Intracranial outcomes following neurosurgical resection in patients with brain metastases secondary to HER2-positive breast cancer versus other subtypes.

PURPOSE: Neurosurgical resection serves an important role in select patients with breast cancer and brain metastases but can delay systemic therapy and yield complications. Consequently, identification of patients most likely to benefit from surgery is important. Given the poorer long-term intracranial responses to radiotherapy sometimes observed in HER2-positive (HER2 +) patients, we investigated whether neurosurgical resection is differentially beneficial in this population. METHODS: We identified 633 patients with newly diagnosed brain metastases arising from breast cancer managed at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2010 and 2022. Patients were stratified by breast cancer subtype: HER2 + (N = 189), hormone receptor positive (HR +)/HER2- (N = 267), and triple negative (N = 177). Per-patient and per-metastasis outcomes were evaluated; interaction models assessing the impact of neurosurgical resection by subtype were constructed. RESULTS: Relative to HR + /HER2- subtype, omission of upfront neurosurgical resection in patients with HER2 + disease was associated with increased subsequent utilization of salvage stereotactic radiation, whole brain radiotherapy, and craniotomy (interaction HR 2.02 [95% CI, 1.04-3.93], p = 0.04; HR 3.92 [95% CI, 1.24-12.40], p = 0.02; HR 4.98 [95% CI, 1.34-18.58], p = 0.02, respectively). Tumors stemming from HER2 + versus HR + /HER2- primaries displayed increased local recurrence when upfront neurosurgical resection was omitted (interaction HR 3.62 [95% CI, 1.06-12.38], p = 0.04). No such associations were noted when comparing triple negative to HR + /HER2- subtype (p-interaction > 0.05 in all cases). CONCLUSION: Patients with HER2 + disease and brain metastases may disproportionately benefit from upfront neurosurgical resection relative to other subtypes. If validated, our results may suggest a lower threshold to consider surgery in brain metastases secondary to HER2 + breast cancer.

The epidemiology of primary and metastatic brain tumors in infancy through childhood.

PURPOSE: To evaluate the epidemiology of primary and metastatic pediatric brain tumors in the United States according to the WHO CNS 4th and 5th editions classifications. METHODS: Pediatric patients (age ≤ 14) presenting between 2004 and 2017 with a brain tumor were identified in the National Cancer Database and categorized by NICHD age stages. Patients' age, sex, race/ethnicity, overall survival, and tumor characteristics were evaluated according to WHO CNS 4th and 5th editions. RESULTS: 23,978 pediatric brain tumor patients were identified. Overall, other (i.e. circumscribed) astrocytic gliomas (21%), diffuse astrocytic/oligodendroglial gliomas (21%; 64% of which were midline), and embryonal tumors (16%) predominated. A minority of brain tumors were of ependymal (6%), glioneuronal & neuronal (6%), germ cell tumor (GCT; 4%), mesenchymal non-meningothelial (2%), cranial nerve (2%), choroid plexus (2%), meningioma (2%), pineal (1%), and hematolymphoid (0.4%) types. GCTs were more likely in patients of Asian/Pacific Islander race/ethnicity. Brain metastases were exceedingly rare, accounting for 1.4% overall, with the most common primary tumor being neuroblastoma (61%) and non-CNS sarcoma (16%). Brain metastatic, choroid plexus, and embryonal tumors peaked during infancy and toddlerhood; whereas diffuse gliomas peaked in middle-late childhood. GCTs and glioneuronal & neuronal tumors uniquely displayed bimodal distributions, with elevated prevalence in both infancy and middle-to-late childhood. CONCLUSION: We systematically described the epidemiology of pediatric brain tumors in the context of contemporary classification schema, thereby validating our current understanding and providing key insights.

Audiovestibular symptoms and facial nerve function comparing microsurgery versus SRS for vestibular schwannomas: a systematic review and meta-analysis.

OBJECTIVE: Surgery and radiosurgery represent the most common treatment options for vestibular schwannoma. A systematic review and meta-analysis were conducted to compare the outcomes of surgery versus stereotactic radiosurgery (SRS). METHODS: The Cochrane library, PubMed, Embase, and clinicaltrials.gov were searched through 01/2021 to find all studies on surgical and stereotactic procedures performed to treat vestibular schwannoma. Using a random-effects model, pooled odds ratios (OR) and their 95% confidence intervals (CI) comparing post- to pre-intervention were derived for pre-post studies, and pooled incidence of adverse events post-intervention were calculated for case series and stratified by intervention type. RESULTS: Twenty-one studies (18 pre-post design; three case series) with 987 patients were included in the final analysis. Comparing post- to pre-intervention, both surgery (OR: 3.52, 95%CI 2.13, 5.81) and SRS (OR: 3.30, 95%CI 1.39, 7.80) resulted in greater odds of hearing loss, lower odds of dizziness (surgery OR: 0.10; 95%CI 0.02, 0.47 vs. SRS OR: 0.22; 95%CI 0.05, 0.99), and tinnitus (surgery OR: 0.23; 95%CI 0.00, 37.9; two studies vs. SRS OR: 0.11; 95%CI 0.01, 1.07; one study). Pooled incidence of facial symmetry loss was larger post-surgery (14.3%, 95%CI 6.8%, 22.7%) than post-SRS (7%, 95%CI 1%, 36%). Tumor control was larger in the surgery (94%, 95%CI 83%, 98%) than the SRS group (80%, 95%CI 31%, 97%) for small-to-medium size tumors. CONCLUSION: Both surgery and SRS resulted in similar odds of hearing loss and similar improvements in dizziness and tinnitus among patients with vestibular schwannoma; however, facial symmetry loss appeared higher post-surgery.

Intracerebral haemorrhage in patients with brain metastases receiving therapeutic anticoagulation.

BACKGROUND: Venous thromboembolism is common in patients with solid malignancies and brain metastases. Whether to anticoagulate such patients is controversial given the possibility of intracerebral haemorrhage (ICH). We evaluated the added risk of ICH in patients with brain metastases receiving therapeutic anticoagulation. METHODS: We performed a matched, retrospective cohort study of 291 patients (100 receiving therapeutic anticoagulation vs 191 controls) with brain metastases managed at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 1998 and 2015. For each patient, all MRI studies of the brain were reviewed to identify ICH. Propensity score matching and multivariable Cox regression were used to mitigate confounding. RESULTS: The risk of ICH was comparable in patients receiving anticoagulation versus controls preanticoagulation. Postanticoagulation, we observed significant or borderline-significant associations between anticoagulation and development of any ICH (HR 1.31, 95% CI 0.96 to 1.79, p=0.09), ICH as identified by gradient echo/susceptibility-weighted imaging (HR 1.46, 95% CI 1.06 to 2.01, p=0.02), symptomatic ICH (HR 1.80, 95% CI 1.01 to 3.22, p=0.05), extralesional ICH (HR 5.82, 95% CI 1.56 to 21.7, p=0.009) and fatal ICH (HR 5.68, 95% CI 0.60 to 54.2, p=0.13). Anticoagulation was associated with differentially higher ICH risk in patients with prior ICH versus no prior ICH (HR 2.20 vs 0.68, respectively, p interaction <0.001) and symptomatic ICH risk in melanoma versus other primary malignancies (HR 6.46 vs 1.36, respectively, p interaction=0.02). CONCLUSIONS: Anticoagulation is associated with clinically significant ICH in patients with brain metastases, especially those with melanoma or prior ICH. The indication for anticoagulation and risk of intracerebral bleeding should be considered on an individual basis among such patients.

Long-term outcomes of pediatric and young adult patients receiving radiotherapy for nonmalignant vascular anomalies.

BACKGROUND: Nonmalignant vascular anomalies (VA) comprise a heterogeneous spectrum of conditions characterized by aberrant growth or development of blood and/or lymphatic vessels and can cause significant morbidity. Little is known about outcomes after radiotherapy in pediatric and young adult patients with nonmalignant VA. METHODS: Thirty patients who were diagnosed with nonmalignant VA and treated with radiotherapy prior to 2017 and before the age of 30 were identified. Clinical and treatment characteristics and outcomes were recorded. RESULTS: Median age at first radiotherapy was 15 years (range 0.02-27). Median follow-up from completion of first radiotherapy was 9.8 years (range 0.02-67.4). Lymphatic malformations (33%), kaposiform hemangioendothelioma (17%), and venous malformations (17%) were the most common diagnoses. The most common indication for first radiotherapy was progression despite standard therapy and/or urgent palliation for symptoms (57%). After first radiotherapy, 14 patients (47%) had a complete response or partial response, defined as decrease in size of treated lesion or symptomatic improvement. After first radiotherapy, 27 (90%) required additional treatment for progression or recurrence. Long-term complications included telangiectasias, fibrosis, xerophthalmia, radiation pneumonitis, ovarian failure, and central hypothyroidism. No patient developed secondary malignancies. At last follow-up, three patients (10%) were without evidence of disease, 26 (87%) with disease, and one died of complications (3.3%). CONCLUSIONS: A small group of pediatric and young adult patients with nonmalignant, high-risk VA experienced clinical benefit from radiotherapy with expected toxicity; however, most experienced progression. Prospective studies are needed to characterize indications for radiotherapy in VA refractory to medical therapy, including targeted inhibitors.

Endoscopic third ventriculostomy versus ventriculoperitoneal shunt in pediatric and adult population: a systematic review and meta-analysis.

Treatment options for hydrocephalus include endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS). Some ambiguity remains regarding indications, safety, and efficacy for these procedures in different clinical scenarios. The objective of the present study was to pool the available evidence to compare outcomes among patients with hydrocephalus undergoing ETV versus VPS. A systematic search of the literature was conducted via PubMed, EMBASE, and Cochrane Library through 11/29/2018 to identify studies evaluating failure and complication rates, following ETV or VPS. Pooled effect estimates were calculated using random effects. Heterogeneity was assessed by the Cochrane Q test and the I2 value. Heterogeneity sources were explored through subgroup analyses and meta-regression. Twenty-three studies (five randomized control trials (RCTs) and 18 observational studies) were meta-analyzed. Comparing ETV to VPS, failure rate was not statistically significantly different with a pooled relative risk (RR) of 1.48, 95%CI (0.85, 2.59) for RCTs and 1.17 (0.89, 1.53) for cohort studies; P-interaction: 0.44. Complication rates were not statistically significantly different between ETV and VPS in RCTs (RR: 1.34, 95%CI: 0.50, 3.59) but were statistically significant for prospective cohort studies (RR: 0.47, 95%CI: 0.30, 0.78); P-interaction: 0.07. Length of hospital stay was no different, when comparing ETV and VPS. These results remained unchanged when stratifying by intervention type and when regressing on age when possible. No significant differences in failure rate were observed between ETV and VPS. ETV was found to have lower complication rates than VPS in prospective cohort studies but not in RCTs. Further research is needed to identify the specific patient populations who may be better suited for one intervention versus another.

Minimally invasive versus open surgery for the correction of adult degenerative scoliosis: a systematic review.

While open surgery has been the primary surgical approach for adult degenerative scoliosis, minimally invasive surgery (MIS) represents an alternative option and appears to be associated with reduced morbidity. Given the lack of consensus, we aimed to conduct a systematic review on available literature comparing MIS versus open surgery for adult degenerative scoliosis. PubMed, Embase, and Cochrane databases were searched through December 16, 2019, for studies that compared both MIS and open surgery in patients with degenerative scoliosis. Four cohort studies reporting on 350 patients met the inclusion criteria. In two studies, patients undergoing open surgery were younger and had more severe disease at baseline as compared with MIS. Patients who underwent MIS had less blood loss, shorter length of stay, and a reduced rate of complications and infections. Both MIS and open surgery resulted in a significant change in pain and disability scores and both approaches provided significant correction of deformity in all studies, although open surgery was associated with a greater change in pelvic incidence-lumbar lordosis mismatch (PI-LL) and sagittal vertical axis (SVA) in two and three studies, respectively. In patients with adult degenerative scoliosis undergoing surgery, both MIS and open approaches appeared to offer comparable improvements in pain and function. However, MIS was associated with better safety outcomes, while open surgery provided greater correction of spinal deformity. Further studies are needed to identify specific subset of patients who may benefit from one approach versus the other.

Validation of a subclassification for high-risk prostate cancer in a prospective cohort.

BACKGROUND: A subgroup of men with favorable high-risk prostate cancer (T1c with either a Gleason score of 4 + 4 = 8 and a prostate-specific antigen [PSA] level <10 ng/mL or a Gleason score of 6 and a PSA level >20 ng/mL) has been associated with improved outcomes in comparison with other standard high-risk patients. This study was designed to validate the prognostic utility of a subclassification for high-risk disease with a prospectively collected data set. METHODS: This study identified 3033 men from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had been diagnosed from 1993 to 2001 with clinically localized prostate cancer-either intermediate-risk disease (clinical stage T2b-c, a Gleason score of 7, or a PSA level of 10 to 20 ng/mL) or high-risk disease (clinical stage T3-T4, a Gleason score of 8-10, or a PSA level >20 ng/mL)-that was managed with radical prostatectomy or radiation therapy. Multivariable logistic regression was used to calculate adjusted odds ratios (aORs) for pathological T3 to T4 or N1 (pT3-T4/pN1) disease. Fine and Gray competing risks regression was used to determine adjusted hazard ratios (aHRs) of prostate cancer-specific mortality (PCSM). RESULTS: The median follow-up was 5.7 years. Patients with favorable high-risk disease had lower 8-year PCSM in comparison with patients with standard high-risk disease (2.2% vs 10.8%; aHR, 0.26; 95% confidence interval [CI], 0.09-0.73; P = .01) but similar PCSM in comparison with patients with intermediate-risk disease (2.2% vs 2.2%; aHR, 0.90; 95% CI, 0.32-2.54; P = .84). Among those who underwent surgery, those with favorable high-risk disease had lower odds of pT3-T4/pN1 disease than those with standard high-risk disease (46.2% vs 63.3%; aOR, 0.50; 95% CI, 0.27-0.94; P = .03). CONCLUSIONS: This study validates the prognostic utility of a subclassification for high-risk disease in a prospectively collected patient cohort. Patients with favorable high-risk disease have PCSM similar to that of patients with intermediate-risk disease and significantly better than that of patients with standard high-risk disease. Future trials are needed to assess possible de-intensification of therapy for favorable high-risk disease.

Systemic therapy following craniotomy in patients with a solitary breast cancer brain metastasis.

PURPOSE: To describe practice patterns and patient outcomes with respect to the use of postoperative systemic therapy (ST) after resection of a solitary breast cancer brain metastasis (BCBM). METHODS: A multi-institutional retrospective review of consecutive patients undergoing resection of a single BCBM without extracranial metastases was performed to describe subtype-specific postoperative outcomes and assess the impact of types of ST on site of recurrence, progression-free survival (PFS), and overall survival (OS). RESULTS: Forty-four patients were identified. Stratified estimated survival was 15, 24, and 23 months for patients with triple negative, estrogen receptor positive (ER+), and HER2+ BCBMs, respectively. Patients receiving postoperative ST had a longer median PFS (8 versus 4 months, adjusted p-value 0.01) and OS (32 versus 15 months, adjusted p-value 0.21). Nine patients (20%) had extracranial progression, 23 (52%) had intracranial progression, three (8%) had both, and nine (20%) did not experience progression at last follow-up. Multivariate analysis showed that postoperative hormonal therapy was associated with longer OS (HR 0.26; 95% CI 0.08-0.89; p = 0.03) but not PFS (HR 0.35, 95% CI 0.08-1.47, p = 0.15) in ER+ patients. Postoperative HER2-targeted therapy was not associated with longer OS or PFS in HER2+ patients. CONCLUSIONS: Disease progression occurred intracranially more often than extracranially following resection of a solitary BCBM. In ER+ patients, postoperative hormonal therapy was associated with longer OS. Postoperative HER2-targeted therapy did not show survival benefit in HER2+ patients. These results should be validated in larger cohorts.

Prescription of memantine during non-stereotactic, brain-directed radiation among patients with brain metastases: a population-based study.

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.

Gender Differences in Preoperative Opioid Use in Spine Surgery Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: Opioids are frequently used in spine surgeries despite their adverse effects, including physical dependence and addiction. Gender difference is an important consideration for personalized treatment. There is no review assessing the prevalence of opioid use between men and women before spine surgeries. DESIGN: We compared the prevalence of preoperative opioid use between men and women. SETTING: Spine surgery. SUBJECTS: Comparison between men and women. METHODS: PubMed, Embase, and Cochrane were searched from inception to November 9, 2018. Clinical characteristics and prevalence of preoperative opioid use were collected. Where feasible, data were pooled from nonoverlapping studies using random-effects models. RESULTS: Four studies with nonoverlapping populations were included in the meta-analysis (one prospective, three retrospective cohorts). The prevalence of preoperative opioid use was 0.64 (95% CI = 0.40-0.83). Comparing men with women, no statistically significant difference in preoperative opioid use was detected (relative risk [RR] = 0.99, 95% CI = 0.96-1.02). Surgery location (cervical, lumbar) and study duration (more than five years or five years or less) did not modify this association. All involved open spine surgery. Only one secondary analysis provided data on both pre- and postoperative opioid use stratified by gender, which showed a borderline significantly higher prevalence of postoperative use in women than men. CONCLUSIONS: The prevalence of opioid use before spine surgery was similar between men and women, irrespective of surgery location or study duration. More studies characterizing the pattern of opioid use between genders are still needed.

Adult spinal deformity surgery: a systematic review of venous thromboprophylaxis and incidence of venous thromboembolic events.

Venous thromboprophylaxis consisting of chemical and/or mechanical prophylaxis is administered to patients undergoing adult spinal deformity (ASD) surgery to prevent venous thromboembolic events. However, the true incidence of venous thromboembolism (VTE) after these surgeries is unknown resulting in weak recommendations and lack of consensus regarding type and timing of prophylaxis in these patients. A systematic literature review was conducted to examine VTE incidence in addition to optimal type and timing of VTE prophylaxis. A detailed search was carried out on Embase, PubMed, and Cochrane Library databases through October 18, 2017, for studies that evaluated venous thromboembolic outcomes, type, and timing of prophylaxis administration among ASD surgery patients who were on VTE prophylaxis. The randomized study was assessed for risk of bias using the Cochrane tool and the observational studies using the Newcastle-Ottawa scale (NOS). The search yielded 1180 studies, and three articles published between 1996 and 2008 met the inclusion criteria. There were 583 surgeries performed on 537 patients with a mean age ranging from 45 to 52 years. Females dominated the study with percentages ranging from 60 to 94% in the different study populations. VTE prophylaxis was initiated before surgery in 87.7% patients and intraoperatively in 12.3% patients. VTE incidence ranged between 0 and 9.1% among the studies. VTE can occur after ASD surgery regardless of the type of prophylaxis, and incidence may be higher when mechanical prophylaxis alone is initiated intraoperatively. Further studies to examine VTE prophylaxis in patients undergoing ASD surgery should be considered.

Use and early mortality outcomes of active surveillance in patients with intermediate-risk prostate cancer.

BACKGROUND: Certain patients with intermediate-risk prostate cancer (PCa) may be appropriate candidates for active surveillance (AS). In the current study, the authors sought to characterize AS use and early mortality outcomes for patients with intermediate-risk PCa in the United States. METHODS: The novel Surveillance, Epidemiology, and End Results Active Surveillance/Watchful Waiting database identified 52,940 men diagnosed with National Comprehensive Cancer Network intermediate-risk PCa (cT2b-c, Gleason score of 7, or a prostate-specific antigen level of 10-20 ng/mL) and actively managed (AS, radiotherapy, or radical prostatectomy) from 2010 through 2015. The Cuzick test assessed AS time trends, and logistic multivariable regression characterized features associated with AS. Fine-Gray and Cox modeling determined PCa-specific mortality (PCSM) and overall survival, respectively. RESULTS: The rate of AS increased from 3.7% in 2010 to 7.3% in 2015, and from 7.2% to 11.7% among men aged ≥70 years. Among men with favorable and unfavorable intermediate-risk disease, the use of AS increased from 7.2% to 14.9% and from 2.2% to 3.8%, respectively (all P value for trend, <.001). The mean age of those patients managed with AS decreased from 69.9 years to 67.9 years (P = .0004). Factors found to be associated with AS included favorable risk disease; black race; higher socioeconomic status; older age; and diagnosis in the West, Northwest, or Midwest regions of the United States. The 5-year PCSM rate was comparable to AS versus treatment among patients with low-risk and favorable intermediate-risk disease, but was worse with AS among those with unfavorable intermediate-risk disease (PCSM, 1.3% vs 0.5%; adjusted hazard ratio, 2.48 [95% CI, 1.11-5.50; P = .026]) and intermediate-risk disease overall (PCSM, 1.1% vs 0.4%; adjusted hazard ratio, 2.34 [95% CI, 1.25-4.37; P = .008]). CONCLUSIONS: The use of AS for patients with intermediate-risk PCa is increasing across the United States, particularly for older men and those with favorable intermediate-risk disease. Early estimates of cancer-specific and overall mortality rates are low with AS, although significantly higher compared with treatment.

Risk stratification by somatic mutation burden in Ewing sarcoma.

BACKGROUND: Up to one-third of patients with localized Ewing sarcoma (ES) develop recurrent disease, but current biomarkers do not accurately identify this high-risk group. Therefore, the objective of this study was to determine the utility of mutational burden in predicting outcomes in patients with localized ES. METHODS: Clinical and genomic data from 99 patients with ES, of whom 63 had localized disease at diagnosis, were obtained from the cBioPortal for Cancer Genomics. Genomic data included the type and number of somatic mutations using cBioPortal mutation calling. Primary endpoints were overall survival (OS) and the time to progression (TTP). RESULTS: Patients had a median number of 11 somatic mutations. Patients were stratified according to whether they had a lower or higher mutational burden if they had ≤11 or >11 mutations, respectively. Higher mutational burden was significantly associated with inferior OS and TTP, a finding that was confirmed by univariate and multivariable analyses. In patients who had localized disease at diagnosis, higher mutational burden was the only variable significantly associated with inferior OS and TTP. The presence of a mutation in either stromal antigen 2 (STAG2) or tumor protein 53 (TP53), both of which were correlated previously with shorter OS in patients with ES, were significantly associated with higher mutational burden. Upon stratifying patients who had localized disease based on a standard panel of cancer genes, higher risk stratification was correlated significantly with inferior TTP and trended toward significance with inferior OS. CONCLUSIONS: Patients who have localized ES and a higher mutational burden have inferior OS and TTP compared with those who have lower mutation burden. The current findings suggest that the somatic mutation burden can be used to better risk stratify these patients and to guide clinical decision making.

Breast cancer subtype and intracranial recurrence patterns after brain-directed radiation for brain metastases.

PURPOSE: Brain metastases from breast cancer are frequently managed with brain-directed radiation but the impact of subtype on intracranial recurrence patterns after radiation has not been well-described. We investigated intracranial recurrence patterns of brain metastases from breast cancer after brain-directed radiation to facilitate subtype-specific management paradigms. METHODS: We retrospectively analyzed 349 patients with newly diagnosed brain metastases from breast cancer treated with brain-directed radiation at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2000 and 2015. Patients were stratified by subtype: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-), HER2+ positive (HER2+), or triple-negative breast cancer (TNBC). A per-metastasis assessment was conducted. Time-to-event analyses were conducted using multivariable Cox regression. RESULTS: Of the 349 patients, 116 had HR+/HER2- subtype, 164 had HER2+ subtype, and 69 harbored TNBC. Relative to HR+/HER2- subtype, local recurrence was greater in HER2+ metastases (HR 3.20, 95% CI 1.78-5.75, p < 0.001), while patients with TNBC demonstrated higher rates of new brain metastases after initial treatment (HR 3.16, 95% CI 1.99-5.02, p < 0.001) and shorter time to salvage whole brain radiation (WBRT) (HR 3.79, 95% CI 1.36-10.56, p = 0.01) and salvage stereotactic radiation (HR 1.86, 95% CI 1.11-3.10, p = 0.02). CONCLUSIONS: We identified a strong association between breast cancer subtype and intracranial recurrence patterns after brain-directed radiation, particularly local progression for HER2+ and distant progression for TNBC patients. If validated, the poorer local control in HER2+ brain metastases may support evaluation of novel local therapy-based approaches, while the increased distant recurrence in TNBC suggests the need for improved systemic therapy and earlier utilization of WBRT.

Combined External Beam Radiation Therapy and Brachytherapy versus Radical Prostatectomy with Adjuvant Radiation Therapy for Gleason 9-10 Prostate Cancer.

PURPOSE: It remains controversial whether external beam radiation therapy with a brachytherapy boost provides oncologic outcomes equivalent to those of radical prostatectomy with or without adjuvant radiation therapy in men with Gleason 9-10 prostate cancer. We compared external beam radiation therapy plus brachytherapy to radical prostatectomy plus adjuvant radiation therapy for Gleason 9-10 prostate cancer in terms of overall survival and prostate cancer specific mortality in 2 large national databases. MATERIALS AND METHODS: Using the NCDB (National Cancer Database) and the SEER (Surveillance, Epidemiology, and End Results) database, we identified 4,367 and 2,276 patients, respectively, diagnosed with clinical T1-T3N0M0, Gleason 9-10, prostate specific antigen 0 to 40 ng/ml prostate cancer treated with external beam radiation therapy plus brachytherapy or radical prostatectomy plus adjuvant radiation therapy. We compared overall survival and prostate cancer specific mortality using inverse probability of treatment weighted multivariable Cox proportional hazards regression modeling after accounting for clinical and demographic factors. RESULTS: Median followup in the NCDB and SEER cohorts was 6.0 years and 5.8 years, respectively. In the NCDB cohort there was no significant difference in 5-year overall survival between radical prostatectomy plus adjuvant radiation therapy vs external beam radiation therapy plus brachytherapy (86.7% vs 87.0%, AHR 1.10, 95% CI 0.95-1.27, p=0.220). Results were unchanged when including only patients who received androgen deprivation therapy. In the SEER cohort there was no difference in 5-year prostate cancer specific mortality (6.0% vs 5.7%, AHR 1.22, 95% CI 0.0.88-1.71, p=0.234). There was no significant interaction between patient age (65 years or greater vs less than 65) and treatment modality in the NCDB or SEER cohorts. CONCLUSIONS: In men with Gleason 9-10 prostate cancer multimodality surgical therapy is equivalent to external beam radiation therapy plus brachytherapy.

Increase of pseudoprogression and other treatment related effects in low-grade glioma patients treated with proton radiation and temozolomide.

INTRODUCTION: Concurrent radiotherapy and temozolomide (TMZ) is associated with radiographic pseudoprogression (PsP) in glioblastoma. The occurrence of PsP and other treatment effects is less well understood in low-grade gliomas (LGG). The purpose of this study is to evaluate whether the addition of TMZ to radiotherapy increases the incidence of PsP in adults with LGG treated with proton radiotherapy (PRT). METHODS: Chart review and volumetric MRI-analysis was performed on radiotherapy-naive adults with WHO grade II or IDH mutant WHO grade III gliomas treated with PRT between 2005 and 2015. Progression was defined by histology, new chemotherapy initiation, or progressive increase in lesion volume beyond 40% from baseline. Post treatment related effects (PTRE) were defined as new/increased T2/FLAIR or abnormal enhancement which eventually resolved or stabilized without evidence of progression for a period of 6-12 months. PsP was defined as the subset of PRTE suspicious for progression or volumetrically increased at least 40% from baseline. Pearson's chi-squared test and Cox-proportional hazards models were used for statistical analysis. RESULTS: There were 119 patients meeting inclusion criteria. There was an increased risk of PsP following PRT + TMZ versus PRT-alone (HR = 2.2, p = 0.006, on Cox univariate analysis). Presence of PsP was associated with improved OS (p = 0.02 with PsP as time-varying covariate). CONCLUSIONS: TMZ use, when added to PRT, was associated with increased PsP in patients with LGG; however, patients with PsP tended to achieve longer survival.

Management of hydrocephalus in patients with leptomeningeal metastases: an ethical approach to decision-making.

PURPOSE: Leptomeningeal metastases (LM) are a rare, but often debilitating complication of advanced cancer that can severely impact a patient's quality-of-life. LM can result in hydrocephalus (HC) and lead to a range of neurologic sequelae, including weakness, headaches, and altered mental status. Given that patients with LM generally have quite poor prognoses, the decision of how to manage this HC remains unclear and is not only a medical, but also an ethical one. METHODS: We first provide a brief overview of management options for hydrocephalus secondary to LM. We then apply general ethical principles to decision making in LM-associated hydrocephalus that can help guide physicians and patients. RESULTS: Management options for LM-associated hydrocephalus include shunt placement, repeated lumbar punctures, intraventricular reservoir placement, endoscopic third ventriculostomy, or pain management alone without intervention. While these options may offer symptomatic relief in the short-term, each is also associated with risks to the patient. Moreover, data on survival and quality-of-life following intervention is sparse. We propose that the pros and cons of each option should be evaluated not only from a clinical standpoint, but also within a larger framework that incorporates ethical principles and individual patient values. CONCLUSIONS: The decision of how to manage LM-associated hydrocephalus is complex and requires close collaboration amongst the physician, patient, and/or patient's family/friends/community leaders. Ultimately, the decision should be rooted in the patients' values and should aim to optimize a patient's quality-of-life.

Visual outcomes after endoscopic endonasal pituitary adenoma resection: a systematic review and meta-analysis.

PURPOSE: Patients with pituitary adenomas often present with visual deficits. While the aim of endoscopic endonasal transsphenoidal surgery (EETS) is to improve these deficits, permanent worsening is a possible outcome. The aim of this meta-analysis was to evaluate the effect of EETS for pituitary adenomas on visual outcomes. METHODS: A meta-analysis was conducted according to the PRISMA guidelines. Pooled prevalence was calculated for complete recovery, improvement, and deterioration of visual field deficits, visual acuity and unspecified visual function in fixed- and random-effect models, including assessment of heterogeneity (I2) and publication bias (Begg's test). RESULTS: Out of 2636 articles, 35 case series were included in the meta-analysis. Results are described for fixed-effect models. For patients with impaired visual acuity, only one study reported complete recovery (27.2%). Pooled prevalence for improvement was 67.5% (95% CI = 59.1-75.0%), but with considerable heterogeneity (I2: 86.0%), and 4.50% (95% CI = 1.80-10.8%) for patients experiencing deterioration. For patients with visual field deficits, the prevalence was 40.4% (95% CI = 34.8-46.3%) for complete recovery, 80.8% (95% CI = 77.7-83.6%) for improvement, and 2.3% (95% CI = 1.1-4.7%) for deterioration. For the unspecified visual outcomes, pooled prevalence of complete recovery was 32.9% (95% CI: 28.5-37.7%), but with considerable heterogeneity (I2 = 84.2%). The prevalence was 80.9% (95% CI = 77.9-83.6) for improvement and 2.00% (95% CI = 1.10-3.40%) for deterioration. Random-effect models yielded similar results. Publication bias was non-significant for all the outcomes. CONCLUSION: While visual deficits improved after EETS in the majority of patients, complete recovery was only achieved in less than half of the patients and some patients even suffered from visual deterioration.

The history of head transplantation: a review.

BACKGROUND: Since the turn of the last century, the prospect of head transplantation has captured the imagination of scientists and the general public. Recently, head transplant has regained attention in popular media, as neurosurgeons have proposed performing this procedure in 2017. Given the potential impact of such a procedure, we were interested in learning the history of the technical hurdles that need to be overcome, and determine if it is even technically possible to perform such a procedure on humans today. METHOD: We conducted a historical review of available literature on the technical challenges and developments of head transplantation. The many social, psychological, ethical, religious, cultural, and legal questions of head transplantation were beyond the scope of this review. RESULTS: Our historical review identified the following important technical considerations related to performing a head transplant: maintenance of blood flow to an isolated brain via vessel anastomosis; availability of immunosuppressive agents; spinal anastomosis and fusion following cord transfection; pain control in the recipient. Several animal studies have demonstrated success in maintaining recipient cerebral perfusion and achieving immunosuppression. However, there is currently sparse evidence in favor of successful spinal anastomosis and fusion after transection. While recent publications by an Italian group offer novel approaches to this challenge, research on this topic has been sparse and hinges on procedures performed in animal models in the 1970s. How transferrable these older methods are to the human nervous system is unclear and warrants further exploration. CONCLUSIONS: Our review identified several important considerations related to performing a viable head transplantation. Besides the technical challenges that remain, there are important ethical issues to consider, such as exploitation of vulnerable patients and informed consent. Thus, besides the remaining technical challenges, these ethical issues will also need to be addressed before moving these studies to the clinic.