NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Post-injury tendon mechanics are not affected by tamoxifen treatment.

PURPOSE: A growing interest in the mechanisms that govern tendon healing has resulted in the develop-ment of tools, such as the tamoxifen-inducible mouse knockdown model, to address these questions. However, tamoxifen is a selective estrogen receptor modulator and may interfere with the tendon healing process. The objective of this study was to evaluate the effects of tamoxifen on post-injury tendon mechanics in wild-type mice. METHODS: The mice underwent treatment at the time of injury using an established mouse injury model and the injured tendons were evaluated 3 weeks post-injury. The treatment contained tamoxifen suspended in corn oil and was compared to a treatment with only corn oil, as well as mice with no treatment. Tendons were evaluated by measuring the quasi-static and viscoelastic mechanics, collagen fiber realignment, cellularity, and nuclear morphology. RESULTS: Mechanical testing of the tendons post-injury revealed no changes to viscoelastic mechanics, quasi-static mechanics, or collagen realignment during loading after tamoxifen treatment with the dosage regimen utilized (three daily injections of 4.5 mg/40 g body weight). Additionally, histological analysis revealed no changes to cellularity or cell nuclear shape. CONCLUSION: Overall, this study revealed that tamoxifen treatment at the time of tendon injury did not result in changes to tendon mechanics or the histological parameters at 3 weeks post-injury.

Need for clarity and context in case reports on kratom use, assessment, and intervention.

This Letter to the Editor is a response to Broyan and colleagues who recently published a Case Report presenting data on 28 patients in the United States who identified kratom as their primary substance of use and who were subsequently induced on buprenorphine/naloxone for a reported diagnosis of kratom use disorder. We applaud the authors for helping to advance the science on kratom and recognize the difficulties in conducting kratom-related clinical assessment and research. However, a number of inconsistences and generalizations were identified in this Case Report, which also lacked some critical context. Importantly, such inconsistencies and generalizations can be observed throughout kratom-specific case reports. We feel this is now an important opportunity to highlight these issues that are present in the Broyan and colleagues Case report but emphasize that they are not unique to it. We do this with the hope that by acknowledging these issues it can help inform editors, clinicians, and researchers who may not be familiar with kratom and, as a result of this unfamiliarity, may inadvertently present findings in a manner that could confuse readers and even misinform clinical researchers and practitioners.

Decreased Clinical Toxicity and Two-Phase Elimination Kinetics Observed After Intravenous Iron Sucrose Overdose.

BACKGROUND: Management of oral iron overdoses is well-established, but there is limited literature regarding intravenous iron sucrose overdoses. Indications for administering deferoxamine after oral iron overdoses include clinical signs and symptoms of toxicity, along with a serum iron concentration ≥ 500 µg/dL. Reported signs and symptoms of iron sucrose overdose do not appear to correlate with those of oral iron overdoses. CASE REPORT: We present a case of intravenous iron sucrose overdose in a clinically well-appearing patient with a presenting serum iron concentration that was several times higher than the usual threshold concentration for initiating deferoxamine treatment. A 21-year-old woman presented to the emergency department after an accidental intravenous iron sucrose overdose. The patient received a home infusion of 1000 mg iron sucrose, which was five times the prescribed dose. Her presenting serum iron concentration was 1799 µg/dL, with bicarbonate and anion gap both within normal limits and an unremarkable physical examination. Because she did not have evidence of severe iron toxicity, she was treated supportively and deferoxamine was not administered. Her serum iron concentration decreased below the toxic range over the next 14 h, and she was discharged home the next day. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This patient was managed successfully with expectant care alone, suggesting that iron sucrose overdose has much lower toxicity than oral iron salt overdose. This discrepancy between measured iron concentrations and clinical presentation may be explained by the elimination kinetics of iron sucrose having separate redistribution and elimination phases.

A comparative analysis of kratom exposure cases in Thailand and the United States from 2010-2017.

Background: Interest in the Southeast Asian natural remedy kratom has increased in Western countries recently, along with increasing concern over its potential toxic effects.Objective: To describe and compare demographics, common co-exposure substances, clinical effects, treatments, and medical outcomes of kratom "abuse" exposures in the United States (US) and Thailand.Methods: This is a retrospective analysis of kratom "abuse" exposures, defined as use when attempting to gain a psychotropic effect, reported to the National Poison Data System (NPDS) in the US and the Ramathibodi Poison Center (RPC) in Thailand from 2010 to 2017. Multivariate analysis identified risk factors for severe medical outcomes, defined as both ICU admissions and death.Results: Nine-hundred-twenty-eight cases were included (760 from NPDS and 168 from RPC). A greater proportion of cases involved co-exposures in Thailand (64.8% versus 37.4%; odds ratio [OR] = 3.10, 95% confidence interval [CI] = 2.15-4.47, p < .01). Both countries had a similar prevalence of opioid and benzodiazepine co-ingestions, but the US had more co-ingestions with other sedatives (4.6% versus 0%, OR = 0, 95% CI = 0-0.47, p < .01). Common clinical effects included tachycardia (30.4%), agitation/irritability (26.2%), and drowsiness/lethargy (21.1%). Six deaths occurred, including one single-substance exposure in the US, three multiple-substance exposures in the US, and two multiple-substance exposures in Thailand. Severe medical outcomes were reported more frequently in the US (OR = 18.82, 95% CI = 5.85-60.56, p < .01).Conclusions: Despite lower frequencies of co-ingestants overall, US kratom abuse exposures yielded greater clinical severity. This disparity may be attributable to differences in the products labeled "kratom," greater sedative co-exposures in the US, and/or differences in population genetics or use patterns.

Spatial and temporal variation in nest temperatures forecasts sex ratio skews in a crocodilian with environmental sex determination.

Species displaying temperature-dependent sex determination (TSD) are especially vulnerable to the effects of a rapidly changing global climate due to their profound sensitivity to thermal cues during development. Predicting the consequences of climate change for these species, including skewed offspring sex ratios, depends on understanding how climatic factors interface with features of maternal nesting behaviour to shape the developmental environment. Here, we measure thermal profiles in 86 nests at two geographically distinct sites in the northern and southern regions of the American alligator's (Alligator mississippiensis) geographical range, and examine the influence of both climatic factors and maternally driven nest characteristics on nest temperature variation. Changes in daily maximum air temperatures drive annual trends in nest temperatures, while variation in individual nest temperatures is also related to local habitat factors and microclimate characteristics. Without any compensatory nesting behaviours, nest temperatures are projected to increase by 1.6-3.7°C by the year 2100, and these changes are predicted to have dramatic consequences for offspring sex ratios. Exact sex ratio outcomes vary widely depending on site and emission scenario as a function of the unique temperature-by-sex reaction norm exhibited by all crocodilians. By revealing the ecological drivers of nest temperature variation in the American alligator, this study provides important insights into the potential consequences of climate change for crocodilian species, many of which are already threatened by extinction.

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

Induced Knockdown of Decorin, Alone and in Tandem With Biglycan Knockdown, Directly Increases Aged Murine Patellar Tendon Viscoelastic Properties.

Tendon injuries increase with age, yet the age-associated changes in tendon properties remain unexplained. Decorin and biglycan are two matrix proteoglycans that play complex roles in regulating tendon formation, maturation, and aging, most notably in extracellular matrix assembly and maintenance. However, the roles of decorin and biglycan have not been temporally isolated in a homeostatic aged context. The goal of this work was to temporally isolate and define the roles of decorin and biglycan in regulating aged murine patellar tendon mechanical properties. We hypothesized that decorin would have a larger influence than biglycan on aged tendon mechanical properties and that biglycan would have an additive role in this regulation. When decorin and biglycan were knocked down in aged tendons, minimal changes in gene expression were observed, implying that these models directly define the roles of decorin and biglycan in regulating tendon mechanical properties. Knockdown of decorin or biglycan led to minimal changes in quasi-static mechanical properties. However, decorin deficiency led to increases in stress relaxation and phase shift that were exacerbated when coupled with biglycan deficiency. This study highlights an important role for decorin, alone and in tandem with biglycan, in regulating aged tendon viscoelastic properties.

Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations.

The delayed-release tablet formulation of posaconazole (POS-tab) results in higher plasma POS trough concentrations (Cmin) than the oral suspension (POS-susp), which raises the question of the utility of therapeutic drug monitoring (TDM). We aimed to compare the variability of the POS Cmin for the two formulations and identify determinants of the POS-tab Cmin and its variability. Demographic, biological, and clinical data from 77 allogeneic hematopoietic stem cell transplant patients (874 Cmin) treated with POS-tab (n = 41), POS-susp (n = 29), or both (n = 7) from January 2015 to December 2016 were collected retrospectively. Interpatient and within-subject coefficients of variation (CVs) of the Cmin adjusted to dose (D) were calculated for each formulation. Between-group comparisons were performed using a linear mixed effects model. The POS Cmin was higher for the tablet than for the suspension (median [25th-75th percentile]: 1.8 [1.2-2.4] mg/liter versus 1.2 [0.7-1.6] mg/liter, P < 0.0001). Interpatient CVs for the tablet and suspension were 60.8 versus 63.5% (P = 0.7), whereas within-subject CVs were 39.7 and 44.9%, respectively (P = 0.3). Univariate analysis showed that age and treatment by POS-tab were significantly and positively associated with the POS Cmin, whereas diarrhea was associated with a diminished POS Cmin Multivariate analysis identified treatment with POS-tab and diarrhea as independent factors of the POS Cmin, with a trend toward a lower impact of diarrhea during treatment with POS-tab (P = 0.07). Despite increased POS exposure with the tablet formulation, the variability of the POS Cmin was not significantly lower than that of the suspension. This suggests that TDM may still be useful to optimize tablet POS therapy.

Breast conservation versus mastectomy in patients with T3 breast cancers (> 5 cm): an analysis of 37,268 patients from the National Cancer Database.

PURPOSE: Breast conservation therapy (BCT) is standard for T1-T2 tumors, but early trials excluded breast cancers > 5 cm. This study was performed to assess patterns and outcomes of BCT for T3 tumors. METHODS: We reviewed the National Cancer Database (NCDB) for noninflammatory breast cancers > 5 cm, between 2004 and 2011 who underwent BCT or mastectomy (Mtx) with nodal evaluation. Patients with skin or chest wall involvement were excluded. Patients having clinical T3 tumors were analyzed to determine outcomes based upon presentation, with those having pathologic T3 tumors, subsequently assessed, irrespective of presentation. Overall survival (OS) was analyzed using multivariable Cox proportional hazards models, with adjusted survival curves estimated using inverse probability weighting. RESULTS: After exclusions, 37,268 patients remained. Median age and tumor size for BCT versus Mtx were 53 versus 54 years (p < 0.001) and 6.0 versus 6.7 cm (p < 0.001), respectively. Predictors of BCT included age, race, location, facility type, year of diagnosis, tumor size, grade, histology, nodes examined and positive, and administration of chemotherapy and radiotherapy. OS was similar between Mtx and BCT (p = 0.36). This held true when neoadjuvant chemotherapy patients were excluded (p = 0.39). BCT percentages declined over time (p < 0.001), while tumor sizes remained the same (p = 0.77). Median follow-up was 51.4 months. CONCLUSIONS: OS for patients with T3 breast cancers is similar whether patients received Mtx or BCT, confirming that tumor size should not be an absolute BCT exclusion. Declining use of BCT for tumors > 5 cm in younger patients may be accounted for by recent trends toward mastectomy.

How the Comprehensive Cancer Control National Partnership shapes the public health workforce.

This paper explores how, through its extensive network of partners, the Comprehensive Cancer Control National Partnership (National Partnership) has provided a robust array of trainings, learning institutes, webinars, workshops, mentorship programs, and direct technical assistance to comprehensive cancer control programs and coalitions over the past 20 years. Mapping these activities to specific cancer control competencies revealed that the efforts of the National Partnership adequately address the core competencies necessary for an effective workforce and have the potential to increase practitioner capacity to adopt and implement evidence-based cancer control programs. Ensuring the continued availability and uptake of these tools, trainings and partnerships could potentially address gaps and barriers in the public health workforce related to evidence-based practice.

Impact of Road Salt on Drinking Water Quality and Infrastructure Corrosion in Private Wells.

Increased road salt use and resulting source water contamination has widespread implications for corrosion of drinking water infrastructure, including chloride acceleration of galvanic corrosion and other premature plumbing failures. In this study, we utilized citizen science sampling, bench-scale corrosion studies, and state-level spatial modeling to examine the potential extent of chloride concentrations in groundwater and the resulting impact on private wells in New York. Across the sampled community, chloride levels varied spatially, with the highest levels in private wells downgradient of a road salt storage facility followed by wells within 30 m of a major roadway. Most well users surveyed (70%) had stopped drinking their well water for aesthetic and safety reasons. In the bench-scale experiment, increasing chloride concentration in water increased galvanic corrosion and dezincification of plumbing materials, resulting in increased metal leaching and pipe wall thinning. Our simple spatial analysis suggests that 2% of private well users in New York could potentially be impacted by road salt storage facilities and 24% could potentially be impacted by road salt application. Our research underscores the need to include the damage to public and privately owned drinking water infrastructure in future discussion of road salt management.

Emerging Trends in the Management of Brain Metastases from Non-small Cell Lung Cancer.

PURPOSE OF REVIEW: To summarize current approaches in the management of brain metastases from non-small cell lung cancer (NSCLC). RECENT FINDINGS: Local treatment has evolved from whole-brain radiotherapy (WBRT) to increasing use of stereotactic radiosurgery (SRS) alone for patients with limited (1-4) brain metastases. Trials have established post-operative SRS as an alternative to adjuvant WBRT following resection of brain metastases. Second-generation TKIs for ALK rearranged NSCLC have demonstrated improved CNS penetration and activity. Current brain metastasis trials are focused on reducing cognitive toxicity: hippocampal sparing WBRT, SRS for 5-15 metastases, pre-operative SRS, and use of systemic targeted agents or immunotherapy. The role for radiotherapy in the management of brain metastases is becoming better defined with local treatment shifting from WBRT to SRS alone for limited brain metastases and post-operative SRS for resected metastases. Further trials are warranted to define the optimal integration of newer systemic agents with local therapies.

ENDOPHTHALMITIS AFTER PARS PLANA VITRECTOMY: Efficacy of Intraoperative Subconjunctival Antibiotics.

PURPOSE: To examine rates of acute infectious endophthalmitis after pars plana vitrectomy (PPV) in eyes that received intraoperative subconjunctival antibiotics versus eyes that did not. METHODS: A retrospective, nonrandomized, comparative case series of 18,886 consecutive cases of transconjunctival 23-, 25-, and 27-gauge PPV over a 5-year period was performed. The impact of prophylactic intraoperative subconjunctival antibiotics on the development of acute infectious postoperative endophthalmitis was examined. RESULTS: Of 18,886 cases of PPV, 14,068 (74.5%) received intraoperative subconjunctival antibiotics, whereas 4,818 (25.5%) did not. Sixteen cases (0.085%, 1/1,176) of post-PPV endophthalmitis were identified. The incidence of endophthalmitis in eyes that received subconjunctival antibiotics was 0.078% (11/14,068 cases, 1/1,282), whereas the incidence in those that did not receive subconjunctival antibiotics was 0.10% (5/4,818 cases, 1/1,000). No statistically significant difference was identified in the incidence of endophthalmitis between those that received subconjunctival antibiotics and those that did not (P = 0.598). Microbial culture was performed in 11 cases with 6 culture-positive cases (5/8 cases that received subconjunctival antibiotics and 1/3 cases that did not). CONCLUSION: Prophylactic subconjunctival antibiotics were not associated with a significantly reduced rate of post-PPV endophthalmitis. With consideration of emerging multidrug-resistant bacteria, routine prophylactic subconjunctival antibiotics may not be justified.

Impact of rheumatoid arthritis on radiation-related toxicity and cosmesis in breast cancer patients: a contemporary matched-pair analysis.

PURPOSE: To evaluate the impact of rheumatoid arthritis (RA) on toxicity and cosmesis in women undergoing radiotherapy for breast cancer. METHODS: We queried an institutional database for women with RA treated with external beam radiotherapy for breast cancer between 1981 and 2016. Matching each patient to three controls without RA was attempted. Radiation toxicity was graded using CTCAE 4.0. Cosmesis was graded using the Global Harris Scoring System of Excellent, Good, Fair, or Poor. Grade 2+ (G2+) acute and late toxicities were compared between women with RA and their matched pairs using a generalized estimating equation (GEE). Wilcoxon test and mixed effects model were used to compare the cosmesis between two groups. RESULTS: Forty women with RA at time of radiation were matched to 117 controls. The median radiation dose was 60 Gy (50-66 Gy) and the median follow-up was 94 months (1-354 months). When comparing the women with RA to their matched pairs, there was no significant difference in the rates of G2+ acute toxicity (25.0 vs. 13.7%, O 2.1, CI 0.91-4.9) or G2+ late toxicity (7.5 vs. 4.3%, OR 1.8, CI 0.48-6.8). Mean cosmesis was between Good and Excellent for both groups of patients, although women with RA were less likely to get Excellent cosmesis compared to their matched pairs (OR 0.35, CI 0.15-0.84). CONCLUSIONS: Among women with RA, radiation for breast cancer was well tolerated without significantly increased toxicity. Their cosmesis was generally Good to Excellent, although they might be less likely to get Excellent cosmesis compared to their matched pairs.

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

Tensile Mechanical Properties and Dynamic Collagen Fiber Re-Alignment of the Murine Cervix are Dramatically Altered Throughout Pregnancy.

The cervix is a unique organ able to dramatically change its shape and function by serving as a physical barrier for the growing fetus and then undergoing dramatic dilation allowing for delivery of a term infant. As a result, the cervix endures changing mechanical forces from the growing fetus. There is an emerging concept that the cervix may change or remodel "early" in many cases of spontaneous preterm birth (sPTB). However, the mechanical role of the cervix in both normal and preterm birth remains unclear. Therefore, the primary objective of this study was to determine the mechanical and structural responses of murine cervical tissue throughout a normal gestational time course. In this study, both tissue structural and material properties were determined via a quasi-static tensile load-to-failure test, while simultaneously obtaining dynamic collagen fiber re-alignment via cross-polarization imaging. This study demonstrated that the majority of the mechanical properties evaluated decreased at midgestation and not just at term, while collagen fiber re-alignment occurred earlier in the loading curve for cervices at term. This suggests that although structural changes in the cervix occur throughout gestation, the differences in material properties function in combination with collagen fiber re-alignment as mechanical precursors to regulate term gestation. This work lays a foundation for investigating cervical biomechanics and the role of the cervix in preterm birth.

Intraoperative Mean Arterial Pressure Variability and 30-day Mortality in Patients Having Noncardiac Surgery.

BACKGROUND: Little is known about the relationship between intraoperative blood pressure variability and mortality after noncardiac surgery. Therefore, the authors tested the hypothesis that blood pressure variability, independent from absolute blood pressure, is associated with increased 30-day mortality. METHODS: Baseline and intraoperative variables plus 30-day mortality were obtained for 104,401 adults having noncardiac surgery lasting 60 min or longer. In confounder-adjusted models, the authors evaluated the associations between 30-day mortality and both time-weighted average intraoperative mean arterial pressure (TWA-MAP) and measures of intraoperative MAP variability--including generalized average real variability of MAP (ARV-MAP) and SD of MAP (SD-MAP). RESULTS: Mean ± SD TWA-MAP was 84 ± 10 mmHg, and ARV-MAP was 2.5 ± 1.3 mmHg/min. TWA-MAP was strongly related to 30-day mortality, which more than tripled as TWA-MAP decreased from 80 to 50 mmHg. ARV-MAP was only marginally related to 30-day mortality (P = 0.033) after adjusting for TWA-MAP. Compared with median ARV-MAP, odds ratio (95% CI) for 30-day mortality was 1.14 (1.03 to 1.25) for low ARV-MAP (first quartile) and 0.94 (0.88 to 0.99) for high ARV-MAP (third quartile). Odds of 30-day mortality decreased as five-level categorized ARV-MAP increased (0.92; 0.87 to 0.99 for one category increase; P = 0.015). Secondarily, cumulative duration of MAP less than 50, 55, 60, 70, and 80 mmHg was associated with increased odds of 30-day mortality (all P < 0.001). CONCLUSION: Although lower mean arterial pressure is strongly associated with mortality, lower intraoperative blood pressure variability per se is only mildly associated with postoperative mortality after noncardiac surgery.