Rapid detection of mutations in CSF-cfTNA with the Genexus Integrated Sequencer.

PURPOSE: Genomic alterations are fundamental for molecular-guided therapy in patients with breast and lung cancer. However, the turn-around time of standard next-generation sequencing assays is a limiting factor in the timely delivery of genomic information for clinical decision-making. METHODS: In this study, we evaluated genomic alterations in 54 cerebrospinal fluid samples from 33 patients with metastatic lung cancer and metastatic breast cancer to the brain using the Oncomine Precision Assay on the Genexus sequencer. There were nine patients with samples collected at multiple time points. RESULTS: Cell-free total nucleic acids (cfTNA) were extracted from CSF (0.1-11.2 ng/µl). Median base coverage was 31,963× with cfDNA input ranging from 2 to 20 ng. Mutations were detected in 30/54 CSF samples. Nineteen (19/24) samples with no mutations detected had suboptimal DNA input (< 20 ng). The EGFR exon-19 deletion and PIK3CA mutations were detected in two patients with increasing mutant allele fraction over time, highlighting the potential of CSF-cfTNA analysis for monitoring patients. Moreover, the EGFR T790M mutation was detected in one patient with prior EGFR inhibitor treatment. Additionally, ESR1 D538G and ESR1::CCDC170 alterations, associated with endocrine therapy resistance, were detected in 2 mBC patients. The average TAT from cfTNA-to-results was < 24 h. CONCLUSION: In summary, our results indicate that CSF-cfTNA analysis with the Genexus-OPA can provide clinically relevant information in patients with brain metastases with short TAT.

Blockade of TGF-ß (Transforming Growth Factor Beta) Signaling by Deletion of Tgfbr2 in Smooth Muscle Cells of 11-Month-Old Mice Alters Aortic Structure and Causes Vasomotor Dysfunction-Brief Report.

BACKGROUND: To test the hypothesis that smooth muscle cell (SMC) TGF-ß (transforming growth factor beta) signaling contributes to maintenance of aortic structure and function beyond the early postnatal period. METHODS: We deleted the TBR2 (type 2 TGF-ß receptor) in SMC of 11-month-old mice (genotype Acta2-CreERT2+/0Tgfbr2f/f, termed TBR2SMΔ) and compared their ascending aorta structure and vasomotor function to controls (Acta2-CreERT20/0Tgfbr2f/f, termed TBR2f/f). RESULTS: We confirmed loss of aortic SMC TBR2 by immunoblotting. Four weeks after SMC TBR2 loss, TBR2SMΔ mice did not have aortic rupture, ulceration, dissection, dilation, or evidence of medial hemorrhage. However, aortic medial area of TBR2SMΔ mice was increased by 27% (0.14±0.01 versus 0.11±0.01 mm2; P=0.01) and medial thickness was increased by 23% (40±1.9 versus 33±1.3 µm; P=0.004) compared with littermate controls. Wire myography performed on ascending aortic rings showed hypercontractility of TBR2SMΔ aortas to phenylephrine (Emax, 15.9±1.2 versus 10.8±0.7 mN; P=0.0003) and reduced relaxation and sensitivity to acetylcholine (Emax, 64±14% versus 96±2%; P=0.001; -logEC50, 6.9±0.1 versus 7.7±0.1; P=0.0001). Neither maximal relaxation nor sensitivity to sodium nitroprusside differed (Emax, 102±0.3% versus 101±0.3%; -logEC50, 8.0±0.04 versus 7.9±0.08; P>0.4 for both). CONCLUSIONS: Loss of TGF-ß signaling in aortic SMC of 1-year-old mice does not cause early severe aortopathy or death; however, it causes mild structural and substantial physiological abnormalities. SMC TGF-ß signaling plays an important role in maintaining aortic homeostasis in older mice. This role should be considered in the design of clinical studies that aim to prevent aortopathy by blocking SMC TGF-ß signaling.

The environmental impact of surgical telemedicine: life cycle assessment of virtual vs. in-person preoperative evaluations for benign foregut disease.

BACKGROUND: Health care accounts for almost 10% of the United States' greenhouse gas emissions, accounting for a loss of 470,000 disability-adjusted life years based on the health effects of climate change. Telemedicine has the potential to decrease health care's carbon footprint by reducing patient travel and clinic-related emissions. At our institution, telemedicine visits for evaluation of benign foregut disease were implemented for patient care during the COVID-19 pandemic. We aimed to estimate the environmental impact of telemedicine usage for these clinic encounters. METHODS: We used life cycle assessment (LCA) to compare greenhouse gas (GHG) emissions for an in-person and a telemedicine visit. For in-person visits, travel distances to clinic were retrospectively assessed from 2020 visits as a representative sample, and prospective data were gathered on materials and processes related to in-person clinic visits. Prospective data on the length of telemedicine encounters were collected and environmental impact was calculated for equipment and internet usage. Upper and lower bounds scenarios for emissions were generated for each type of visit. RESULTS: For in-person visits, 145 patient travel distances were recorded with a median [IQR] distance travel distance of 29.5 [13.7, 85.1] miles resulting in 38.22-39.61 carbon dioxide equivalents (kgCO2-eq) emitted. For telemedicine visits, the mean (SD) visit time was 40.6 (17.1) min. Telemedicine GHG emissions ranged from 2.26 to 2.99 kgCO2-eq depending on the device used. An in-person visit resulted in 25 times more GHG emissions compared to a telemedicine visit (p < 0.001). CONCLUSION: Telemedicine has the potential to decrease health care's carbon footprint. Policy changes to facilitate telemedicine use are needed, as well as increased awareness of potential disparities of and barriers to telemedicine use. Moving toward telemedicine preoperative evaluations in appropriate surgical populations is a purposeful step toward actively addressing our role in health care's large carbon footprint.

Opioid versus non-opioid postoperative pain management in otolaryngology.

BACKGROUND: The opioid epidemic in the United States has had devastating consequences, with many opioid-related deaths and a significant economic toll. Opioids have a significant role in postoperative pain management. Here we aim to analyze differences in postoperative opioid and non-opioid pain medications regimens following common otolaryngological surgeries between two large tertiary care medical centers: the Milton S. Hershey Medical Center, USA (HMC) and The Chaim Sheba Medical center, Israel (SMC). METHODS: A retrospective chart review of patients undergoing common otolaryngological procedures during the years 2017-2019 was conducted at two tertiary care centers, one in the U.S. and the other in Israel. Types and doses of postoperative pain medications ordered and administered during admission were analyzed. Average doses ordered and administered in 24 h were calculated. Opioid medications were converted to a standardized unit of morphine milliequivalents (MME). Chi-square test and Wilcoxon rank-sum test were used to compare the groups. RESULTS: The study included 204 patients (103 U.S., 101 Israel). Patient demographics were similar except for a longer length of stay in Israel (p < 0.01). In the U.S., 95% of patients were ordered opioids compared to 70% in Israel (P < 0.01). In the U.S., 68.9% of patients ordered opioids received the medications compared to 29.7% in Israel. The median opioid dose ordered in the U.S. was 45MME/24 h compared to 30MME/24 h in Israel (P < 0.01), while median dose received in the U.S. was 15MME/24 h compared to 3.8MME/24 h in Israel (P < 0.01). Opioid prescriptions at discharge were given to 92% of patients in the U.S. compared to 4% of patients in Israel (p < 0.01). A significantly higher number of patients in the U.S. were prescribed acetaminophen and ibuprofen (p < 0.0001). Dipyrone was prescribed to 78% of patients in Israel. CONCLUSIONS: HMC demonstrated a significantly more permissive approach to both prescribing and consuming opioid medications for postoperative pain management than SMC for similar, common otolaryngological surgeries. Non-opioid alternatives and examining the cultural and medical practice-based differences contributing to the opioid epidemic should be discussed and reevaluated.

BRAF/MEK Dual Inhibitors Therapy in Progressive and Anaplastic Pleomorphic Xanthoastrocytoma: Case Series and Literature Review.

Recurrent and anaplastic pleomorphic xanthoastrocytoma (r&aPXA) is a rare primary brain tumor that is challenging to treat. Two-thirds of PXA tumors harbor a BRAF gene mutation. BRAF inhibitors have been shown to improve tumor control. However, resistance to BRAF inhibition develops in most cases. Concurrent therapy with MEK inhibitors may improve tumor control and patient survival. In this study, we identified 5 patients diagnosed with BRAF-mutated PXA who received BRAF and MEK inhibitors over a 10-year interval at our institution. Patient records were evaluated, including treatments, adverse effects (AEs), outcomes, pathology, next-generation sequencing, and MRI. The median age was 22 years (range, 14-66 years), 60% male, and 60% anaplastic PXA. Median overall survival was 72 months (range, 19-112 months); 1 patient died of tumor-related hemorrhage while off therapy, and the other 4 experienced long-term disease control (21, 72, 98, and 112 months, respectively). Dual BRAF/MEK inhibitors were well tolerated, with only grade 1-2 AEs, including rash, neutropenia, fatigue, abdominal discomfort, and diarrhea. No grade 3-5 AEs were detected. A literature review was also performed of patients diagnosed with BRAF-mutated PXA and treated with BRAF and/or MEK inhibitors through August 2021, with a total of 32 cases identified. The median age was 29 years (range, 8-57 years) and the median PFS and OS were 8.5 months (range, 2-35 months) and 35 months (range, 10-80 months), respectively. The most common AEs were grade 1-2 fatigue and skin rash. Results of this case series and literature review indicate that dual-drug therapy with BRAF and MEK inhibitors for r&aPXA with BRAF V600E mutation may delay tumor progression without unexpected AEs.

IDH1 p.R132H ctDNA and D-2-hydroxyglutarate as CSF biomarkers in patients with IDH-mutant gliomas.

INTRODUCTION: We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas. METHODS: CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images. RESULTS: The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 of the 9 samples from patients with IDH-mutant glioma, and IDH1 p.R132H mutation was detected in 5 of the 7 samples. The MAF ranged from 0.3 to 39.95%. Total 2HG level, D-2HG level, and D/L-2HG ratio in CSF were significantly higher in patients with IDH-mutant gliomas than in patients with IDH-wildtype gliomas. D-2HG level and D/L-2HG ratio correlated with total tumor volume in patients with IDH-mutant gliomas but not in patients with IDH-wildtype gliomas. CONCLUSION: Our results suggest that detection of IDH1 p.R132H mutation by ddPCR and increased D-2HG level in CSF may help identify IDH-mutant gliomas. Our results also suggest that D-2HG level and D/L-2HG ratio correlate with tumor volume in patients with IDH-mutant gliomas. Further prospective studies with larger cohorts are needed to validate these findings.

Impacts of genotypic variants on survival following reoperation for recurrent glioblastoma.

INTRODUCTION: Recurrent glioblastoma (rGBM) prognosis is dismal. In the absence of effective adjuvant treatments for rGBM, re-resections remain prominent in our arsenal. This study evaluates the impact of reoperation on post-progression survival (PPS) considering rGBM genetic makeup. METHODS: To assess the genetic heterogeneity and treatment-related changes (TRC) roles in re-operated or medically managed rGBMs, we compiled demographic, clinical, histopathological, and next-generation genetic sequencing (NGS) characteristics of these tumors from 01/2005 to 10/2019. Survival data and reoperation were analyzed using conventional and random survival forest analysis (RSF). RESULTS: Patients harboring CDKN2A/B loss (p = 0.017) and KDR mutations (p = 0.031) had notably shorter survival. Reoperation or bevacizumab were associated with longer PPS (11.2 vs. 7.4-months, p = 0.006; 13.1 vs 6.2, p < 0.001). Reoperated patients were younger, had better performance status and greater initial resection. In 136/273 (49%) rGBMs undergoing re-operation, CDKN2A/B loss (p = 0.03) and KDR mutations (p = 0.02) were associated with shorter survival. In IDH-WT rGBMs with NGS data (n = 166), reoperation resulted in 7.0-month longer survival (p = 0.004) than those managed medically. This reoperation benefit was independently identified by RSF analysis. Stratification analysis revealed that EGFR-mutant, CDKN2A/B-mutant, NF1-WT, and TP53-WT rGBM IDH-WT subgroups benefit most from reoperation (p = 0.03). Lastly, whether or not TRC was prominent at re-operation does not have any significant impact on PPS (10.5 vs. 11.5-months, p = 0.77). CONCLUSIONS: Maximal safe re-resection significantly lengthens PPS regardless of genetic makeup, but reoperations are especially beneficial for IDH-WT rGBMs with EGFR and CDKN2A/B mutations with TP53-WT, and NF1-WT. Histopathology at recurrence may be an imperfect gauge of disease severity at progression and the imaging progression may be more reflective of the prognosis.

Postmortem study of organ-specific toxicity in glioblastoma patients treated with a combination of temozolomide, irinotecan and bevacizumab.

PURPOSE: Systemic chemotherapy including monotherapy with temozolomide (TMZ) or bevacizumab (BEV); two-drug combinations, such as irinotecan (IRI) and BEV, TMZ and BEV and a three-drug combination with TMZ, IRI and BEV (TIB) have been used in treating patients with progressive high-grade gliomas including glioblastoma (GBM). Most patients tolerated these regimens well with known side effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ- or system- specific toxicities from chemotherapy agents have never been examined by postmortem study. This is the largest cohort used to address this issue in glioma patients. METHODS: Postmortem tissues (from all major systems and organs) were prospectively collected and examined by standard institution autopsy and neuropathological procedures from 76 subjects, including gliomas (N = 68, 44/M, and 24/F) and brain metastases (N = 8, 5/M, and 3/F) between 2009 and 2019. Standard hematoxylin and eosin (H&E) were performed on all major organs including brain specimens. Electronic microscopic (EM) study was carried out on 14 selected subject's kidney samples per standard EM protocol. Medical records were reviewed with adverse events (AEs) analyzed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. A swimmer plot was utilized to visualize the timelines of patient history by treatment group. The binary logistic regression models were performed to explore any associations between treatment strategies and incident myelosuppression. RESULTS: Twenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1-25) cycles] at tumor recurrence. Exposure to IRI significantly increased the frequency of CM (p = 0.05). No unexpected adverse events clinically, or permanent end-organ damage during postmortem examination was identified in glioma subjects who had received standard or prolonged duration of BEV, TMZ or TIB regimen-based chemotherapies except rare events of bone marrow suppression. The most common causes of death (COD) were tumor progression (63.2%, N = 43) followed by aspiration pneumonia (48.5%, N = 33) in glioma subjects. No COD was attributed to acute toxicity from TIB. The study also demonstrated that postmortem kidney specimen is unsuitable for studying renal ultrastructural pathological changes due to autolysis. CONCLUSION: There is no organ or system toxicity by postmortem examinations among glioma subjects who received BEV, TMZ or TIB regimen-based chemotherapies regardless of durations except for occasional bone marrow suppression and reversible myelosuppression clinically. IRI, but not the extended use of TMZ, significantly increased CM in recurrent glioma patients. COD most commonly resulted from glioma tumor progression with infiltration to brain stem and aspiration pneumonia.

Loss of Transforming Growth Factor Beta Signaling in Aortic Smooth Muscle Cells Causes Endothelial Dysfunction and Aortic Hypercontractility.

[Figure: see text].

The impact of socioeconomic status on telemedicine utilization during the COVID-19 pandemic among surgical clinics at an academic tertiary care center.

BACKGROUND: The COVID-19 pandemic caused many surgical providers to conduct outpatient evaluations using remote audiovisual conferencing technology (i.e., telemedicine) for the first time in 2020. We describe our year-long institutional experience with telemedicine in several general surgery clinics at an academic tertiary care center and examine the relationship between area-based socioeconomic measures and the likelihood of telemedicine participation. METHODS: We performed a retrospective review of our outpatient telemedicine utilization among four subspecialty clinics (including two acute care and two elective surgery clinics). Geocoding was used to link patient visit data to area-based socioeconomic measures and a multivariable analysis was performed to examine the relationship between socioeconomic indicators and patient participation in telemedicine. RESULTS: While total outpatient visits per month reached a nadir in April 2020 (65% decrease in patient visits when compared to January 2020), there was a sharp increase in telemedicine utilization during the same month (38% of all visits compared to 0.8% of all visits in the month prior). Higher rates of telemedicine utilization were observed in the two elective surgery clinics (61% and 54%) compared to the two acute care surgery clinics (14% and 9%). A multivariable analysis demonstrated a borderline-significant linear trend (p = 0.07) between decreasing socioeconomic status and decreasing odds of telemedicine participation among elective surgery visits. A sensitivity analysis to examine the reliability of this trend showed similar results. CONCLUSION: Telemedicine has many patient-centered benefits, and this study demonstrates that for certain elective subspecialty clinics, telemedicine may be utilized as the preferred method for surgical consultations. However, to ensure the equitable adoption and advancement of telemedicine services, healthcare providers will need to focus on mitigating the socioeconomic barriers to telemedicine participation.

The Role of Apparent Diffusion Coefficient Values in Glioblastoma: Differentiating Tumor Progression Versus Treatment-Related Changes.

OBJECTIVE: Glioblastoma represents the most common primary brain malignancy with a median survival of 15 months. Follow-up examinations are crucial to establish the presence of tumor recurrence, as well as treatment-associated changes such as ischemic infarction and radiation effects. Even though magnetic resonance imaging is a valuable tool, a histopathological diagnosis is often required because of imaging overlap between tumor recurrence and treatment associated changes. We set out to measure the apparent diffusion coefficient (ADC) values of the lesions in magnetic resonance imaging scans of treated glioblastoma patients to investigate if ADC values could accurately differentiate between tumor progression, radiation-related changes, and ischemic infarctions. METHODS: We evaluated ADC values among 3 groups, patients with tumor progression, radiation necrosis, and ischemic infarctions. The regions of interest were placed in the areas of greatest hypointensity among solid lesions using the ADC maps, excluding areas with necrotic, cystic, or hemorrhagic changes. The ADC values of the contralateral normal appearing white matter were also measured as the reference value for each patient. The relative ADC (rADC) values were measured for all 3 groups. Comparison between lesions and normal white matter was evaluated by Wilcoxon signed test. RESULTS: A total of 157 patients were included in the study; 49 patients classified as tumor progression, 58 patients as radiation necrosis, and 50 patients as ischemic infarctions. The mean ± SD ADC value was 752.8 ± 132.5 for tumor progression, 479.0 ± 105.2 for radiation-related changes, and 250.1 ± 57.2 for ischemic infarctions. The mean ± SD rADC value was 1.07 ± 0.22 for tumor progression, 0.66 ± 0.14 for radiation necrosis, and 0.34 ± 0.08 for ischemic infarctions. The mean rADC values were significantly higher in tumor progression, compared with both radiation necrosis and ischemic changes ( P < 0.001). CONCLUSIONS: The present study demonstrates that ADC values are a helpful tool to differentiate between tumor progression, radiation necrosis, and posttreatment ischemic changes.

PTEN mutations predict benefit from tumor treating fields (TTFields) therapy in patients with recurrent glioblastoma.

INTRODUCTION: Optimal treatment for recurrent glioblastoma isocitrate dehydrogenase 1 and 2 wild-type (rGBM IDH-WT) is not standardized, resulting in multiple therapeutic approaches. A phase III clinical trial showed that tumor treating fields (TTFields) monotherapy provided comparable survival benefits to physician's chemotherapy choice in rGBM. However, patients did not equally benefit from TTFields, highlighting the importance of identifying predictive biomarkers of TTFields efficacy. METHODS: A retrospective review of an institutional database with 530 patients with infiltrating gliomas was performed. Patients with IDH-WT rGBM receiving TTFields at first recurrence were included. Tumors were evaluated by next-generation sequencing for mutations in 205 cancer-related genes. Post-progression survival (PPS) was examined using the log-rank test and multivariate Cox-regression analysis. RESULTS: 149 rGBM patients were identified of which 29 (19%) were treated with TTFields. No significant difference in median PPS was observed between rGBM patients who received versus did not receive TTFields (13.9 versus 10.9 months, p = 0.068). However, within the TTFields-treated group (n = 29), PPS was improved in PTEN-mutant (n = 14) versus PTEN-WT (n = 15) rGBM, (22.2 versus 11.6 months, p = 0.017). Within the PTEN-mutant group (n = 70, 47%), patients treated with TTFields (n = 14) had longer median PPS (22.2 versus 9.3 months, p = 0.005). No PPS benefit was observed in PTEN-WT patients receiving TTFields (n = 79, 53%). CONCLUSIONS: TTFields therapy conferred a significant PPS benefit in PTEN-mutant rGBM. Understanding the molecular mechanisms underpinning the differences in response to TTFields therapy could help elucidate the mechanism of action of TTFields and identify the rGBM patients most likely to benefit from this therapeutic option.

Genomic alterations predictive of response to radiosurgery in recurrent IDH-WT glioblastoma.

INTRODUCTION: Despite aggressive treatment, glioblastoma invariably recurs. The optimal treatment for recurrent glioblastoma (rGBM) is not well defined. Stereotactic radiosurgery (SRS) for rGBM has demonstrated favorable outcomes for selected patients; however, its efficacy in molecular GBM subtypes is unknown. We sought to identify genetic alterations that predict response/outcomes from SRS in rGBM-IDH-wild-type (IDH-WT). METHODS: rGBM-IDH-WT patients undergoing SRS at first recurrence and tested by next-generation sequencing (NGS) were reviewed (2009-2018). Demographic, clinical, and molecular characteristics were evaluated. NGS interrogating 205-genes was performed. Primary outcome was survival from GK-SRS assessed by Kaplan-Meier method and multivariable Cox proportional-hazards. RESULTS: Sixty-three lesions (43-patients) were treated at 1st recurrence. Median age was 61-years. All patients were treated with resection and chemoradiotherapy. Median time from diagnosis to 1st recurrence was 8.7-months. Median cumulative volume was 2.895 cm3 and SRS median marginal dose was 18 Gy (median isodose-54%). Bevacizumab was administered in 81.4% patients. PFS from SRS was 12.9-months. Survival from SRS was 18.2-months. PTEN-mutant patients had a longer PFS (p = 0.049) and survival from SRS (p = 0.013) in multivariable analysis. Although no statistically significant PTEN-mutants patients had higher frequency of radiation necrosis (21.4% vs. 3.4%) and lower in-field recurrence (28.6% vs. 37.9%) compared to PTEN-WT patients. CONCLUSIONS: SRS is a safe and effective treatment option for selected rGBM-IDH-WT patients following first recurrence. rGBM-IDH-WT harboring PTEN-mutation have improved survival with salvage SRS compared to PTEN-WT patients. PTEN may be used as a molecular biomarker to identify a subset of rGBM patients who may benefit the most from SRS.

Siderophore piracy enhances Vibrio cholerae environmental survival and pathogenesis.

Vibrio cholerae, the aetiological agent of cholera, possesses multiple iron acquisition systems, including those for the transport of siderophores. How these systems benefit V. cholerae in low-iron, polymicrobial communities in environmental settings or during infection remains poorly understood. Here, we demonstrate that in iron-limiting conditions, co-culture of V. cholerae with a number of individual siderophore-producing microbes significantly promoted V. cholerae growth in vitro. We further show that in the host environment with low iron, V. cholerae colonizes better in adult mice in the presence of the siderophore-producing commensal Escherichia coli. Taken together, our results suggest that in aquatic reservoirs or during infection, V. cholerae may overcome environmental and host iron restriction by hijacking siderophores from other microbes.

Global post-marketing safety surveillance of Tumor Treating Fields (TTFields) in patients with high-grade glioma in clinical practice.

INTRODUCTION: Tumor Treating Fields (TTFields; antimitotic treatment) delivers low-intensity, intermediate-frequency, alternating electric fields through skin-applied transducer arrays. TTFields (200 kHz) was FDA-approved in glioblastoma (GBM), based on the phase 3 EF-11 (recurrent GBM, rGBM) and EF-14 (newly diagnosed GBM, ndGBM) trials. The most common TTFields-related adverse event (AE) in both trials was array-associated skin irritation. We now report on TTFields-related AEs in the real-world, clinical practice setting. METHODS: Unsolicited, post-marketing surveillance data from TTFields-treated patients (October 2011-February 2019) were retrospectively analyzed using MedDRA v21.1 preferred terms, stratified by region (US, EMEA [Europe, Middle East, Africa], Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma/oligodendroglioma, other brain tumors), and age (< 18 [pediatric], 18-64 [adults], ≥ 65 [elderly]; years of age). RESULTS: Of 11,029 patients, 53% were diagnosed with ndGBM and 39% were diagnosed with rGBM at any line of disease recurrence. Most were adults (73%), 26% were elderly, and the male-to-female ratio was ~ 2:1 (close to published ratios of typical GBM populations). The most commonly reported TTFields-related AE was array-associated skin reaction, occurring in patients with ndGBM (38%), rGBM (29%), anaplastic astrocytoma/oligodendroglioma (38%), and other brain tumors (31%); as well as 37% of pediatric, 34% of adult, and 36% of elderly patients. Most skin AEs were mild/moderate and manageable. Other TTFields-related AEs in patients with ndGBM/rGBM included under-array heat sensation (warmth; 11%, 10%, respectively) and electric sensation (tingling; 11%, 9%, respectively), and headache (7%, 6%, respectively). CONCLUSIONS: This TTFields safety surveillance analysis in > 11,000 patients revealed no new safety concerns, with a favorable safety profile comparable with published TTFields/GBM trials. The safety profile remained consistent among subgroups, suggesting feasibility in multiple populations, including elderly patients.

Additional genetic alterations in BRAF-mutant gliomas correlate with histologic diagnoses.

INTRODUCTION: Recently, the term "Diffuse glioma, BRAF V600E-mutant" has been recommended for IDH-wildtype gliomas with BRAF p.V600E mutation and without CDKN2A/B deletion. However, additional alterations in gliomas that coexist with BRAF-mutations are poorly defined. METHODS: We analyzed next-generation sequencing results in 315 cancer-associated genes for 372 gliomas from our institution (2010 to 2017). In addition, we reviewed IDH-WT gliomas with mutation and copy-number alterations available in cBioPortal, to further characterize BRAF-mutant gliomas. RESULTS: Seventeen (4.6%) showed BRAF mutations. Tumor types included 8 glioblastomas, 2 epithelioid glioblastomas (E-GBM), 2 pleomorphic xanthoastrocytomas (PXA), 1 anaplastic oligodendroglioma, 1 diffuse astrocytoma, and 3 pilocytic astrocytomas. Fifty-three percent (53%) of cases exhibited BRAF-alterations other than p.V600E. The majority of the tumors were localized in the temporal lobe (52.9%). In addition to BRAF mutations, glioblastomas showed concomitant mutations in TP53 (3/8), CDKN2A/B-loss (6/8), TERT-promoter (6/8), and/or PTEN (5/8). Both E-GBMs and PXAs showed CDKN2A/B-loss and BRAF p.V600E with absence of TERTp, TP53, and PTEN mutations. Similar findings were observed in BRAF-mutant infiltrating gliomas from cBioPortal. CONCLUSIONS: Knowledge of additional alterations that co-occur with BRAF-mutations in gliomas may improve diagnosis and help identify patients that could benefit from targeted therapies. Furthermore, we provide examples of two patients whose tumors responded to BRAF pathway inhibitors, arguing in favor of these therapies in patients with BRAF-mutant gliomas.

Staged margin-controlled excision (SMEX) for lentigo maligna melanoma in situ.

BACKGROUND: No consensus exists regarding the best surgical strategy to achieve clear surgical margins while minimizing tissue excision when definitely excising lentigo maligna melanoma in situ (LM). The staged margin controlled excision (SMEX) technique is a modification of the spaghetti technique that allows surgeons to minimize margins and ensure complete excision of LM. OBJECTIVES: Our objectives were twofold: a) to evaluate the effectiveness of SMEX for treatment of LM and b) detail the SMEX technique. METHODS: A retrospective chart review of adult patients who underwent the SMEX technique for treatment of LM from 2011 to 2016 was conducted. RESULTS: Twenty-four patients were identified with predominantly facial lesions. The mean defect size was 12.1 cm2 . A mean number of two SMEX procedures, with an average margin of 9 mm, were required to obtain complete excision of the LM. Using SMEX, we achieved 100% clearance of LM over a median follow up period of 18 months, with a range of 1-63 months. CONCLUSIONS: SMEX offers a reliable surgical excision method that ensures complete excision of LM in a cosmetically sensitive manner. The recurrence outcomes of SMEX are comparable, if not better, than those of alternative excision techniques in the literature.

Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma.

We characterized health-related quality of life (HRQoL), cognitive, and functional status in newly diagnosed glioblastoma (GBM) patients receiving Tumor treating fields (TTFields) with temozolomide (TMZ) versus TMZ alone in a planned interim analysis of a randomized phase III trial [NCT00916409], which showed significant improvement in progression-free and overall survival with TTFields/TMZ. After radiotherapy with concomitant TMZ, newly diagnosed GBM patients were randomized (2:1) to TTFields/TMZ (n = 210) or TMZ (n = 105). Interim analysis was performed in 315 patients with ≥18 months of follow-up. HRQoL, a secondary endpoint, was evaluated in per-protocol patient population and expressed as change from baseline (CFB) at 3, 6, and 9 months for each subscale in the EORTC QLQ-C30/BN20. Karnofsky performance scores (KPS) and Mini-Mental State Examination scores (MMSE) were assessed. CFB in HRQoL was balanced in treatment groups at the 12-month time point. Initially, HRQoL improved in patients treated with TTFields/TMZ (CFB3: 24% and CFB6: 13%) versus TMZ (CFB3: -7% and CFB6: -17%), though this difference was no longer evident at the 9-month point. General scales, including physical and social functioning, showed no difference at 9 and 12 months. TTFields/TMZ group reported higher concerns of "itchy skin". KPS over 12 months was just below 90 in both groups. Cognitive status (MMSE) was stable over time. HRQoL, KPS, and MMSE were balanced in both groups over time. There was no preliminary evidence that HRQoL, cognitive, and functional status is adversely affected by the continuous use of TTFields.

Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial.

Importance: Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Objective: To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. Design, Setting, and Participants: In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Interventions: Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles). Main Outcomes and Measures: Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. Results: Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone. Conclusions and Relevance: In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. Trial Registration: clinicaltrials.gov Identifier: NCT00916409.