Results of COVID-minimal Surgical Pathway During Surge-phase of COVID-19 Pandemic.

OBJECTIVE: The outcomes of patients treated on the COVID-minimal pathway were evaluated during a period of surging COVID-19 hospital admissions, to determine the safety of continuing to perform urgent operations during the pandemic. SUMMARY OF BACKGROUND DATA: Crucial treatments were delayed for many patients during the COVID-19 pandemic, over concerns for hospital-acquired COVID-19 infections. To protect cancer patients whose survival depended on timely surgery, a "COVID-minimal pathway" was created. METHODS: Patients who underwent a surgical procedure on the pathway between April and May 2020 were evaluated. The "COVID-minimal surgical pathway" consisted of: (A) evolving best-practices in COVID-19 transmission-reduction, (B) screening patients and staff, (C) preoperative COVID-19 patient testing, (D) isolating pathway patients from COVID-19 patients. Patient status through 2 weeks from discharge was determined as a reflection of hospital-acquired COVID-19 infections. RESULTS: After implementation, pathway screening processes excluded 7 COVID-19-positive people from interacting with pathway (4 staff and 3 patients). Overall, 122 patients underwent 125 procedures on pathway, yielding 83 admissions (42 outpatient procedures). The median age was 64 (56-79) and 57% of patients were female. The most common surgical indications were cancer affecting the uterus, genitourinary tract, colon, lung or head and neck. The median length of admission was 3 days (1-6). Repeat COVID-19 testing performed on 27 patients (all negative), including 9 patients evaluated in an emergency room and 8 readmitted patients. In the postoperative period, no patient developed a COVID-19 infection. CONCLUSIONS: A COVID-minimal pathway comprised of physical space modifications and operational changes may allow urgent cancer treatment to safely continue during the COVID-19 pandemic, even during the surge-phase.

Pandemic Recovery Using a COVID-Minimal Cancer Surgery Pathway.

The coronavirus disease 2019 (COVID-19) pandemic has created unprecedented disruption in health care delivery around the world. In an effort to prevent hospital-acquired COVID-19 infections, most hospitals have severely curtailed elective surgery, performing only surgeries if the patient's survival or permanent function would be compromised by a delay in surgery. As hospitals emerge from the pandemic, it will be necessary to progressively increase surgical activity at a time when hospitals continue to care for COVID-19 patients. In an attempt to mitigate the risk of nosocomial infection, we have created a patient care pathway designed to minimize risk of exposure of patients coming into the hospital for scheduled procedures. The COVID-minimal surgery pathway is a predetermined patient flow, which dictates the locations, personnel, and materials that come in contact with our cancer surgery population, designed to minimize risk for virus transmission. We outline the approach that allowed a large academic medical center to create a COVID-minimal cancer surgery pathway within 7 days of initiating discussions. Although the pathway represents a combination of recommended practices, there are no data to support its efficacy. We share the pathway concept and our experience so that others wishing to similarly align staff and resources toward the protection of patients may have an easier time navigating the process.

Cost-effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for up to 10 brain metastases.

OBJECTIVE The JLGK0901 study found that stereotactic radiosurgery (SRS) is a safe and effective treatment option for treating up to 10 brain metastases. The purpose of this study is to determine the cost-effectiveness of treating up to 10 brain metastases with SRS, whole-brain radiation therapy (WBRT), or SRS and immediate WBRT (SRS+WBRT). METHODS A Markov model was developed to evaluate the cost effectiveness of SRS, WBRT, and SRS+WBRT in patients with 1 or 2-10 brain metastases. Transition probabilities were derived from the JLGK0901 study and modified according to the recurrence rates observed in the Radiation Therapy Oncology Group (RTOG) 9508 and European Organization for Research and Treatment of Cancer (EORTC) 22952-26001 studies to simulate the outcomes for patients who receive WBRT. Costs are based on 2015 Medicare reimbursements. Health state utilities were prospectively collected using the Standard Gamble method. End points included cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The willingness-to-pay (WTP) threshold was $100,000 per QALY. One-way and probabilistic sensitivity analyses explored uncertainty with regard to the model assumptions. RESULTS In patients with 1 brain metastasis, the ICERs for SRS versus WBRT, SRS versus SRS+WBRT, and SRS+WBRT versus WBRT were $117,418, $51,348, and $746,997 per QALY gained, respectively. In patients with 2-10 brain metastases, the ICERs were $123,256, $58,903, and $821,042 per QALY gained, respectively. On the sensitivity analyses, the model was sensitive to the cost of SRS and the utilities associated with stable post-SRS and post-WBRT states. In patients with 2-10 brain metastases, SRS versus WBRT becomes cost-effective if the cost of SRS is reduced by $3512. SRS versus WBRT was also cost effective at a WTP of $200,000 per QALY on the probabilistic sensitivity analysis. CONCLUSIONS The most cost-effective strategy for patients with up to 10 brain metastases is SRS alone relative to SRS+WBRT. SRS alone may also be cost-effective relative to WBRT alone, but this depends on WTP, the cost of SRS, and patient preferences.

Spine Stereotactic Body Radiotherapy Outcomes in Patients with Concurrent Brain Metastases.

OBJECTIVES:  Stereotactic body radiotherapy (SBRT) is an emerging technique for maximizing tumor and pain control in selected patients with spinal metastases. Outcomes for those with concurrent brain metastases (CBM) have not been well-described previously. The goal of this study was to compare outcomes for patients with or without CBM treated with spine SBRT. METHODS:  Records of all patients treated with SBRT for spine metastases at our institution from January 2008 to January 2014 were reviewed. Chi-square analyses and the Mann-Whitney test were used to assess the association of CBM (defined as brain metastasis present prior to or at the time of spinal SBRT) with potential covariates. The log-rank test and Cox proportional hazards regression were used to evaluate the impact of CBM on overall survival and local control from the time of the first course of spine SBRT. RESULTS:  Seventy-eight patients and a total of 86 SBRT lesions were treated. Median patient age was 60 years (range: 38-84 years); 28.2% had radioresistant histologies. A single fraction was used in 91.0% of treatments. One-year local control was 89.4%, and one-year overall survival was 45.8%. A total of 19 patients (24.4%) had CBM. Among these CBM patients, 18 (94.7%) underwent intracranial radiosurgery and nine (47.4%) were diagnosed synchronously with their spine metastases. Local control was not significantly different between patients with or without CBM on univariable (median: 58 months vs. not reached, p = 0.53) or multivariable analyses (HR 0.52, 95% CI 0.06-4.33). Overall survival was also not significantly different between patients with or without CBM on univariable (median: 7 vs. 11 months, log-rank p = 0.12) or multivariable analyses (HR 1.62, 95% CI 0.87-3.03). CONCLUSIONS:  Patients with CBM do not appear to have a statistically significant detriment in clinical outcomes, suggesting that CBM should not necessarily be considered a contraindication for spine SBRT. Although our study is limited by significant heterogeneity in tumor type within our series, future work should focus on the development of reliable survival prognosticators for patients undergoing spinal radiosurgery. Nearly half of the patients with CBM were diagnosed synchronously with their spine metastases, emphasizing the usefulness of obtaining a brain MRI for complete staging prior to spine SBRT.

Practice Building: Achieving Growth Through Computed Tomographic Myelography-Based Stereotactic Body Radiation Therapy for Spinal Metastases.

Stereotactic body radiation therapy (SBRT) is as an effective method to treat spinal metastases. Imaging is a critical component in the workup of patients who undergo stereotactic radiation treatment. Computed tomographic myelography may be more accurate than magnetic resonance imaging in the delineation of neural elements during SBRT. The task we faced was to offer a standardized method to rapidly and safely obtain high-quality computed tomographic myelography as part of a robust spine SBRT program. In detailing our experience, we support the greater, active participation of radiologists in the multidisciplinary care of patients with spinal metastases, while encouraging other radiologists to foster similar collaborations at their own institutions.

Time trends in glioblastoma multiforme survival: the role of temozolomide.

BACKGROUND: In 2005, maximum safe surgical resection, followed by radiotherapy with concomitant temozolomide (TMZ), followed by adjuvant TMZ became the standard of care for glioblastoma (GBM). Furthermore, a modest, but meaningful, population-based survival improvement for GBM patients occurred in the US between 1999 (when TMZ was first introduced) and 2008. We hypothesized that TMZ usage explained this GBM survival improvement. METHODS: We used national Veterans Health Administration (VHA) databases to construct a cohort of GBM patients, with detailed treatment information, diagnosed 1997-2008 (n = 1645). We compared survival across 3 periods of diagnosis (1997-2000, 2001-2004, and 2005-2008) using Kaplan-Meier curves. We used proportional hazards models to calculate period hazard rate ratios (HRs) and 95% confidence intervals (CIs), adjusted for demographic, clinical, and treatment covariates. RESULTS: Survival increased over calendar time (stratified log-rank P < .0001). After adjusting for age and Charlson comorbidity score, for cases diagnosed in 2005-2008 versus 1997-2000, the HR was 0.72 (95% CI, 0.64-0.82; p-trend < .0001). Sequentially adding non-TMZ treatment variables (ie, surgery, radiotherapy, non-TMZ chemotherapy) to the model did not change this result. However, adding TMZ to the model containing age, Charlson comorbidity score, and all non-TMZ treatments eliminated the period effect entirely (HR = 1.01; 95% CI, 0.86-1.19; p-trend = 0.84). CONCLUSIONS: The observed survival improvement among GBM patients diagnosed in the VHA system between 1997 and 2008 was completely explained by TMZ. Similar studies in other populations are warranted to test the generalizability of our finding to other patient cohorts and health care settings.

Removal of nail penetrating the basilar artery.

Nail-gun injuries have become an increasingly prevalent source of penetrating intracranial trauma. Few cases of intracranial nail-gun injuries disturbing major cerebrovascular structures have been reported, and none entailing basilar artery involvement. We report here the case of a 51-year-old male with an intracranial nail-gun injury involving penetration of the distal basilar artery. Operative removal was accomplished under direct vision using a double concentric cranioorbital zygomatic osteotomy for a trans-Sylvian approach. We highlight the principles involved in removing foreign bodies penetrating critical neurovascular structures.

Krev1 interaction trapped-1/cerebral cavernous malformation-1 protein expression during early angiogenesis.

OBJECT: Molecular genetic studies of cerebral cavernous malformation (CCM) have identified three loci, CCM1-3, that can lead to CCM when mutated. Examination of the CCM1 locus established KRIT1 (Krev1 Interaction Trapped genre 1) as the CCM1 gene. Despite the identification of KRIT1 as the gene mutated in CCM1, little has been learned regarding its function. The authors recently demonstrated specific KRIT1 expression in endothelial cells. Based on this result and the fact that the CCM phenotype features defects in microvasculature, we hypothesized that KRIT1 may take an active part in normal angiogenesis. METHODS: In this study, the authors investigated the spatial and temporal expression of KRIT1 during normal vessel development and maturation by examining KRIT1 protein in both in vitro and in vivo angiogenic systems with the use of postconfluent endothelial cell cultures along with placental tissues from different developmental stages. CONCLUSIONS: The results demonstrate that KRIT1 is expressed during capillary-like tube formation in the early stages of angiogenesis in vitro. Histological examination of placental tissue, a well-established in vivo model of angiogenesis, shows KRIT1 expression in active angiogenic and vasculogenic areas of the immature placental villi. As the placenta matures, KRIT1 expression is restricted to microvascular and small arterial endothelial cells with little or no expression seen in the intima of large vessels. It can therefore be concluded that KRIT1 is expressed during early angiogenesis by endothelial cells and may play a key role in vessel formation and/or development.

Mutational analysis of 206 families with cavernous malformations.

OBJECT: A gene contributing to the autosomal-dominant cerebral cavernous malformation (CCM) phenotype, KRIT1 (an acronym for Krev Interaction Trapped 1), has been identified through linkage analysis and mutation screening. The authors collected blood samples from 68 patients with familial CCM and 138 patients with apparently sporadic CCM as well as from their families, in an effort to characterize the prevalence and spectrum of disease-causing sequence variants in the KRIT1 gene. METHODS: The authors used single-strand conformational polymorphism analysis to identify genomic variants in KRIT1, which were sequenced to determine the specific mutation. Among 43 Hispanic-American kindreds who immigrated to the southwestern US from northern Mexico, 31 share an identical founder mutation. This Q455X mutation is found in 18 (86%) of 21 persons with a positive family history and in 13 (59%) of 22 persons with apparently sporadic CCM. This mutation was not found among 13 persons with CCM who were recruited from Mexico. These findings establish the key role of a recent founder mutation in Hispanic persons with CCM who live in the US. Although nearly all Hispanic families in the US in which there are multiple CCM cases linked to the CCM1 locus, only 13 of 25 non-Hispanic CCM-carrying families have displayed evidence of linkage to the CCM1 locus. Among these 13 families, the authors identified eight independent mutations in nine kindreds. They identified four additional mutations among 22 familial CCM kindreds with no linkage information, bringing the total number of independent mutations to 12. Inherited KRIT1 mutations were not detected among 103 non-Hispanic persons in whom a family history of CCM was rigorously excluded. CONCLUSIONS: All mutations were nonsense mutations, frame-shift mutations predicting premature termination, or splice-site mutations located throughout the KRIT1 gene, suggesting that these are genetic loss-of-function mutations. These genetic findings, in conjunction with the clinical phenotype, are consistent with a two-hit model for the occurrence of CCM.

KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein.

Mutations in Krev1 interaction trapped gene 1 (KRIT1) cause cerebral cavernous malformation, an autosomal dominant disease featuring malformation of cerebral capillaries resulting in cerebral hemorrhage, strokes, and seizures. The biological functions of KRIT1 are unknown. We have investigated KRIT1 expression in endothelial cells by using specific anti-KRIT1 antibodies. By both microscopy and coimmunoprecipitation, we show that KRIT1 colocalizes with microtubules. In interphase cells, KRIT1 is found along the length of microtubules. During metaphase, KRIT1 is located on spindle pole bodies and the mitotic spindle. During late phases of mitosis, KRIT1 localizes in a pattern indicative of association with microtubule plus ends. In anaphase, the plus ends of the interpolar microtubules show strong KRIT1 staining and, in late telophase, KRIT1 stains the midbody remnant most strongly; this is the site of cytokinesis where plus ends of microtubules from dividing cells overlap. These results establish that KRIT1 is a microtubule-associated protein; its location at plus ends in mitosis suggests a possible role in microtubule targeting. These findings, coupled with evidence of interaction of KRIT1 with Krev1 and integrin cytoplasmic domain-associated protein-1 alpha (ICAP1 alpha), suggest that KRIT1 may help determine endothelial cell shape and function in response to cell-cell and cell-matrix interactions by guiding cytoskeletal structure. We propose that the loss of this targeting function leads to abnormal endothelial tube formation, thereby explaining the mechanism of formation of cerebral cavernous malformation (CCM) lesions.