19 cases. The median interval to progression was 6.0 months. CONCLUSIONS: The most common subtypes of RMS in middle to old aged patients are ERMS and PRMS. In general, Rhabdomyosarcomas of middle to old aged patients shows a highly aggressive behavior. Patients may benefit from multi-disciplinary therapy.

Comparison of different adjuvant radiotherapy approaches in childhood bladder/prostate rhabdomyosarcoma treated with conservative surgery.

BACKGROUND AND PURPOSE: Multimodality treatment approaches provide high local control and satisfying overall survival (OS) for children with localized bladder and/or prostate rhabdomyosarcoma (BP-RMS). However, current strategies including surgery and conventional radiotherapy are compromised by high rates of long-term genitourinary adverse effects. Therefore, a planning study combining organ preserving surgery with three different innovative adjuvant radiotherapy approaches was performed. PATIENTS AND METHODS: A case of a 21-month-old boy with BP-RMS treated with polychemotherapy according to the CWS 2002-P protocol, prostatectomy, partial cystectomy, and adjuvant high dose rate brachytherapy (HDR-BT) was used to perform a planning study comparing HDR-BT with intensity-modulated radiotherapy (IMRT) and intensity-modulated proton therapy (IMPT) planning. RESULTS: All modalities provide good coverage of the target volume and spare critical normal tissues. Rectum doses could be reduced by 2/3 using IMPT and by 1/3 using BT compared to IMRT. In terms of sparing the pelvis growth plates, BT and IMPT are also superior to IMRT. CONCLUSION: All modalities provide good sparing of normal tissue. BT and IMPT are superior to IMRT with regard to doses on rectum and growth plates. BT is equivalent to IMPT in adequately selected tumors.

Treatment efficiency, outcome and surgical treatment problems in patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma: a report from the Cooperative Soft Tissue Sarcoma trial CWS-96.

BACKGROUND: To analyze the clinical course, treatment modalities, complications and outcome of patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma (BPRMS) treated on the CWS-96 trial. PROCEDURE: There were 85 patients with BPRMS enrolled and 63 patients with embryonal non-metastatic BPRMS were analyzed. Fifty-six patients received neoadjuvant chemotherapy and response was assessed radiographically after 9 weeks. Local therapy with radiation and or surgery was performed based on age, tumor size, and response. Patients were treated with adjuvant chemotherapy following local control. RESULTS: Patient's age ranged from 0 to 16 years with a median follow up of 5.3 years. Eighty nine percent of the patients had IRS group III disease. The 5-year overall survival (OS) for the whole group was 76.3 ± 5.6% and the 5-year event-free survival (EFS) 69.8 ± 6.2%. Seventeen patients underwent preoperative radiochemotherapy followed by tumor resection (5-year-OS: 87.8 ± 8.1%). Eight patients were treated with solely radiochemotherapy (87.5 ± 11.7%). Twenty-five patients received chemotherapy and tumor resection (OS: 83.6 ± 7.5%). Thirteen patients underwent incomplete tumor resection and were treated with radiochemotherapy postoperatively (OS: 39.9 ± 14.8%, P < 0.05 vs. other groups). CONCLUSIONS: Local therapy is an important factor for prognosis of localized embryonal BPRMS. Inadequate primary or secondary surgery compromises the outcome and should be avoided. Radiotherapy alone, complete surgical tumor resection or combined preoperative radiotherapy with surgical resection lead to similar good local control rates and prognosis.

Rhabdomyosarcoma in 8 horses.

This multi-institutional report describes 8 cases of rhabdomyosarcoma in horses. Four neoplasms were in the tongue and other areas of the mouth or head, 2 were in the abdominal wall, and 1 each was in right shoulder muscles and heart. Four rhabdomyosarcomas that were less than 10 cm in diameter were treated by surgical excision or radiation with no recurrence. Two neoplasms greater than 10 cm in diameter in the abdominal wall and the right shoulder were considered inoperable and led to decisions to euthanize the horses. Two neoplasms were incidental findings at necropsy. All the neoplasms were classified as embryonal except for 1 pleomorphic rhabdomyosarcoma. These 8 cases were evaluated with 9 published case reports of equine rhabdomyosarcoma. For all cases, the most common sites were limb muscles (5/17) and tongue (4/17). Metastasis was reported in 4 of the previously published cases; none was found in this study.

DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Recently, we demonstrated the overexpression of both DNA methyltransferase 3A (DNMT3A) and 3B (DNMT3B) in RMS tumour biopsies and cell lines compared to normal skeletal muscle. Radiotherapy may often fail due to the abnormal expression of some molecules able to drive resistance mechanisms. The aim of this study was to analyse the involvement of DNMT3A and DNMT3B in radioresistance in RMS. RNA interference experiments against DNMT3A/3B were performed in embryonal RMS cells, upon ionizing radiation (IR) exposure and the effects of the combined treatment on RMS cells were analysed. DNMT3A and DNMT3B knocking down increased the sensitivity of RMS cells to IR, as indicated by the drastic decrease of colony formation ability. Interestingly, DNMT3A/3B act in two different ways: DNMT3A silencing triggers the cellular senescence program by up-regulating p16 and p21, whilst DNMT3B depletion induces significant DNA damage and impairs the DNA repair machinery (ATM, DNA-PKcs and Rad51 reduction). Our findings demonstrate for the first time that DNMT3A and DNMT3B overexpression may contribute to radiotherapy failure, and their inhibition might be a promising radiosensitizing strategy, mainly in the treatment of patients with metastatic or recurrent RMS tumours.

Disease Control and Patterns of Failure After Proton Beam Therapy for Rhabdomyosarcoma.

PURPOSE: Pediatric patients with rhabdomyosarcoma (RMS) are treated with multimodal therapy, often with radiation therapy (RT) as part of local therapy. We report on the efficacy and patterns of failure after proton beam therapy (PBT) for RMS. METHODS AND MATERIALS: Between January 2006 and February 2017, patients with RMS were enrolled in a prospective institutional review board-approved registry protocol for pediatric patients undergoing PBT. Demographics, clinical characteristics, and treatment related outcomes were reviewed. RESULTS: Ninety-four RMS patients were treated with a combination of chemotherapy (CT) and PBT. The majority of patients had head and neck (49%) and genitourinary (30%) primaries. Median tumor size was 4.1 cm (range, 1.0-16.5 cm); 33 patients (35%) had primary tumors >5 cm. Median cyclophosphamide equivalent dose was 14.4 g/m2 (range, 0-30.8 g/m2). Median time from CT initiation to RT initiation was 13 weeks (range, 1-58 weeks). With median follow-up of 4 years, 4-year overall survival (OS) was 71%, and 4-year progression-free survival (PFS) was 63%. Thirty patients (32%) experienced relapse (13% with local failure [LF]). Four-year local control (LC) was 85% overall; 4-year LC rates were 100% for low-risk, 85% for intermediate-risk, and 55% for high-risk patients (P = .02). Tumor size predicted LC (P = .007), with 7% versus 33% LF rate by tumor size (≤5 cm vs >5 cm). Delayed RT delivery (≥13 weeks from initiation of CT) predicted worse LC (P = .01). Increased tumor size predicted both inferior PFS (P = .02) and OS (P = .01). Delayed RT delivery predicted both inferior PFS (P = .04) and OS (P = .03). CONCLUSIONS: PBT provides LC comparable to prior studies using photon RT. Inferior LC, PFS, and OS rates were observed for patients with larger tumors and those treated with delayed RT. This finding supports ongoing prospective efforts to dose-escalate treatment of tumors >5 cm; however, these data call into question the optimal timing of local therapy, particularly for patients treated with reduced-dose cyclophosphamide.

Dose-Effect Analysis of Early Changes in Orbital Bone Morphology After Radiation Therapy for Rhabdomyosarcoma.

PURPOSE: In survivors of orbital embryonal rhabdomyosarcoma (ERMS), late effects include facial deformation and asymmetry. We sought to quantify orbital asymmetry in ERMS survivors and characterize the dose effect of radiation to the orbital bones. METHODS AND MATERIALS: We evaluated the most recent follow-up magnetic resonance imaging (MRI) in 17 children (≤21 years old) with stage 1 group III orbital ERMS treated with proton therapy between 2007 and 2018. For all patients, the orbital socket volumes were calculated and compared with the contralateral, unirradiated orbital socket. Patient age, orbital tumor quadrant, and the radiation dose delivered to the major orbital bones (maxillary, frontal, and zygomatic bones) were recorded and correlated with the orbital socket volume difference. RESULTS: The mean age at diagnosis was 5.4 years old (range, 1.1-9.7 years). All patients received a prescription dose of 45 GyRBE. The mean time interval between radiation and MRI was 2.9 years (range, 0.8-3.2 years). The mean age at most recent MRI was 8.4 years (range, 2.3-12.9 years). In 16 of 17 patients, the volume of the ipsilateral orbit was significantly smaller than the contralateral orbit on follow-up MRI (P ≤ .0001). In one patient with nonviable tumor in situ, the irradiated orbit was larger. The volume difference increased with follow-up time and did not correlate with age at treatment or age at MRI. A dose >40 GyRBE to all bones of the orbital rim was associated with a significant decrease in orbital volume (P < .05), but an isolated dose of >40 GyRBE to either the frontal, maxillary, or zygomatic bone was not. CONCLUSIONS: Despite the dosimetric precision of proton therapy, orbital asymmetry will develop after >40 GyRBE to multiple bones of the orbital rim. These data may be used to guide treatment planning and counsel patients on expected cosmesis.

Perioperative intensity-modulated brachytherapy for refractory orbital rhabdomyosarcomas in children.

PURPOSE: To evaluate the feasibility and toxicity of perioperative intensity-modulated brachytherapy (IMBT) as well as functional outcome in children with therapy-refractory orbital rhabdomyosarcomas (RMS). PATIENTS AND METHODS: Since 1993, children with therapy-refractory orbital RMS have been treated by a multidisciplinary approach combining function-preserving, mostly R1 tumor resection and perioperative IMBT at the University Hospital of Schleswig-Holstein, Germany. All children with orbital RMS, who were enrolled in this multidisciplinary treatment protocol between 1993 and 2002, were prospectively assessed with respect to evaluation of side effects and functional outcome. RESULTS: Ten children (six boys, four girls) were included. Median age was 6.5 years (range, 1-19 years) at the beginning of our treatment and 6.0 years (range 1-17 years) at diagnosis. All children were in Intergroup Rhabdomyosarcoma Study Group (IRSG) group III and had embryonal subtype. Estimated 5-year survival was 62% +/- 18%. There was no radiation-related toxicity grade 3 or 4 observed. The eyes were primarily preserved in all cases. One child underwent secondary orbital exenteration 10 months after completion of IMBT. Visual acuity could be preserved apart from one child developing significant visual deterioration due to radiation cataract grade 2. The cosmetic results were good or very good in eight and moderate in two children. Four children died of their disease. CONCLUSION: This interdisciplinary, individually tailored and function-preserving treatment procedure has proven to be a well-tolerated therapeutic option in cases with refractory orbital RMS. It provides both improvement of local tumor control and quality of life.

Nerve-sparing radical vaginectomy: two case reports and description of the surgical technique.

BACKGROUND: Radical vaginectomy (RV) is related to significant bladder dysfunctions. We describe 2 cases of RV with nerve-sparing technique (NSRV). CASE REPORTS: A 58-year-old woman with a diagnosis of locally advanced cervical cancer underwent neoadjuvant chemotherapy with local and nodal progression of disease. The patient underwent NS radical hysterectomy plus NSRV, with prompt recovery of bladder function. A 14-year-old adolescent girl with a diagnosis of recurrent embryonal-botryoidal rhabdomyosarcoma was referred to us. She underwent 6 courses of chemotherapy with persistent disease. She then underwent NSRV. Two months after the surgical procedure, she was able to void the bladder. CONCLUSIONS: These are the first 2 cases of NSRV reported in literature. This new surgical technique is feasible, with prompt recovery of bladder function.

Cementless bilateral total hip arthroplasty in a patient with a history of pelvic irradiation for sarcoma botryoides.

OBJECTIVE: To report a case of bilateral secondary coxarthrosis in a patient with a history of pelvic irradiation for sarcoma botryoides. CLINICAL PRESENTATION AND INTERVENTION: The patient had surgery and radiation therapy for sarcoma botryoides when she was 18 months old. Left and right cementless total hip arthroplasties were performed at the age of 36 and 40 years, respectively. Harris hip scores improved from 28.4 to 93 on the left hip after 84 months of follow-up and from 29.5 to 91.3 on the right hip after 38 months of follow-up. CONCLUSION: Cementless total hip arthroplasty may be considered for irradiated hips, if radiation damage in bone has been stable for a long period of time.

NRF2 orchestrates the redox regulation induced by radiation therapy, sustaining embryonal and alveolar rhabdomyosarcoma cells radioresistance.

PURPOSE: Tumor cells generally exhibit higher levels of reactive oxygen species (ROS), however, when stressed, tumor cells can undergo a process of 'Redox Resetting' to acquire a new redox balance with stronger antioxidant systems that enable cancer cells to become resistant to radiation therapy (RT). Here, we describe how RT affects the oxidant/antioxidant balance in human embryonal (RD) and alveolar (RH30) rhabdomyosarcoma (RMS) cell lines, investigating on the molecular mechanisms involved. METHODS: Radiations were delivered using an x-6 MV photon linear accelerator and their effects were assessed by vitality and clonogenic assays. The expression of specific antioxidant-enzymes, such as Superoxide Dismutases (SODs), Catalase (CAT) and Glutathione Peroxidases 4 (GPx4), miRNAs (miR-22, -126, -210, -375, -146a, -34a) and the transcription factor NRF2 was analyzed by quantitative polymerase chain reaction (q-PCR) and western blotting. RNA interference experiments were performed to evaluate the role of NRF2. RESULTS: Doses of RT higher than 2 Gy significantly affected RMS clonogenic ability by increasing ROS production. RMS rapidly and efficiently brought back ROS levels by up-regulating the gene expression of antioxidant enzymes, miRNAs as well as of NRF2. Silencing of NRF2 restrained the RMS ability to counteract RT-induced ROS accumulation, antioxidant enzyme and miRNA expression and was able to increase the abundance of γ-H2AX, a biomarker of DNA damage, in RT-treated cells. CONCLUSIONS: Taken together, our data suggest the strategic role of oxidant/antioxidant balance in restraining the therapeutic efficiency of RT in RMS treatment and identify NRF2 as a new potential molecular target whose inhibition might represent a novel radiosensitizing therapeutic strategy for RMS clinical management.