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1.
Neurology ; 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32631922

RESUMO

OBJECTIVE: This study aimed to develop and validate a nomogram to predict epilepsy in patients with radiation-induced brain necrosis (RN). METHODS: The nomogram was based on a retrospective analysis of 302 patients who were diagnosed with symptomatic RN from January 2005 to January 2016 in Sun Yat-sen Memorial Hospital using the Cox proportional hazards model. Discrimination of the nomogram was assessed by the concordance index (C-index) and the calibration curve. The results were internally validated using bootstrap resampling and externally validated using 128 RN patients from two additional hospitals. RESULTS: A total of 302 RN patients with a median follow-up of 3.43 years (IQR 2.54-5.45) were included in the training cohort, among which 65 (21.5%) developed symptomatic epilepsy during follow-up. Seven variables remained significant predictors of epilepsy after multivariable analyses: MRI lesion volume, creatine phosphokinase, the maximum radiation dose to the temporal lobe, RN treatment, history of hypertension and/or diabetes, gender, and total cholesterol level. In the validation cohort, twenty-eight out of 128 (21.9%) patients had epilepsy after RN within a median follow-up of 3.2 years. The nomogram showed comparable discrimination between the training and validation cohort (corrected C-index 0.76 [training] vs. 0.72 [95% CI 0.62-0.81; validation]). CONCLUSION: Our study developed an easily applied nomogram for the prediction of RN-related epilepsy in a large RN cohort. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a nomogram predicts post-RN epilepsy.

2.
JAMA Oncol ; 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32496550

RESUMO

Importance: Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited. Objective: To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT. Design, Setting, and Participants: FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019. Interventions: SRS and WBRT for small cell lung cancer brain metastases. Main Outcomes and Measures: Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score-matched analyses. Results: In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score-matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P < .001), without an improvement in overall survival (median, 6.5 months [95% CI, 5.5-8.0] for SRS vs 5.2 months [95% CI, 4.4-6.7] for WBRT; P = .003) or CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79). Multivariable analyses comparing SRS and WBRT, including subset analyses controlling for extracranial metastases and extracranial disease control status, demonstrated similar results. Conclusions and Relevance: Results of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP without a decrease in overall survival, are similar to those observed in settings in which SRS is already established.

3.
Semin Radiat Oncol ; 30(3): 218-222, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32503786

RESUMO

Treatment of recurrent gliomas is especially challenging, as many of these patients have previously been treated with extensive surgery, radiation, or systemic therapy. Due to this, the optimum therapy for patients with recurrent glioma is controversial, with widely variable practice patterns. In this opinion piece, a multidisciplinary panel of experts provides rationale for their treatment approach in a patient with recurrent glioma following subtotal resection with adjuvant chemoradiation for an anaplastic astrocytoma. In summary, the consensus of the panel was to recommend re-resection if possible with hypofractionated radiotherapy schedules, with re-irradiation and systemic therapy as directed by a multidisciplinary team through repeat analysis of the tumor specimen for an updated mutational burden.

4.
J Neurooncol ; 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32468331

RESUMO

PURPOSE: Whole brain radiation therapy (WBRT) remains an important component of treatment for patients with multiple brain metastases (BrM) but is associated with significant neurotoxicity and memory impairment. Although RTOG 0614 demonstrated that administration of memantine to patients receiving WBRT may reduce radiation-associated cognitive decline, prior literature has suggested that radiation oncologists are hesitant to prescribe memantine. We sought to assess the frequency of memantine prescription in patients managed with non-stereotactic, brain-directed radiation for BrM. METHODS: Patients > 65 years old with newly diagnosed BrM between 2007 and 2016 receiving non-stereotactic, brain-directed radiation (including WBRT) were identified using the SEER-Medicare database. Receipt of memantine with non-stereotactic, brain-directed radiation was defined as any Part D claim for memantine 30 days before or after initiation of non-stereotactic, brain-directed radiation. Clinical and demographic variables among patients who did and did not receive memantine were compared. RESULTS: Between 2007 and 2016, we identified 6220 patients with BrM receiving non-stereotactic, brain-directed radiation. Only 2.20% of patients (n = 137) received memantine with radiation. Rates were 1.10% versus 5.14% in the period preceding (2007-2013) and following (2014-2016) the publication of RTOG 0614, respectively. Overall utilization of memantine remained low across several clinical, demographic, and prognostic variables. CONCLUSION: Despite phase 3 evidence supporting memantine utilization among patients receiving WBRT, our population-based study indicates that rates of memantine prescription are strikingly low, although memantine utilization seems to be increasing since publication of RTOG 0614. Further investigation is needed to identify provider and practice-related barriers preventing incorporation of memantine into management paradigms.

6.
Neurosurgery ; 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32267504

RESUMO

BACKGROUND: Stereotactic radiosurgery (SRS) is a safe and effective treatment for acromegaly. OBJECTIVE: To improve understanding of clinical and dosimetric factors predicting biochemical remission. METHODS: A single-institution cohort study of nonsyndromic, radiation-naïve patients with growth hormone-producing pituitary adenomas (GHA) having single-fraction SRS between 1990 and 2017. Exclusions were treatment with pituitary suppressive medications at the time of SRS, or <24 mo of follow-up. The primary outcome was biochemical remission-defined as normalization of insulin-like growth factor-1 index (IGF-1i) off suppression. Biochemical remission was assessed using Cox proportional hazards. Prior studies reporting IGF-1i were assessed via systematic literature review and meta-analysis using random-effect modeling. RESULTS: A total of 102 patients met study criteria. Of these, 46 patients (45%) were female. The median age was 49 yr (interquartile range [IQR] = 37-59), and the median follow-up was 63 mo (IQR = 29-100). The median pre-SRS IGF-1i was 1.66 (IQR = 1.37-3.22). The median margin dose was 25 Gy (IQR = 21-25); the median estimated biologically effective dose (BED) was 169.49 Gy (IQR = 124.95-196.00). Biochemical remission was achieved in 58 patients (57%), whereas 22 patients (22%) had medication-controlled disease. Pre-SRS IGF-1i ≥ 2.25 was the strongest predictor of treatment failure, with an unadjusted hazard ratio (HR) of 0.51 (95% CI = 0.26-0.91, P = .02). Number of isocenters, margin dose, and BED predicted remission on univariate analysis, but after adjusting for sex and baseline IGF-1i, only BED remained significant-and was independently associated with outcome in continuous (HR = 1.01, 95% CI = 1.00-1.01, P = .02) and binary models (HR = 2.27, 95% CI = 1.39-5.22, P = .002). A total of 24 patients (29%) developed new post-SRS hypopituitarism. Pooled HR for biochemical remission given subthreshold IGF-1i was 2.25 (95% CI = 1.33-3.16, P < .0001). CONCLUSION: IGF-1i is a reliable predictor of biochemical remission after SRS. BED appears to predict biochemical outcome more reliably than radiation dose, but confirmatory study is needed.

7.
J Neurooncol ; 148(1): 89-95, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32303974

RESUMO

PURPOSE: Stereotactic radiosurgery (SRS) is commonly performed after surgical resection of brain metastases to reduce the chance of local tumor recurrence while maintaining cognitive function. Target delineation in these cases is typically based off T1-weighted post-gadolinium MRI (T1Gd). In this study, we report outcomes for patients having postoperative SRS in which the planning target volume (PTV) was based on T2-weighted MRI (T2W). METHODS: Sixty-two consecutive patients having single-fraction SRS after brain metastases resection were retrospectively reviewed. Excluded were patients with prior whole brain radiation therapy, multiple resection cavities, and small cell pathologies. RESULTS: The median time from surgery to SRS was 11 days; 26 patients (42%) had SRS ≤ 7 days. The median PTV was 8.0 cm3; the median margin dose was 18 Gy. The crude rates of local tumor control (LC), leptomeningeal disease (LMD), distant brain recurrence (DBR), and radiation necrosis (RN) were 85%, 19%, 37%, and 2%, respectively. The 1-year LC, LMD, DBR, and RN rates were 88%, 25%, 36%, and 0%, respectively. No tumor or dosimetric factor was associated with LC. Sub-total tumor resection was a risk factor for LMD (HR 5.11, P = 0.003), whereas patients with multiple brain metastases had a greater risk of DBR (HR 2.88, P = 0.01). The median PTV was smaller compared to the median PTV based off the consensus guidelines utilizing T1Gd MRI (8.0 cm3 vs. 9.1 cm3, P = 0.004). CONCLUSION: T2W MRI provided accurate resection cavity delineation even in the early postoperative period and was associated with decreased PTV compared to T1Gd MRI in the majority of cases.

8.
Radiother Oncol ; 147: 136-143, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32294607

RESUMO

BACKGROUND: Gamma knife (GK) and linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) both offer excellent local control in the management of multiple brain metastases. The efficacy and toxicity of LINAC and GK SRS have not been directly compared in the modern era. We studied outcomes in patients treated with LINAC SRS and GK at two separate institutions. METHODS: We identified patients treated with either LINAC or GK who were treated to ≥2 lesions and had available follow up. LINAC patients were treated using single-isocenter multitarget technique. We used Cox regression, Fine and Gray competing risks regression, and nearest neighbor propensity score matching to account for confounders and imbalance between cohorts. Kaplan-Meier curves were used to estimate overall survival and rates of radionecrosis. RESULTS: We identified 391 patients who were treated in 537 courses to a total 2699 lesions (LINAC: 1014, GK: 1685). After propensity score matching, GK was associated with similar overall survival (HR = 0.86; 95% CI 0.59-1.24; p = 0.41) and higher rate of radionecrosis (HR = 3.83; 95% CI 1.66-8.84; p = 0.002) compared to LINAC. In a secondary propensity score matched analysis comparing radionecrosis in single-fraction LINAC and GK, GK remained associated with higher incidence of radionecrosis (HR = 4.42; 95% CI 1.28-15.29; p = 0.019). CONCLUSIONS: In this multi-institutional study, we found similar overall survival with lower incidence of radionecrosis in patients treated with LINAC compared to GK SRS. These findings are hypothesis generating and should be validated in an independent cohort.

9.
Neuro Oncol ; 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32034917

RESUMO

BACKGROUND: Breast cancer treatment is based on receptors for estrogen (ER), progesterone (PR) and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). METHODS: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR or HER2 receptor status differed between the primary tumor and the BCBM. RESULTS: The overall receptor discordance rate was 132/316 (42%) and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) of patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) of patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors nonetheless median survival (MS) improved but did not reach statistical significance [HR (17 to 28 months, p=0.12), HER2 (15 to 19 months, p=0.39)]. MS for patients who lost receptors was worse [(HR (27 to 18 months, p=0.02), HER2 (30 to 18 months, p=0.08)). CONCLUSIONS: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly.

10.
J Clin Oncol ; 38(10): 1019-1029, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32058845

RESUMO

PURPOSE: Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS: This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS: Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [P = .049] and 16.4% v 33.3% [P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue (P = .04), less difficulty with remembering things (P = .01), and less difficulty with speaking (P = .049) and using imputed data, less interference of neurologic symptoms in daily activities (P = .008) and fewer cognitive symptoms (P = .01). CONCLUSION: HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

11.
Neuro Oncol ; 22(6): 830-837, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32002556

RESUMO

BACKGROUND: The optimal radiation dose for adult supratentorial low-grade glioma is unknown. The aim of this study was to provide a final update on oncologic and cognitive outcomes of high-dose versus low-dose radiation for low-grade glioma. METHODS: Between 1986 and 1994, 203 patients with supratentorial low-grade glioma were randomized (1:1) to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. RESULTS: For all patients, median overall survival (OS) was 8.4 years (95% CI: 7.2-10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3-6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve 15-year OS (22.4%) versus low-dose radiation (24.9%, log-rank P = 0.978) or 15-year PFS (high dose, 15.2% vs low dose, 9.5%; P = 0.7142). OS was significantly better for patients with preoperative tumor diameter <5 cm and baseline Mini-Mental State Examination (MMSE) >27 and who underwent gross total resection. PFS was improved for patients with oligodendroglioma versus astrocytoma, preoperative tumor diameter <5 cm, patients who had gross total resection, and patients with baseline MMSE >27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. CONCLUSIONS: Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Cognitive function appeared to be stable after radiation as measured by MMSE.

12.
Int J Radiat Oncol Biol Phys ; 107(2): 334-343, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32084525

RESUMO

PURPOSE: Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts. METHODS AND MATERIALS: A multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively. RESULTS: Median survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01). CONCLUSIONS: MS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.

13.
Neuro Oncol ; 22(6): 757-772, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32048719

RESUMO

A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The "minimum standard" recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)-prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An "ideal" protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.

14.
Int J Radiat Oncol Biol Phys ; 106(2): 255-260, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31654784

RESUMO

PURPOSE: Whole brain radiation therapy (WBRT) remains a commonly used cancer treatment, although controversy exists regarding the optimal dose/fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits. METHODS AND MATERIALS: NCCTG N107C [Alliance]/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the dose/fractionation that would be used for all patients treated at that site (either 30 Gy in 10 fractions or 37.5 Gy in 15 fractions). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher's exact tests. RESULTS: Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fractions (53%), and 43 were treated with 37.5 Gy in 15 fractions (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology was more frequent with protracted WBRT: 72% vs 45%, P = .01), and 93% of patients completed the full course of WBRT. A more protracted WBRT dose regimen (37.5 Gy in 15 fractions) did not significantly affect time to cognitive failure (hazard ratio [HR], 0.9; 95% confidence interval [CI], 0.6-1.39; P = .66), surgical bed control (HR, 0.52 [95% CI, 0.22-1.25], P = .14), intracranial tumor control (HR, 0.56 [95% CI, 0.28-1.12], P = .09), or overall survival (HR, 0.72 [95% CI, 0.45-1.16], P = .18). Although there was no reported radionecrosis, there is a statistically significant increase in the risk of at least 1 grade ≥3 adverse event with 37.5 Gy in 15 fractions versus 30 Gy in 10 fractions (54% vs 31%, respectively, P = .03). CONCLUSIONS: This post hoc analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with the lengthened course of WBRT. For patients with brain metastases where WBRT is recommended, shorter course hypofractionated regimens remain the current standard of care.


Assuntos
Neoplasias Encefálicas/radioterapia , Transtornos Cognitivos/prevenção & controle , Irradiação Craniana/normas , Melhoria de Qualidade , Radiocirurgia/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Intervalos de Confiança , Irradiação Craniana/efeitos adversos , Fracionamento da Dose de Radiação , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Radiocirurgia/efeitos adversos , Radioterapia Adjuvante/efeitos adversos , Radioterapia Adjuvante/normas
16.
Radiother Oncol ; 144: 165-179, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31812932

RESUMO

BACKGROUND AND PURPOSE: To analyze outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases harboring EGFR or ALK mutations and examine for differences between tyrosine kinase inhibitors (TKIs) alone, radiotherapy (RT) alone (either whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS)), or combined TKIs and RT. MATERIALS AND METHODS: Thirty studies were identified. PATIENTS: with brain metastases from NSCLC. INTERVENTION: initial TKIs alone with optional salvage RT, RT alone, or TKIs and RT. CONTROL: wild-type NSCLC and TKIs alone for mutational and treatment analysis, respectively. OUTCOMES: overall survival (OS) and intracranial progression-free survival (PFS). SETTING: studies with mutation information. RESULTS: A total of 2649 patients were included. Patients with ALK and EGFR mutations had significantly higher median OS (48.5 months, p < 0.0001; and 20.9 months; p = 0.0006, respectively) compared to wild-type patients (9.9 months). Similar median OS was noted between TKIs and RT (28.3 months), RT alone (32.2 months; p = 0.22), or TKIs alone (23.9 months; p = 0.2). Patients treated with TKIs and RT had higher median PFS (18.6 months; p = 0.06) compared to TKIs alone (13.6 months) with no difference between TKIs and RT vs. RT alone (16.9 months; p = 0.72). No PFS difference was found between WBRT and TKI (23.2 months; p = 0.72) vs. WBRT alone (24 months) or SRS and TKI (16.7 months; p = 0.56) vs. SRS alone (13.6 months). CONCLUSION: NSCLC patients with brain metastases harboring EGFR or ALK mutations have superior OS compared to wild-type patients. No PFS or OS benefit was found with the addition of TKIs to RT.

17.
Int J Radiat Oncol Biol Phys ; 106(3): 579-586, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31605786

RESUMO

PURPOSE: For brain metastases, surgical resection with postoperative stereotactic radiosurgery is an emerging standard of care. Postoperative cavity stereotactic radiosurgery is associated with a specific, underrecognized pattern of intracranial recurrence, herein termed nodular leptomeningeal disease (nLMD), which is distinct from classical leptomeningeal disease. We hypothesized that there is poor consensus regarding the definition of LMD, and that a formal, self-guided training module will improve interrater reliability (IRR) and validity in diagnosing LMD. METHODS AND MATERIALS: Twenty-two physicians at 16 institutions, including 15 physicians with central nervous system expertise, completed a 2-phase survey that included magnetic resonance imaging and treatment information for 30 patients. In the "pretraining" phase, physicians labeled cases using 3 patterns of recurrence commonly reported in prospective studies: local recurrence (LR), distant parenchymal recurrence (DR), and LMD. After a self-directed training module, participating physicians completed the "posttraining" phase and relabeled the 30 cases using the 4 following labels: LR, DR, classical leptomeningeal disease, and nLMD. RESULTS: IRR increased 34% after training (Fleiss' Kappa K = 0.41 to K = 0.55, P < .001). IRR increased most among non-central nervous system specialists (+58%, P < .001). Before training, IRR was lowest for LMD (K = 0.33). After training, IRR increased across all recurrence subgroups and increased most for LMD (+67%). After training, ≥27% of cases initially labeled LR or DR were later recognized as nLMD. CONCLUSIONS: This study highlights the large degree of inconsistency among clinicians in recognizing nLMD. Our findings demonstrate that a brief self-guided training module distinguishing nLMD can significantly improve IRR across all patterns of recurrence, and particularly in nLMD. To optimize outcomes reporting, prospective trials in brain metastases should incorporate central imaging review and investigator training.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Carcinomatose Meníngea/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico por imagem , Neuroimagem/normas , Radiocirurgia , Autoaprendizagem como Assunto , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Transtornos Cognitivos/prevenção & controle , Consenso , Diagnóstico Diferencial , Humanos , Imagem por Ressonância Magnética , Carcinomatose Meníngea/radioterapia , Carcinomatose Meníngea/cirurgia , Neurologistas , Variações Dependentes do Observador , Cuidados Pós-Operatórios , Reprodutibilidade dos Testes , Terminologia como Assunto
18.
APMIS ; 128(1): 48-60, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31693234

RESUMO

Klebsiella pneumoniae is an important opportunistic pathogen with significant potential for virulence and multidrug resistance. Treatment failure often occurs because the pathogen may couple virulence and drug resistance with the stringent response. This study assessed the role of the spoT gene in environmental and nutritional stress tolerance, exopolysaccharide capsule production and biofilm formation. spoT mutants were constructed using the lambda red recombinase technique, and mutant and wild-type (WT) strains were exposed to limiting concentrations of carbon (glucose), phosphate and aminoacid, and environmental stresses of ethanol, salt and heat. Cell viability, capsule production and cell length were assessed as well as the ability to grow biofilm under antibiotic pressure using gentamicin and ceftazidime. spoT mutants were more susceptible to stresses versus WT; the reverse was true for survival during biofilm susceptibility assay (p < 0.05), especially when carbon and phosphate were present. spoT mutants were elongated and lacked a capsule versus WT and non-starved strains. The inability to produce capsule in mutants before and after starvation was likely a general effect of spoT mutation. These data suggest that the spoT-mediated stringent response is important for K. pneumoniae in conditions of nutrient limitation, environmental stress and antimicrobial pressure.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Biofilmes/crescimento & desenvolvimento , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/fisiologia , Estresse Fisiológico , Aminoácidos/química , Farmacorresistência Bacteriana , Etanol/farmacologia , Regulação Bacteriana da Expressão Gênica , Glucose/química , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Fosfatos/química , Cloreto de Sódio/farmacologia , Virulência/genética , Fatores de Virulência
19.
Neurooncol Pract ; 6(1): 71-77, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31386012

RESUMO

Background: Cognitive function is an important outcome measure in many brain tumor clinical trials, and investigators are interested in employing the most efficient methods of cognitive assessment for this purpose. Computerized testing can be appealing because of the perceived ease of use and electronic data generated. Traditional tests may have the advantage of accumulated validity evidence and comparability across historic trials. Methods: We evaluated feasibility of a Cogstate battery in 39 patients with high-grade glioma, and compared it with a commonly used paper-and-pencil battery. Results: Both batteries were well tolerated and rated equally likeable. Correlations between the batteries were low to low-moderate. More patients showed impairment at baseline and decline across trials on traditional tests. Conclusions: Both batteries were well tolerated, but the most complicated tasks (from both batteries) could not be completed by all subjects. Preliminary validity evidence for the Cogstate tasks was mixed, but a larger sample is needed.

20.
Neurooncol Pract ; 6(4): 283-288, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31386061

RESUMO

Background: Cognitive function is an important outcome in brain-tumor clinical trials. Cognitive examiners are often needed across multiple sites, many of whom have no prior testing experience. To ensure quality, we looked at examiner errors in administering a commonly used cognitive test battery, determined whether the errors were correctable upon central review, and considered whether the same errors would be detected using onsite electronic data entry. Methods: We looked at 500 cognitive exams administered for brain-tumor trials led by the Alliance for Clinical Trials in Oncology (Alliance). Of 2277 tests examined, 32 noncorrectable errors were detected with routine central review (1.4% of tests administered), and thus removed from the database of the respective trial. The invalidation rate for each test was 0.8% for each part of the Hopkins Verbal Learning Test-Revised, 0.8% for Controlled Oral Word Association, 1.8% for Trail Making Test-A and 2.6% for Trail Making Test-B. It was estimated that, with onsite data entry and no central review, 4.9% of the tests entered would have uncorrected errors and 1.3% of entered tests would be frankly invalid but not removed. Conclusions: Cognitive test results are useful and robust outcome measures for brain-tumor clinical trials. Error rates are extremely low, and almost all are correctable with central review of scoring, which is easy to accomplish. We caution that many errors could be missed if onsite electronic entry is utilized instead of central review, and it would be important to mitigate the risk of invalid scores being entered. ClinicalTrialsgov identifiers: NCT01781468 (Alliance A221101), NCT01372774 (NCCTG N107C), NCT00731731 (NCCTG N0874), and NCT00887146 (NCCTG N0577).

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