Severe labile hypertension in a patient with catecholamine-secreting neuroblastoma: a case report.

Neuroblastoma is a common pediatric tumor arising from the post-ganglionic sympathetic nervous system and is associated with hypertension in 25% of cases. We describe an unusual case of labile, multi-drug resistant hypertension associated with chemotherapy administration for neuroblastoma and provide potential management strategies in this scenario. We report the case of a 4-year-old female with a history of headaches who presented with hypertensive emergency and evidence of end-organ damage, including posterior reversible encephalopathy syndrome, acute cerebral infarct, concentric left ventricular hypertrophy, and growth failure secondary to a large, abdominal catecholamine-secreting neuroblastoma, which compressed the kidney vasculature and inferior vena cava. She was classified as intermediate risk according to Children's Oncology Group criteria and underwent chemotherapy, complicated by labile hypertension, followed by surgical resection. Vigilance in monitoring and treatment of hypertension is recommended during chemotherapy for neuroblastoma due to the potential catecholamine release in the setting of tumor lysis.

Patients with completely resected nongenitourinary low-risk embryonal rhabdomyosarcoma are candidates for reduced duration low-intensity chemotherapy.

BACKGROUND: The survival of patients with localized embryonal rhabdomyosarcoma (RMS) completely resected at diagnosis is greater than 90%. Most patients have paratesticular, uterine, or vaginal RMS, limiting specific analyses of RMS localized in other anatomic regions. This international study was conducted to define the outcome for completely resected embryonal RMS at sites other than paratesticular, uterine, or vaginal primary sites. METHODS: A total of 113 patients aged 0-18 years were identified who were enrolled from January 1995 to December 2016 in Children's Oncology Group (COG) (64 patients) and European protocols (49). Genitourinary nonbladder and prostate RMS were excluded. The recommended chemotherapy was vincristine and actinomycin-D (VA) for 24 weeks or ifosfamide plus VA in the European protocols and VA for 48 weeks or VA plus cyclophosphamide in the COG protocols. RESULTS: The most common primary sites were nonparameningeal head and neck (40.7%), other (23.9%), and extremities (20.4%). In the COG studies, 42% of patients received VA and 58% VA plus cyclophosphamide. In Europe, 53% received VA and 47% ifosfamide plus VA. With a median follow-up of 97.5 months, the 5-year progression-free and overall survival was 80.0% (71.2%-86.4%) and 92.5% (85.6%-96.2%), respectively, without significant differences between chemotherapy regimens. Tumor size (< or >5 cm) significantly influenced overall survival: 96.2% (88.6%-98.8%) vs. 80.6% (59.5%-91.4%), respectively (p = .01). CONCLUSIONS: Survival of patients with nonalveolar RMS completely resected at diagnosis is excellent among tumors arising from nonparatesticular, uterine, and vaginal sites, and patients may be treated successfully with low-intensity chemotherapy. To reduce the burden of treatment, VA for 24 weeks may be considered in children with tumors <5 cm.

CRISPR editing of the GLI1 first intron abrogates GLI1 expression and differentially alters lineage commitment.

GLI1 is one of three GLI family transcription factors that mediate Sonic Hedgehog signaling, which plays a role in development and cell differentiation. GLI1 forms a positive feedback loop with GLI2 and likely with itself. To determine the impact of GLI1 and its intronic regulatory locus on this transcriptional loop and human stem cell differentiation, we deleted the region containing six GLI binding sites in the human GLI1 intron using CRISPR/Cas9 editing to produce H1 human embryonic stem cell (hESC) GLI1-edited clones. Editing out this intronic region, without removing the entire GLI1 gene, allowed us to study the effects of this highly complex region, which binds transcription factors in a variety of cells. The roles of GLI1 in human ESC differentiation were investigated by comparing RNA sequencing, quantitative-real time PCR (q-rtPCR), and functional assays. Editing this region resulted in GLI1 transcriptional knockdown, delayed neural commitment, and inhibition of endodermal and mesodermal differentiation during spontaneous and directed differentiation experiments. We found a delay in the onset of early osteogenic markers, a reduction in the hematopoietic potential to form granulocyte units, and a decrease in cancer-related gene expression. Furthermore, inhibition of GLI1 via antagonist GANT-61 had similar in vitro effects. These results indicate that the GLI1 intronic region is critical for the feedback loop and that GLI1 has lineage-specific effects on hESC differentiation. Our work is the first study to document the extent of GLI1 abrogation on early stages of human development and to show that GLI1 transcription can be altered in a therapeutically useful way.

Clinical group and modified TNM stage for rhabdomyosarcoma: A review from the Children's Oncology Group.

The Children's Oncology Group (COG) uses Clinical Group (CG) and modified Tumor Node Metastasis (TNM) stage to classify rhabdomyosarcoma (RMS). CG is based on surgicopathologic findings and is determined after the completion of initial surgical procedure(s) but prior to chemotherapy and/or radiation therapy. The modified TNM stage is based on clinical and radiographic findings and is assigned prior to any treatment. These systems have evolved over several decades. We review the history, evolution, and rationale behind the current CG and modified TNM classification systems used by COG for RMS. Data from the seven most recently completed and reported frontline COG trials (D9602, D9802, D9803, ARST0331, ARST0431, ARST0531, ARST08P1) were analyzed, and confirm that CG and modified TNM stage remain relevant and useful for predicting prognosis in RMS. We propose updates based on recent data and discuss factors warranting future study to further optimize these classification systems.

Suboptimal outcome for patients with biliary rhabdomyosarcoma treated on low-risk clinical trials: A report from the Children's Oncology Group.

BACKGROUND: Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The biliary tract is classified as a favorable primary site. Therefore, patients with localized biliary RMS were included in two consecutive low-risk studies, D9602 and ARST0331, by the Children's Oncology Group (COG). The outcome for these patients treated with low-risk therapy has not been reported. PROCEDURE: Patients with biliary RMS enrolled on COG low-risk trials D9602 or ARST0331 were analyzed. All patients received systemic chemotherapy and those with Group II (microscopic residual) or Group III (macroscopic residual) disease received 36-50.4 Gy adjuvant radiotherapy (RT). Delayed primary excision (DPE) was allowed on both studies. RESULTS: Seventeen patients with biliary RMS were treated on D9602 (n = 7) or ARST0331 (n = 10). Median age was 3.5 years (range 1.7-10.3). Ten (59%) patients had tumors >5 cm and 14 (82%) had Group III disease. Fifteen (88%) patients received RT. The 5-year event-free survival (EFS) and overall survival (OS) were 70.6% (95% confidence interval [CI]: 46.9-94.3%) and 76.5% (95% CI: 54.6-98.4%), respectively. The majority of patients (80%) who received RT did not have disease recurrence while both patients who did not receive RT had local relapse. Five (36%) of 14 patients with Group III disease underwent DPE; two experienced a local relapse. In the nine patients without DPE, two developed local relapse. CONCLUSIONS: Patients with localized biliary RMS treated on low-risk studies had suboptimal outcomes. These patients may benefit from therapy on intermediate-risk studies.

Impact of local control and surgical lymph node evaluation in localized paratesticular rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

Paratesticular rhabdomyosarcoma (PT-RMS) carries a favorable prognosis, but questions persist regarding optimal management. Our goal was to determine the importance of primary tumor resection and surgical assessment of retroperitoneal lymph nodes during staging in patients with PT-RMS. We analyzed patients with localized PT-RMS enrolled onto one of four Children's Oncology Group studies (D9602, ARST0331, D9803 or ARST0531). Surgical resection of the primary tumor prior to chemotherapy and radiotherapy was encouraged when possible with retroperitoneal lymph node dissection (RPLND) recommended for patients ≥10 years of age. Among 279 patients (median 8.1 years old), most tumors were resected with negative margins (78.5%) and most patients did not have radiographic enlargement of regional lymph nodes (90.3%). In patients older than 10 years, imaging alone will miss over 51.5% of nodal disease. Five-year event-free survival (EFS) was 92.0% (95% CI 88.4%-95.6%). Sampling ≥7 to 12 retroperitoneal lymph nodes appeared optimal for detecting positive nodes; while there was a trend toward improved EFS among those undergoing template RPLND, this was not statistically significant (P = .068). Age (P = .28), N-stage (P = .39), T-stage (P = .11) and pathologic node involvement (P = .53) were not associated with overall survival. However, older age and larger tumor size had an additive impact on EFS (P = .027) though not overall survival (P = .13). In conclusion, outcomes for patients with PT-RMS are excellent. Reliance on imaging to detect nodal involvement will miss pathologic node involvement and may result in undertreatment. Surgical nodal staging requires at least 7 to 12 nodes to accurately identify patients with regional nodal disease.

Sonic hedgehog regulation of Foxf2 promotes cranial neural crest mesenchyme proliferation and is disrupted in cleft lip morphogenesis.

Cleft lip is one of the most common human birth defects, yet our understanding of the mechanisms that regulate lip morphogenesis is limited. Here, we show in mice that sonic hedgehog (Shh)-induced proliferation of cranial neural crest cell (cNCC) mesenchyme is required for upper lip closure. Gene expression profiling revealed a subset of Forkhead box (Fox) genes that are regulated by Shh signaling during lip morphogenesis. During cleft pathogenesis, reduced proliferation in the medial nasal process mesenchyme paralleled the domain of reduced Foxf2 and Gli1 expression. SHH ligand induction of Foxf2 expression was dependent upon Shh pathway effectors in cNCCs, while a functional GLI-binding site was identified downstream of Foxf2 Consistent with the cellular mechanism demonstrated for cleft lip pathogenesis, we found that either SHH ligand addition or FOXF2 overexpression is sufficient to induce cNCC proliferation. Finally, analysis of a large multi-ethnic human population with cleft lip identified clusters of single-nucleotide polymorphisms in FOXF2 These data suggest that direct targeting of Foxf2 by Shh signaling drives cNCC mesenchyme proliferation during upper lip morphogenesis, and that disruption of this sequence results in cleft lip.

Risk-based treatment for patients with first relapse or progression of rhabdomyosarcoma: A report from the Children's Oncology Group.

BACKGROUND: The purpose of this study was to evaluate risk and response-based multi-agent therapy for patients with rhabdomyosarcoma (RMS) at first relapse. METHODS: Patients with RMS and measurable disease at first relapse with unfavorable-risk (UR) features were randomized to a 6-week phase 2 window with 1 of 2 treatment schedules of irinotecan with vincristine (VI) (previously reported). Those with at least a partial response to VI continued to receive 44 weeks of multi-agent chemotherapy including the assigned VI regimen. UR patients who did not have measurable disease at study entry, did not have a radiographic response after the VI window, or declined VI window therapy received 31 weeks of multi-agent chemotherapy including tirapazamine (TPZ) at weeks 1, 4, 10, 19, and 28. Favorable-risk (FR) patients received 31 weeks of the same multi-agent chemotherapy without VI and TPZ. RESULTS: One hundred thirty-six eligible patients were enrolled. For 61 patients not responding to VI, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 17% (95% confidence interval [CI], 8%-29%) and 24% (13%-37%), respectively. For 30 UR patients not treated with VI, the 3-year FFS and OS rates were 21% (8%-37%) and 39% (20%-57%), respectively. FR patients had 3-year FFS and OS rates of 79% (47%-93%) and 84% (50%-96%), respectively. There were no unexpected toxicities. CONCLUSIONS: Patients with UR RMS at first relapse or disease progression have a poor prognosis when they are treated with this multi-agent therapy, whereas FR patients have a higher chance of being cured with second-line therapy.

Prolonged response to sorafenib in a patient with refractory metastatic osteosarcoma and a somatic PDGFRA D846V mutation.

Outcome for patients with metastatic or recurrent/refractory osteosarcoma remains poor. Responses to sorafenib, a multikinase inhibitor, have been seen in recurrent/refractory osteosarcoma, although specific biomarkers of response have not been described. We report a partial response in a 7-year-old with refractory osteosarcoma treated with sorafenib 200 mg twice daily. Toxicities included Common Terminology Criteria for Adverse Events Grade 2 skin toxicities and growth suppression. After 51 months of therapy, he suffered a recurrence. Tumor sequencing later revealed a PDGFRA D846V mutation that was not identified in the relapse specimen. This case demonstrates prolonged partial response to sorafenib and provides a potential biomarker for response.

Reduction of cyclophosphamide dose for patients with subset 2 low-risk rhabdomyosarcoma is associated with an increased risk of recurrence: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

BACKGROUND: Failure-free survival (FFS) and overall survival (OS) rates were found to improve on Intergroup Rhabdomyosarcoma Study (IRS) IV (IRS-IV) compared with IRS-III for patients with subset 2 (IRS stage 1, group III nonorbit or stage 3, group I/II) low-risk embryonal rhabdomyosarcoma with the addition of cyclophosphamide (total cumulative cyclophosphamide dose of 26.4 g/m2 ) to the combination of vincristine and dactinomycin (VAC). The goal of Children's Oncology Group ARST0331 for subset 2 low-risk patients was to reduce the total cumulative cyclophosphamide dose without compromising FFS. METHODS: Therapy included 4 cycles of VAC (total cumulative cyclophosphamide dose of 4.8 g/m2 ) followed by 12 cycles of vincristine and dactinomycin over 46 weeks. Patients with group II or III tumors received radiotherapy, except for girls with group III vaginal tumors who enrolled before September 2009 and achieved a complete response with chemotherapy with or without delayed surgical resection. RESULTS: Among 66 eligible patients who were followed for a median of 3.5 years, there were 20 failures versus 10.53 expected failures. The estimated 3-year FFS and OS rates were 70% (95% confidence interval [95% CI], 57%-80%) and 92% (95% CI, 83%-97%), respectively. The estimated 3-year FFS rate was 57% (95% CI, 33%-75%) for girls with subset 2 genital tract embryonal rhabdomyosarcoma (21 patients) and 77% (95% CI, 61%-87%) for all other subset 2 patients (45 patients) (P = .02). CONCLUSIONS: The authors observed suboptimal FFS among patients with subset 2 low-risk rhabdomyosarcoma using reduced total cyclophosphamide. Eliminating radiotherapy for girls with group III vaginal tumors in combination with reduced total cyclophosphamide appeared to contribute to the suboptimal outcome. Cancer 2017;123:2368-2375. © 2017 American Cancer Society.

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

Serologic response and clinical efficacy of influenza vaccination in children and young adults on chemotherapy for cancer.

BACKGROUND: Influenza is a health risk to children receiving chemotherapy for cancer. An absolute lymphocyte count (ALC) >1,000 cells/mm(3) has been associated with the ability to produce an immune response to influenza vaccine during chemotherapy. However, clinical efficacy of influenza vaccination during chemotherapy remains unclear. PROCEDURE: We conducted a prospective cohort study in children receiving chemotherapy for cancer during two consecutive influenza seasons. Assessments of immune cells and serologic response were measured immediately before and after receiving influenza vaccine. Patients were monitored for influenza or influenza-like illness (ILI). RESULTS: Two hundred fifty-nine patients were studied over 2 years. The seroresponse rate was 62% (98/157). The median ALC at vaccination was higher in seroresponders than nonresponders, 854 cells/mm(3) versus 602 cells/mm(3) , respectively (P < 0.036). Univariate analysis showed that patients with an ALC <1,000 cells/mm(3) at the time of vaccination were twice as likely to be sero-nonresponders (P < 0.02, OR = 2.4, 95% CI: 1.1-5.0). Twelve percent (31/259) of patients developed influenza, of whom all had fever at presentation, 26% (8/31) required hospitalization, and 81% (25/31) had chemotherapy delays. No deaths were associated with influenza infection. The proportion of patients with influenza was not different between seroresponders and nonresponders. CONCLUSIONS: Influenza infection following immunization remains a source of morbidity in children undergoing chemotherapy. Lymphopenia at vaccination predicted sero-nonresponse. Seroresponse was not associated with a decreased frequency of influenza infection or ILI when compared to sero-nonresponders, suggesting clinical effectiveness of vaccination is likely multifactorial. Further investigation into the efficacy of the influenza vaccine is needed to refine immunization recommendations.

Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group.

BACKGROUND: Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) is of prognostic and therapeutic importance. Criteria for classifying these entities evolved significantly from 1995 to 2013. ARMS is associated with inferior outcome; therefore, patients with alveolar histology have generally been excluded from low-risk therapy. However, patients with ARMS and low-risk stage and group (Stage 1, Group I/II/orbit III; or Stage 2/3, Group I/II) were eligible for the Children's Oncology Group (COG) low-risk rhabdomyosarcoma (RMS) study D9602 from 1997 to 1999. The characteristics and outcomes of these patients have not been previously reported, and the histology of these cases has not been reviewed using current criteria. PROCEDURE: We re-reviewed cases that were classified as ARMS on D9602 using current histologic criteria, determined PAX3/PAX7-FOXO1 fusion status, and compared these data with outcome for this unique group of patients. RESULTS: Thirty-eight patients with ARMS were enrolled onto D9602. Only one-third of cases with slides available for re-review (11/33) remained classified as ARMS by current histologic criteria. Most cases were reclassified as ERMS (17/33, 51.5%). Cases that remained classified as ARMS were typically fusion-positive (8/11, 73%), therefore current classification results in a similar rate of fusion-positive ARMS for all clinical risk groups. In conjunction with data from COG intermediate-risk treatment protocol D9803, our data demonstrate excellent outcomes for fusion-negative ARMS with otherwise low-risk clinical features. CONCLUSIONS: Patients with fusion-positive RMS with low-risk clinical features should be classified and treated as intermediate risk, while patients with fusion-negative ARMS could be appropriately treated with reduced intensity therapy.

Treatment of neuroblastoma in congenital central hypoventilation syndrome with a PHOX2B polyalanine repeat expansion mutation: New twist on a neurocristopathy syndrome.

Neuroblastoma in patients with congenital central hypoventilation syndrome (CCHS) as part of a neurocristopathy syndrome is a rare finding and has only been associated with paired-like homeobox 2b (PHOX2B) non-polyalanine-repeat-expansion mutations. To the best of our knowledge, we report the first case of a child with CCHS and Hirschsprung disease who had a PHOX2B polyalanine-repeat-expansion mutation (PARM) (genotype 20/33) and developed high-risk neuroblastoma. We further describe his treatment including chemotherapy and therapeutic I(131) -metaiodobenzylguanidine. This case highlights the need to consider neuroblastoma in patients with CCHS and the longest PHOX2B PARMs and to individualize treatment based on co-morbidities.

Irinotecan and temozolomide for treatment of neuroblastoma in a patient with renal failure on hemodialysis.

Renal failure is a rare complication of neuroblastoma or its therapy. To our knowledge, no reports describe treatment of children with neuroblastoma with chemotherapy in the setting of renal failure and maintenance hemodialysis. We report a 6-year-old child with high-risk neuroblastoma who developed renal failure requiring long-term hemodialysis. She was subsequently treated with 13 cycles of intravenous irinotecan 20 mg/m(2)/day and oral temozolomide 100 mg/m(2)/day for 5 days before disease progression without any dose adjustments, transfusions, febrile neutropenia or diarrhea. This case demonstrates that irinotecan and temozolomide can be safely administered in children with renal failure requiring hemodialysis.

The significance of margins in pediatric Non-Rhabdomyosarcoma soft tissue sarcomas: Consensus on surgical margin definition harmonization from the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT).

BACKGROUND: Margin status following surgery in children, adolescents, and young adults with soft tissue sarcomas is controversial and has been defined differently by various specialties, with definitions changing over time and by cooperative group. The International Soft Tissue Sarcoma Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, European pediatric Soft Tissue sarcoma Study Group (EpSSG), and the European Cooperative Weichteilsarkom Studiengruppe (CWS) devoted to improving patient outcomes by pooling and mining cooperative group clinical trial data. METHODS: The INSTRuCT non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) working group aimed to develop international harmonized recommendations regarding surgical margin assessment and definitions in children and adolescents with soft tissue tumors. RESULTS AND CONCLUSION: This review addresses accepted principles and areas of controversy, including the perspectives of surgeons, pathologists, radiation oncologists, and pediatric oncologists, to develop a framework for building common guidelines for future research.

The treatment approach to pediatric non-rhabdomyosarcoma soft tissue sarcomas: a critical review from the INternational Soft Tissue SaRcoma ConsorTium.

The current article focuses on non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), the heterogeneous group of mesenchymal tumours different from rhabdomyosarcoma that may affect children and adolescents, with clinical behaviour varying from relatively benign to highly malignant. This review represents the effort of the international scientific paediatric community within the context of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT), a project founded by the leadership of three large cooperative groups - Children's Oncology Group, Cooperative Weichteilsarkom Studiengruppe and European paediatric Soft tissue sarcoma Study Group - with the main goal to pool expertise and resources on a broader international level in order to improve knowledge of soft tissue sarcomas of children, adolescents and young adults. This article describes the current standard treatment approach in NRSTS, with a focus on the controversies and challenges in the management of these tumours. Developing research projects and clinical protocols for NRSTS has always been challenging, supporting the need to develop international integrated prospective dedicated programs, including paediatric NRSTS experts together with the adult sarcoma community. INSTRuCT provides a unique mechanism to increase international collaboration by agreeing on a common language, developing consensus standards to guide diagnosis and treatment, comparing clinical trial results across cooperative groups, and through a shared data dictionary providing answers to questions that can only be addressed by a larger data set.

Local control and outcome in children with localized vaginal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma committee of the Children's Oncology Group.

BACKGROUND: The local control approach for girls with non-resected vaginal rhabdomyosarcoma (RMS) enrolled onto Intergroup RMS Study Group (IRSG)/Children's Oncology Group (COG) studies has differed from that used at other primary sites by delaying or eliminating radiotherapy (RT) based on response achieved with chemotherapy and delayed primary resection. PROCEDURES: We reviewed locoregional treatment and outcome for patients with localized RMS of the vagina on the two most recent COG low-risk RMS studies. RESULTS: Forty-one patients with localized vaginal RMS were enrolled: 25 onto D9602 and 16 onto Subset 2 of ARST0331. Only four of the 39 with non-resected tumors received RT. The 5-year cumulative incidence of local recurrence was 26% on D9602, and the 2-year cumulative incidence of local recurrence was 43% on ARST0331. Increased local failure rates appeared to correlate with chemotherapy regimens that incorporated lower cumulative doses of cyclophosphamide. Estimated 5-year and 2-year failure free survival rates were 70% (95% CI: 46%, 84%) on D9602 and 42% (95% CI: 11%, 70%) on ARST0331, respectively. CONCLUSIONS: To prevent local recurrence, we recommend a local control approach for patients with non-resected RMS of the vagina that is similar to that used for other primary sites and includes RT. We recognize that potential long-term effects of RT are sometimes unacceptable, especially for children less than 24 months of age. However, when making the decision to eliminate RT, the risk of local recurrence must be considered especially when using a chemotherapy regimen with a total cumulative cyclophosphamide dose of ≤ 4.8 g/m².

Survival of Patients With Non-Rhabdomyosarcoma Soft Tissue Sarcomas of the Head and Neck.

OBJECTIVE: To evaluate factors associated with overall survival (OS) of patients with non-rhabdomyosarcoma soft tissue sarcomas of the head and neck. STUDY DESIGN: Retrospective cohort study. METHODS: The National Cancer Database was queried for cases of non-rhabdomyosarcoma soft tissue sarcomas of the head and neck between 2004 and 2014. Cases were categorized according to the World Health Organization classification of soft tissue tumors. A multivariable Cox proportional hazards model was used to evaluate associations with OS. RESULTS: A total of 4,555 patients (63.6% male, 36.4% female, mean age 59.6 years) met inclusion criteria. The majority of tumors were classified as miscellaneous (35.9%), followed by vascular (20.1%), smooth muscle (13.5%), fibroblastic/myofibroblastic (12.1%), peripheral nerve (8.5%), adipocytic (7.4%), and undifferentiated (2.5%) sarcomas. The mean follow-up was 37.9 months, and overall mortality (MR) was 45.3%. The best prognosis was seen with fibroblastic/myofibroblastic sarcomas (MR = 20.6%, P < .001), whereas vascular sarcomas had the worst prognosis (MR = 67.6%, P < .001). Resection with clear margins had better OS than microscopically positive margins (hazard ratio [HR] = 1.43, P < .001) or grossly positive margins (HR = 2.97, P < .001). Radiation therapy was associated with better OS than no radiation (HR = 0.86, P = .001). CONCLUSION: Non-rhabdomyosarcoma soft tissue sarcomas of the head and neck are associated with significant mortality. OS differs based on histologic subcategorization. Resection of the primary tumor with clear margins demonstrates improved OS for all histologies, suggesting this modality remains the preferred primary treatment when feasible. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E500-E508, 2021.

GLI1 genotypes do not predict basal cell carcinoma risk: a case control study.

BACKGROUND: Susceptibility to basal cell carcinoma results from complex interactions between ultraviolet radiation exposure and genetic factors. The GLI1 oncogene is believed to play a role in the genesis of these tumors. We determined whether GLI1 polymorphisms were risk factors for developing basal cell carcinoma, either alone or in combination with patterns of past sun exposure, and whether there were functional differences among different GLI1 haplotypes. RESULTS: GLI1 genotypes at c.2798 and c.3298 from 201 basal cell carcinoma patients were compared to 201 age and sex-matched controls. Neither genotype nor haplotype frequencies differed between cases and controls. However, the odds of developing basal cell carcinoma on the trunk compared to the head/neck appeared somewhat lower with carriers of the c.3298GC than the CC genotype. There was no evidence for interactions between skin type, childhood sunburning, average adult sun exposure, adult sunbathing, or intermittency of sun exposure and GLI1 haplotype. Additionally, we found no significant differences in transcription activation or cell transforming ability among the four GLI1 haplotypes. CONCLUSION: These results suggest that different GLI1 genotypes alone or in combination with past sun exposure patterns as assessed in this study do not affect basal cell carcinoma risk.