Intraoperative radiotherapy for brain metastases: first-stage results of a single-arm, open-label, phase 2 trial.

OBJECTIVE: Focal stereotactic radiosurgery to the surgical cavity lowers local recurrence after resection of brain metastases (BM). To evaluate local control (LC) and brain disease control (BDC) after intraoperative radiotherapy (IORT) for resected BM. METHODS: Adult patients with completely resected single supratentorial BM were recruited and underwent IORT to the cavity with a prescribed dose of 18 Gy to 1 mm-depth. Primary endpoints were actuarial LC and BDC. Local failure (LF) and distant brain failure (DBF), with death as a competing risk, were estimated. Secondary endpoints were overall survival (OS) and incidence of radiation necrosis (RN). Simon's two-stage design was used and estimated an accrual of 10 patients for the first-stage analysis and a LC higher than 63% to proceed to second stage. We report the final analysis of the first stage. RESULTS: Between June 2019 to November 2020, 10 patients were accrued. Median clinical and imaging FU was 11.2 and 9.7 months, respectively. Median LC was not reached and median BDC was 5 months. The 6-month and 12-month LC was 87.5%. The 6-month and 12-month BDC was 39% and 13%, respectively. Incidence of LF at 6 and 12 months was 10% and of DBF at 6 and 12 months was 50% and 70%, respectively. Median OS was not reached. The 6-month and 12-month OS was 80%. One patient had asymptomatic RN. CONCLUSION: IORT for completely resected BM is associated with a potential high local control and low risk of RN, reaching the pre-specified criteria to proceed to second stage and warranting further studies.

Nuclear unphosphorylated STAT3 correlates with a worse prognosis in human glioblastoma.

Glioblastoma (GBM) is currently the most aggressive form of brain tumor identified, and STAT3 is known to play an important role in gliomagenesis. Moreover, while several studies have used pharmacological approaches to modulate STAT3 activity, the results have been contradictory. In this study, expressions of STAT3, pSTAT3 (Y705), and pSTAT3 (S727) were evaluated using immunohistochemistry assays of tissue microarrays containing non-neoplastic tissue (NN, n=12), grade II astrocytomas (n=33), grade III astrocytomas (n=12), and GBM (n=85) specimens. In GBM specimens, STAT3 was overexpressed and exhibited greater nuclear localization compared with lower grade astrocytomas and NN. Conversely, nuclear localization of pSTAT3 (Y705) and pSTAT3 (S727) exhibited a similar phenotype in both GBMs and NNs. MET was also detected as a non-canonical pathway marker for STAT3. For tumors with higher levels of STAT3 nuclear localization, and not pSTAT3 (Y705) and pSTAT3 (S727), these specimens exhibited increased levels of MET expression. Thus, a non-canonical pathway may mediate a proportion of the STAT3 that translocates to the nucleus. Moreover, tumors which exhibited greater nuclear localization of STAT3 corresponded with patients that presented with lower rates of recurrence-free survival and overall survival. In contrast, the phosphorylated forms of STAT3 did not correlate with patient survival. These findings suggest that phosphorylation-independent mechanisms may mediate the nuclear translocation and activation of STAT3. Further studies are needed to identify the mechanisms involved, especially those that provide targets to achieve efficient inhibition and control of GBM progression.

Local control after radiosurgery for brain metastases: predictive factors and implications for clinical decision.

BACKGROUND: To evaluate the local control of brain metastases (BM) in patients treated with stereotactic radiosurgery (SRS), correlate the outcome with treatment parameters and lesion characteristics, and define its implications for clinical decisions. METHODS: Between 2007 and 2012, 305 BM in 141 consecutive patients were treated with SRS. After exclusions, 216 BM in 100 patients were analyzed. Doses were grouped as follows: ≤15 Gy, 16-20 Gy, and ≥21 Gy. Sizes were classified as ≤10 mm and >10 mm. Local control (LC) and overall survival (OS) were estimated using the Kaplan-Meier method. Log-rank statistics were used to identify the prognostic factors affecting LC and OS. For multivariate analyses, a Cox proportional model was applied including all potentially significant variables reached on univariate analyses. RESULTS: Median age was 54 years (18-80). Median radiological follow-up of the lesions was 7 months (1-66). Median LC and the LC at 1 year were 22.3 months and 69.7%, respectively. On univariate analysis, tumor size, SRS dose, and previous whole brain irradiation (WBRT) were significant factors for LC. Patients with lesions >10 and ≤10 mm had an LC at 1 year of 58.6% and 79.1%, respectively (p = 0.008). In lesions receiving ≤15 Gy, 16-20 Gy, and ≥21 Gy, the 1-year LC rates were 39.6%, 71.7%, and 92.3%, respectively (p < 0.001). When WBRT was done previously, LC at 1 year was 57.9% compared with 78.4% for those who did not undergo WBRT (p = 0.004). On multivariate analysis, dose remained the single most powerful prognostic factor for LC. Median OS for all patients was 17 months, with no difference among the groups. CONCLUSIONS: Dose is the most important predictive factor for LC of BM. Doses below 16 Gy correlated with poor LC. The SRS dose as salvage treatment after previous WBRT should not be reduced unless there is a pressing reason to do so.

Natural history and surgical treatment of chordoma: a retrospective cohort study / História natural e tratamento cirúrgico de cordoma: um estudo retrospectivo de coorte

CONTEXT AND OBJECTIVE: Chordoma is a rare tumor with a high risk of locoregional recurrences. The aim of this study was analyze the long-term results from treating this pathological condition. DESIGN AND SETTING: Cohort study in a single hospital in São Paulo, Brazil. METHODS: This was a retrospective cohort study on 42 patients with chordoma who were treated at Hospital A. C. Camargo between 1980 and 2006. The hospital records were reviewed and a descriptive analysis was performed on the clinical-pathological variables. Survival curves were estimated using the Kaplan-Meier method and these were compared using the log-rank test. RESULTS: Nineteen patients were men and 23 were women. Twenty-five tumors (59.5%) were located in the sacrum, eleven (26.2%) in the skull base and six (14.3%) in the mobile spine. Surgery was performed on 28 patients (66.7%). The resection was considered to have negative margins in 14 cases and positive margins in 14 cases. The five-year overall survival (OS) was 45.4%. For surgical patients, the five-year OS was 64.3% (82.2% for negative margins and 51.9% for positive margins). In the inoperable group, OS was 37.7% at 24 months and 0% at five years. CONCLUSION: Complete resection is related to local control and definitively has a positive impact on long-term survival. .

CONTEXTO E OBJETIVO: Cordoma é um tumor raro e com alto risco de recidiva locorregional. O objetivo deste estudo foi analisar os resultados a longo prazo do tratamento dessa doença. TIPO DE ESTUDO E LOCAL: Estudo de coorte realizado em um único hospital em São Paulo, Brasil. MÉTODOS: Estudo de coorte retrospectivo com 42 pacientes com cordoma tratados de 1980 e 2006 no Hospital A. C. Camargo. Os prontuários foram revistos e foi realizada a análise descritiva das variáveis clínicas e patológicas. As curvas de sobrevida foram estimadas pelo método de Kaplan-Meier e a comparação entre elas, pelo teste de log-rank. RESULTADOS: Dezenove pacientes eram homens e 23, mulheres. Vinte e cinco tumores (59,5%) estavam localizados no sacro, 11 (26,2%) na base do crânio e 6 (14,3%), na coluna móvel. A cirurgia foi realizada em 28 pacientes (66,7%). A ressecção foi considerada como tendo margens negativas em 14 casos e margens comprometidas em 14 pacientes. A sobrevida global (SG) em 5 anos foi de 45,4%. Para os pacientes cirúrgicos, a SG em 5 anos foi de 64,3% (82,2% para as margens negativas e 51,9% de margens positivas). No grupo inoperável, a SG em 24 meses foi de 37,7% e 0% em 5 anos. CONCLUSÃO: A ressecção completa está relacionada com o controle local e, definitivamente, tem impacto positivo na sobrevida a longo prazo. .

Natural history and surgical treatment of chordoma: a retrospective cohort study.

CONTEXT AND OBJECTIVE: Chordoma is a rare tumor with a high risk of locoregional recurrences. The aim of this study was analyze the long-term results from treating this pathological condition. DESIGN AND SETTING: Cohort study in a single hospital in São Paulo, Brazil. METHODS: This was a retrospective cohort study on 42 patients with chordoma who were treated at Hospital A. C. Camargo between 1980 and 2006. The hospital records were reviewed and a descriptive analysis was performed on the clinical-pathological variables. Survival curves were estimated using the Kaplan-Meier method and these were compared using the log-rank test. RESULTS: Nineteen patients were men and 23 were women. Twenty-five tumors (59.5%) were located in the sacrum, eleven (26.2%) in the skull base and six (14.3%) in the mobile spine. Surgery was performed on 28 patients (66.7%). The resection was considered to have negative margins in 14 cases and positive margins in 14 cases. The five-year overall survival (OS) was 45.4%. For surgical patients, the five-year OS was 64.3% (82.2% for negative margins and 51.9% for positive margins). In the inoperable group, OS was 37.7% at 24 months and 0% at five years. CONCLUSION: Complete resection is related to local control and definitively has a positive impact on long-term survival.

Regulation of stress-inducible phosphoprotein 1 nuclear retention by protein inhibitor of activated STAT PIAS1.

Stress-inducible phosphoprotein 1 (STI1), a cochaperone for Hsp90, has been shown to regulate multiple pathways in astrocytes, but its contributions to cellular stress responses are not fully understood. We show that in response to irradiation-mediated DNA damage stress STI1 accumulates in the nucleus of astrocytes. Also, STI1 haploinsufficiency decreases astrocyte survival after irradiation. Using yeast two-hybrid screenings we identified several nuclear proteins as STI1 interactors. Overexpression of one of these interactors, PIAS1, seems to be specifically involved in STI1 nuclear retention and in directing STI1 and Hsp90 to specific sub-nuclear regions. PIAS1 and STI1 co-immunoprecipitate and PIAS1 can function as an E3 SUMO ligase for STI. Using mass spectrometry we identified five SUMOylation sites in STI1. A STI1 mutant lacking these five sites is not SUMOylated, but still accumulates in the nucleus in response to increased expression of PIAS1, suggesting the possibility that a direct interaction with PIAS1 could be responsible for STI1 nuclear retention. To test this possibility, we mapped the interaction sites between PIAS1 and STI1 using yeast-two hybrid assays and surface plasmon resonance and found that a large domain in the N-terminal region of STI1 interacts with high affinity with amino acids 450-480 of PIAS1. Knockdown of PIAS1 in astrocytes impairs the accumulation of nuclear STI1 in response to irradiation. Moreover, a PIAS1 mutant lacking the STI1 binding site is unable to increase STI1 nuclear retention. Interestingly, in human glioblastoma multiforme PIAS1 expression is increased and we found a significant correlation between increased PIAS1 expression and STI1 nuclear localization. These experiments provide evidence that direct interaction between STI1 and PIAS1 is involved in the accumulation of nuclear STI1. This retention mechanism could facilitate nuclear chaperone activity.

Qual o papel da cirurgia de resgate em pacientes com recidiva de carcinoma epidermoide de seio maxilar? / Is there a role for salvage surgery of recurrent squamous cell carcinoma of the maxillary sinus?

Introdução: Há, na literatura, poucos artigos que abordam a cirurgia de resgate do carcinoma epidermoide do seio maxilar. Objetivo: Avaliar os resultados da cirurgia de resgate em pacientes com carcinoma epidermoide do seio maxilar. Método: Análise retrospectiva dos pacientes tratados em hospital oncológico terciário no período de janeiro de 1985 e dezembro de 2005. Resultados: Trinta e seis pacientes foram inclusos nesta série. A idade média era de 54,4 +/- 15,8 anos. A recidiva foi classificada como rT1 em 2 casos (5,5%), rT2 em 1 caso (2,8%), rT3 em 7 casos (19,4%) e rT4a em 26 casos (72.2%). O tratamentoprévio foi: cirurgia em 25 casos (69,44%), cirurgia e radioterapia adjuvante em 7 casos (19,44%), quimioterapia e radioterapia em 3 casos (8,33%) e radioterapia em 1 caso (2,78%). Ao final do seguimento, 11 pacientes (30,5%) não apresentavam doença em atividade, 22 haviam falecido por progressão da doença(61,0%) e 3 (8,3%) por outras causas. Foram significativos na análise univariada: tratamento prévio realizado, necessidade de abordagem craniofacial e a situação das margens cirúrgicas. A única variável significativa após a realização de análise multivariada foi a presença de margens livres (HR:3,03, 95% CI: 1,24 - 7,37, p=0,014). Conclusões: A cirurgia de resgate do carcinoma epidermoide do seio maxilar deve ser considerada, apresentando sobrevida em 5 anos de 40% nesta série. O fator significativo para sobrevida foi a presença de margens livres, enfatizando a necessidade de cirurgia oncologicamente adequada.

Introduction: There are few reports in literature about salvage surgery for maxillary sinus squamous cell carcinoma. Objective: Evaluation of surgical salvage in patients with recurrent squamous cell carcinoma of the maxillary sinus. Method: Retrospective analysis of patients treated at a single tertiary cancer center from January 1985 to December 2005. Results: Thirty-six patients were included. Mean age was 54.4 +/- 15.8 years. Recurrence was staged as rT1 in 2 patients (5,5%), rT2 in 1 patient (2,8%), rT3 in 7 patients (19,4%) and rT4a in 26 patients (72.2%). Previous treatment was: surgery in 25 patients (69,44%), surgery and radiotherapy in 7 patients (19,44%), chemotherapy in 3 patients (8,33%) and radiotherapy in 1 patient (2,78%). At the end of followup, 11 patients (30,5%) were alive with no evidence of disease, 22 were dead due to disease progression (61,0%) e 3 (8,3%) by other causes. Significant factors in univariate analysis were: previous treatment, craniofacial surgery and surgical margins status. In multivariate analysis, only compromised surgical margins remained significant (HR:3,03, 95% CI: 1,24 - 7,37, p=0,014). Conclusion: Salvage surgery should be considered, presenting a 40% Five-year survival rate. The impact of surgical margins status emphasizes the need for adequate oncological resection.

Complicações e fatores prognósticos em 175 ressecções craniofaciais de tumores malígnos da base anterior do crânio / Complications and prognostic factors in 175 craniofacial resections for malignant tumors of the anterior skull base

Introdução: A ressecção radical de tumores malígnos originários na base do crânio permanece um desafio, principalmente pelo risco de complicações graves. Embora vários fatores prognósticos estejam bem estabelecidos, a maioria das informações foi baseada em séries de casos retrospectivas e heterogêneas. Objetivo: analisar as taxas de complicação e os fatores prognósticos de uma série de pacientes submetidos à ressecção craniofacial de tumores malignos da base anterior do crânio na instituição. Pacientes e Método: Foram revisados os prontuários de 175 pacientes tratados entre 1955 e 1998 na instituição, incluindo pacientes com tumores envolvendo a base anterior do crânio que necessitaram exposição ou ressecção de dura-máter ou nasofaringe, independente de tratamento prévio. Resultados: Os tumores localizavam-se nos seios paranasais (75), órbita (58), cavidade nasal (26) e nasofaringe (16). A maioria era carcinomas espinocelulares (91 casos). As margens cirúrgicas foram negativas em 104 pacientes (60%), exíguas em 18 (10%) e positivas em 53 (30%). Complicações cirúrgicas ocorreram em 39 pacientes (22,3%), sendo infecção/deiscência em 12,1% dos casos e fístula liqüórica em 13,4%. A sobrevida atuarial em 5 anos foi de 57%. A análise multivariada usando o modelo de regressão de Cox identificou que a infiltração de dura-máter, margens positivas, tipo histológico, tratamento oncológico prévio e metástases cervicais foram fatores prognósticos independentes neste estudo. Conclusão: A ressecção craniofacial permite a remoção em bloco de diversos tumores da base anterior do crânio, com morbidade aceitável e significante impacto na sobrevida desses pacientes.

Background: Radical resection of malignant tumors arising in the skull base remains a challenge because of the risk of serious complications. Although several prognostic factors are well established, the available information is most based on heterogeneous retrospective case series. Objective: to analyze complication rates and prognostic factors in a large series of patients submitted to anterior craniofacial resection in a single institution. Materials and methods: We reviewed 175 patients treated from 1955 to 1998, including patients with involvement of the anterior skull base that required exposure or resection of the dura mater or the nasopharynx, independently of previous treatment. Results: The tumor sites were: paranasal sinuses (75), orbit (58), nasal cavity (26), and nasopharynx (16). Most tumors were squamous cell carcinomas (91 cases). Surgical margins were negative in 104 patients (60%), close in 18 (10%) and positive in 53 (30%). Surgical complications occurred in 39 patients (22.3%) (soft tissue infection/dehiscence, 12.1%; cerebrospinal fluid leak, 13.4%). The 5-year actuarial overall survival was 57%. Multivariate analysis using Cox regression model identified infiltration of dura mater, positive margins, histological type, prior oncological treatment, and neck metastasis as independent prognostic predictors. Conclusion: Craniofacial oncologic resection allows en bloc removal of several tumors of the anterior skull base, with acceptable morbidity and significant impact on survival of these patients.

Neurinoma do acústico em crianças sem associaçäo com neurofibromatose: relato de dois casos / Acoustic neuroma in children without association with neurofibromatosis: report of 2 cases

O neurinoma do acústico é o tumor da regiao ângulo ponto-cerebelar mais comum em indivíduos adultos, sendo raro em crianças sem neurofibromatose. A literatura consultada mostra 18 casos bem documentados de crianças portadoras de neurinomas do VII nervo craniano com idade inferior a 16 anos. Relatamos dois casos de crianças com idade de 9 a 15 anos, portadoras desta patologia e submetidas a tratamento cirúrgico. Nestes casos, assim como nos relatados na literatura, o quadro clínico é semelhante ao do adulto, em que o primeiro sintoma é a surdez progressiva, mais tardiamente seguindo-se sinais e sintomas relacionados à lesao expansiva na fossa posterior.

Distúrbios da coagulaçäo nos pacientes neurocirúrgicos: revisäo / Blood coagulation disorders in neurosurgical patients: a review

Esta revisao analisa as alteraçoes hemostáticas na prática neurocirúrgica e os possíveis métodos profiláticos e terapêuticos, já que os distúrbios da coagulaçao, particularmente a tendência à hipercoaguabilidade, podem ocorrer nos pacientes neurocirúrgicos, favorecendo a instalaçao dos fenômenos troboembólicos. O troboembolismo pulmonar é uma complicaçao grave realcionada à trombose venosa profunda e é responsável por 3 por cento dos óbitos em neurocirurgia. O estudo mais detalhado do mecanismo pelo qual alguns tumores do sistema nervoso central interferem nos sistemas de coagulaçao e fibrinólise poderia auxiliar no desenvolvimento de uma opçao terapêutica antineoplásica e, também, na profilaxia e tratamento das coagulopatias.