Practice and principles of stereotactic body radiation therapy for spine and non-spine bone metastases.

Radiotherapy is the dominant treatment modality for painful spine and non-spine bone metastases (NSBM). Historically, this was achieved with conventional low dose external beam radiotherapy, however, stereotactic body radiotherapy (SBRT) is increasingly applied for these indications. Meta-analyses and randomized clinical trials have demonstrated improved pain response and more durable tumor control with SBRT for spine metastases. However, in the setting of NSBM, there is limited evidence supporting global adoption and large scale randomized clinical trials are in need. SBRT is technically demanding requiring careful consideration of organ at risk tolerance, and strict adherence to technical requirements including immobilization, simulation, contouring and image-guidance procedures. Additional considerations include follow up practices after SBRT, with appropriate imaging playing a critical role in response assessment. Finally, there is renewed research into promising new technologies that may further refine the use of SBRT in both spinal and NSBM in the years to come.

A Rare Presentation of Postaxial Polydactyly in a 2-Year-Old Female with Ellis-van Creveld Syndrome.

Postaxial or ulnar polydactyly is the most common form of polydactyly that may present with the duplication of soft-tissue structures only or with additional bony involvement. Surgical excision is the only viable treatment option for postaxial polydactyly with bony involvement, and psychological or cosmetic reasons are the main rationale for treatment. Ellis-van Creveld syndrome (EVC) is a rare congenital disorder characterized by chondral and ectodermal dysplasia, particularly postaxial polydactyly. The exact prevalence of EVC is unknown, and fewer than 300 cases have been reported. We present a case of a 2-year-old Hispanic female with EVC who presented with bilateral postaxial polydactyly and complete duplication of the metacarpal and phalanges. We describe the presentation and treatment of this patient, who ultimately underwent staged resection of the duplicated digits with reconstruction of the abductor muscle.

Predictors of pathologic fracture and local recurrence following stereotactic body radiation therapy to 505 non-spine bone metastases.

PURPOSE: Stereotactic Body Radiation Therapy (SBRT) is increasingly applied to treat non-spine bone metastases (NSBM) though data remains limited on this approach. In this retrospective study, we report outcomes and predictors of local failure (LF) and pathological fracture (PF) post-SBRT for NSBM using a mature single-institution database. METHODS: Patients with NSBM treated with SBRT between 2011 and 2021 were identified. The primary objective was to assess the rates of radiographic LF. Secondary objectives were to assess the rates of in-field PF, overall survival (OS), and late grade ≥ 3 toxicity. Competing risks analysis was used to assess rates of LF and PF. Univariable regression and multivariable regression (MVR) were performed to investigate predictors of LF and PF. RESULTS: A total of 373 patients with 505 NSBM were included in this study. Median follow-up was 26.5 months. The cumulative incidence of LF at 6, 12, and 24 months were 5.7%, 7.9%, and 12.6%, respectively. The cumulative incidence of PF at 6, 12, and 24 months were 3.8%, 6.1%, and 10.9%, respectively. Lytic NSBM (HR = 2.18; p < 0.01), a lower biologically effective dose (HR = 1.11 per 5 Gy10 decrease; p = 0.04), and a PTV ≥ 54 cc (HR = 4.32; p < 0.01) predicted for a higher risk of LF on MVR. Lytic NSBM (HR = 3.43; p < 0.01), mixed (lytic/sclerotic) lesions (HR = 2.70; p = 0.04), and rib metastases (HR = 2.68; p < 0.01) predicted for a higher risk of PF on MVR. CONCLUSION: SBRT is an effective modality to treat NSBM with high rates of radiographic local control with an acceptable rate of PF. We identify predictors of both LF and PF that can serve to inform practice and trial design.

Stereotactic body radiotherapy for spine metastases: a review of 24 Gy in 2 daily fractions.

PURPOSE: Stereotactic body radiotherapy (SBRT) has proven to be a highly effective treatment for selected patients with spinal metastases. Randomized evidence shows improvements in complete pain response rates and local control with lower retreatment rates favoring SBRT, compared to conventional external beam radiotherapy (cEBRT). While there are several reported dose-fractionation schemes for spine SBRT, 24 Gy in 2 fractions has emerged with Level 1 evidence providing an excellent balance between minimizing treatment toxicity while respecting patient convenience and financial strain. METHODS: We provide an overview of the 24 Gy in 2 SBRT fraction regimen for spine metastases, which was developed at the University of Toronto and tested in an international Phase 2/3 randomized controlled trial. RESULTS: The literature summarizing global experience with 24 Gy in 2 SBRT fractions suggests 1-year local control rates ranging from 83-93.9%, and 1-year rates of vertebral compression fracture ranging from 5.4-22%. Reirradiation of spine metastases that failed prior cEBRT is also feasible with 24 Gy in 2 fractions, and 1-year local control rates range from 72-86%. Post-operative spine SBRT data are limited but do support the use of 24 Gy in 2 fractions with reported 1-year local control rates ranging from 70-84%. Typically, the rates of plexopathy, radiculopathy and myositis are under 5% in those series reporting mature follow up, with no cases of radiation myelopathy (RM) reported in the de novo setting when the spinal cord avoidance structure is limited to 17 Gy in 2 fractions. However, re-irradiation RM has been observed following 2 fraction SBRT. More recently, 2-fraction dose escalation with 28 Gy, with a higher dose constraint to the critical neural tissues, has been reported suggesting improved rates of local control. This regimen may be important in those patients with radioresistant histologies, high grade epidural disease, and/or paraspinal disease. CONCLUSION: The dose-fractionation of 24 Gy in 2 fractions is well-supported by published literature and is an ideal starting point for centers looking to establish a spine SBRT program.

Planning for the Effect of the SC.24 Trial on Spine Stereotactic Body Radiation Therapy Utilization at a Tertiary Cancer Center.

Purpose: The goal of this study was to assess the potential real-world effect of the recently reported SC.24 trial on spine stereotactic body radiation therapy (SBRT) utilization. We estimated the proportion of patients treated with conventional radiation therapy (CRT) who would have been eligible for spine SBRT per trial inclusion criteria and analyzed the potential estimated increased costs to our institution. Methods and Materials: This was a retrospective review of patients who received spine CRT at our institution between August and October 2020. Data abstracted included demographics, SC.24 eligibility criteria, provider-reported pain response, and survival. A cost analysis and time survey was performed using institutional and provincial data. Results: Of 73 patients reviewed, 24 patients (33%) were eligible. The most common exclusion factors included irradiation of ≥3 consecutive spinal segments (n = 32, 44%), Eastern Cooperative Oncology Group performance status >2 (n = 17, 23%), and symptomatic spinal cord compression (n = 13, 18%). Of eligible patients, the mean age was 68.92 years, median spinal instability in neoplasia score was 8 (interquartile range, 7-9), and median Eastern Cooperative Oncology Group performance status was 2 (interquartile range, 1-2). The most common primary cancer types among eligible patients were lung (n = 10) and breast (n = 4). The median survival of eligible patients was 10 months (95% confidence interval, 4 months to not reached) with 58% surviving longer than 3 months. Of patients who had subjective pain documented after CRT, 54% had at least some response. The cost of spine SBRT was estimated at CA$4764.80 compared with $3589.10 for CRT, and tasks for spine SBRT took roughly 3 times as long as those for CRT. Conclusions: One-third of patients who received palliative spine CRT met eligibility criteria for SC.24. This possible expanded indication for spine SBRT can have a substantial effect on resource utilization. These data may be useful in guiding resource planning at institutions looking to commence a spine SBRT program.

High resolution imaging with focused kV x-rays for small animal radio-neuromodulation.

BACKGROUND: High precision radiotherapy with small irradiator size has potential in many treatment applications involving small shallow targets, with small animal radio-neuromodulation as an intriguing example. A focused kV technique based on novel usage of polycapillary x-ray lenses can focus x-ray beams to <0.2 mm in diameter, which is ideal for such uses. PURPOSE: Such an application also requires high resolution CT images for treatment planning and setup. In this work, we demonstrate the feasibility of using a virtual focal spot generated with an x-ray lens to perform high-resolution CBCT acquisition. METHOD: The experiment with x-ray lens was set up on an x-ray tabletop system to generate a virtual focal spot. The flood field images with and without the x-ray lens were first compared. A pinhole image was acquired for the virtual focal spot and compared with the one acquired with the conventional focal spot without the lens. The planar imaging resolution with and without the lens were evaluated using a line pair resolution phantom. The spatial resolution of the two settings were estimated by reconstructing a 0.15-mm wire phantom and comparing its full width half maximum (FWHM). A CBCT scan of a rodent head was also acquired to further demonstrate the improved resolution using the x-ray lens. RESULT: The proposed imaging setup with x-ray lens had a limited exposure area of 5 cm by 5 cm on the detector, which was suitable for guiding radio-neuromodulation to a small target in rodent brain. Compared to conventional imaging acquisition with a measured x-ray focal spot of 0.395 mm FWHM, the virtual focal spot size was measured at 0.175 mm. The reduction in focal spot size with lens leads to an almost doubled planar imaging resolution and a 26% enhancement in 3D spatial resolution. A realistic CBCT acquisition of a rodent head mimicked the imaging acquisition step for radio-neuromodulation and further showed the improved visualization for fine structures. CONCLUSION: This work demonstrated that the focused kV x-ray technique was capable of generating small focal spot size of <0.2 mm, which substantially improved x-ray imaging resolution for small animal imaging.

Toxicity and Efficacy of Multitarget Thoracic Stereotactic Body Radiation Therapy.

PURPOSE: With the increasing use of stereotactic body radiation therapy (SBRT) for primary and metastatic cancer, use of multitarget thoracic (MTT) SBRT is rising. Given the limited safety and efficacy data, we report the experience of this strategy from a large academic center. METHODS AND MATERIALS: Between 2012 and 2021, patients who received SBRT for ≥2 thoracic targets separated by ≤1 year were retrospectively reviewed. The primary endpoint was clinically significant radiation pneumonitis (CSRP) requiring steroids, oxygen, or intubation. Secondary endpoints included local failure (LF), initiation or change of systemic therapy (ICST), progression-free survival, and overall survival. Competing risk analysis was used to evaluate the cumulative incidence of CSRP, LF, and ICST. Univariate and multivariable analyses were performed to look for clinical and dosimetric predictive factors of CSRP and LF. RESULTS: One hundred ninety patients (481 lesions) were treated with MTT SBRT with a median follow-up of 19.7 months. Indications for SBRT were oligometastases (n = 70; 36.8%), oligoprogression (n = 62; 32.6%), curative intent in patients with primary lung cancer (n = 37; 19.5%), and control of dominant areas of metastatic progression (n = 21; 11.0%). The number of irradiated tumors ranged from 2 to 7 and the majority of SBRT courses were delivered simultaneously (88.2%). Overall, 14 patients (7.4%) had CSRP, with 5 cases requiring oxygen. The cumulative incidence of CSRP at 6 and 12 months was 5.3% and 7.6%, respectively. The cumulative incidence of LF at 2 years was 10.5%. The cumulative incidence of ICST at 2 years was 41.1%. Median progression-free survival was 11.8 months and median overall survival was 51.3 months. On multivariable analysis, a higher lung V35Gy (hazard ratio, 2.59; P = .02) was a statistically significant predictor of CSRP and colorectal histology predicted for higher LF (hazard ratio, 2.12; P = .02). CONCLUSIONS: In one of the largest institutional series of MTT SBRT, rates of CSRP and LF were low. Optimizing plans to lower the lung V35Gy may decrease the risk of CSRP.

Increased histologic inflammation is an independent risk factor for nonconventional dysplasia in ulcerative colitis.

AIMS: Several types of nonconventional dysplasia have been described in inflammatory bowel disease. Hypermucinous, goblet cell-deficient, and crypt cell dysplasias are considered high-risk subtypes, as they often have molecular features of advanced neoplasia (e.g. aneuploidy) and are more frequently associated with advanced neoplasia than conventional dysplasia. This study investigated if increased colonic inflammation is a risk factor for nonconventional dysplasia. METHODS AND RESULTS: A cohort of 125 patients with ulcerative colitis (UC)-associated dysplasia were analyzed and compared with 50 control UC patients without a history of neoplasia. For each patient, all biopsies prior to the initial detection of dysplasia were scored using a 4-point inflammatory activity score. Both mean and maximum scores from all biopsies taken during each colonoscopy were derived. Inflammation burden was calculated by multiplying the average maximum score between each pair of surveillance episodes by length of surveillance interval in years. The average scores of all colonoscopies were used to calculate overall mean, maximum, and inflammation burden scores. In multivariate analyses, higher maximum (odds ratio [OR] 3.4) and inflammation burden (OR 4.2) scores were significantly associated with the detection of dysplasia (P < 0.05). Similarly, higher mean and maximum scores increased the odds of nonconventional dysplasia by 2.7 and 4.9, respectively (P < 0.05). There was a stronger association between these two scores and high-risk subtypes (ORs 4.0 and 7.5, respectively, P < 0.05). CONCLUSION: The risk of nonconventional dysplasia is significantly associated with increased colonic inflammation, which may contribute to its higher rates of aneuploidy and malignancy.

Outcomes of Radiation Therapy Plus Immunotherapy in Metastatic Renal Cell Carcinoma: Results From the Canadian Kidney Cancer Information System.

Purpose: With the integration of immunotherapy (IO) agents in the management of metastatic renal cell carcinoma (mRCC), there has been interest in the combined use with radiation therapy (RT). However, real world data are limited. The purpose of this study was to evaluate outcomes in patients with mRCC receiving both RT and IO compared with IO alone. Methods and Materials: Data were collected from Canadian Kidney Cancer Information System from January 2011 to September 2019 across 14 academic centers. Patients with mRCC who received IO as first- or second-line therapy were included. RT was categorized as radical dose or palliative dose. Kaplan-Meier estimates were reported for overall survival (OS) and time to treatment failure. Cox proportional hazard models were used adjusted for age and International Metastatic RCC Database Consortium risk categories. Results: In total, 505 patients were included in the study: 179 received RT + IO and 326 received IO alone. Two-year OS for the RT + IO group was 55.0% compared with 66.4% in the IO alone cohort (adjusted hazard ratio [aHR], 1.38; P = .07). At 2 years, 12.2% of the RT + IO patients remained on therapy versus 30.9% in the IO alone group (aHR, 1.30; P = .02). For patients receiving first-line therapy, 2-year OS in the RT + IO group was 56.4% versus 78.4% in the IO alone arm, though this difference was not statistically significant (aHR, 1.23; P = .56). For patients receiving radical dose and palliative dose, 2-year OS was 57.0% and 53.9%, respectively (aHR, 0.86; P = .63). Conclusions: In this descriptive analysis, more than one-third of patients with mRCC received RT and demonstrated inferior outcomes compared with IO alone. Potential explanations include greater presence of adverse metastatic sites in those receiving RT. Prospective clinical trials evaluating potential benefits of RT in an IO era remain an important need.

hTERT DNA Methylation Analysis Identifies a Biomarker for Retinoic Acid-Induced hTERT Repression in Breast Cancer Cell Lines.

Telomerase reactivation is responsible for telomere preservation in about 90% of cancers, providing cancer cells an indefinite proliferating potential. Telomerase consists of at least two main subunits: a catalytic reverse transcriptase protein (hTERT) and an RNA template subunit. Strategies to inhibit hTERT expression seem promising for cancer treatment. Previous works showed that all-trans retinoic acid (ATRA) induces hTERT repression in acute promyelocytic leukemia cells, resulting in their death. Here, we investigated the effects of ATRA in a subset of breast cancer cell lines. The mutational status of hTERT promoter and the methylation patterns at a single CpG resolution were assessed. We observed an inverse relationship between hTERT expression after ATRA treatment and the methylation level of a specific CpG at chr5: 1,300,438 in a region of hTERT gene at -5 kb of the transcription initiation site. This observation highlighted the significance of this region, whose methylation profile could represent a promising biomarker to predict the sensitivity to ATRA-induced hTERT repression in specific breast cancer subtypes. As hTERT repression promotes drug-induced cell death, checking the methylation status of this unique region and the specific CpG included can help in decision-making to include ATRA in combination therapy and contributes to a better clinical outcome.

Detection of Neoplasms by Metagenomic Next-Generation Sequencing of Cerebrospinal Fluid.

Importance: Cerebrospinal fluid (CSF) cytologic testing and flow cytometry are insensitive for diagnosing neoplasms of the central nervous system (CNS). Such clinical phenotypes can mimic infectious and autoimmune causes of meningoencephalitis. Objective: To ascertain whether CSF metagenomic next-generation sequencing (mNGS) can identify aneuploidy, a hallmark of malignant neoplasms, in difficult-to-diagnose cases of CNS malignant neoplasm. Design, Setting, and Participants: Two case-control studies were performed at the University of California, San Francisco (UCSF). The first study used CSF specimens collected at the UCSF Clinical Laboratories between July 1, 2017, and December 31, 2019, and evaluated test performance in specimens from patients with a CNS malignant neoplasm (positive controls) or without (negative controls). The results were compared with those from CSF cytologic testing and/or flow cytometry. The second study evaluated patients who were enrolled in an ongoing prospective study between April 1, 2014, and July 31, 2019, with presentations that were suggestive of neuroinflammatory disease but who were ultimately diagnosed with a CNS malignant neoplasm. Cases of individuals whose tumors could have been detected earlier without additional invasive testing are discussed. Main Outcomes and Measures: The primary outcome measures were the sensitivity and specificity of aneuploidy detection by CSF mNGS. Secondary subset analyses included a comparison of CSF and tumor tissue chromosomal abnormalities and the identification of neuroimaging characteristics that were associated with test performance. Results: Across both studies, 130 participants were included (median [interquartile range] age, 57.5 [43.3-68.0] years; 72 men [55.4%]). The test performance study used 125 residual laboratory CSF specimens from 47 patients with a CNS malignant neoplasm and 56 patients with other neurological diseases. The neuroinflammatory disease study enrolled 12 patients and 17 matched control participants. The sensitivity of the CSF mNGS assay was 75% (95% CI, 63%-85%), and the specificity was 100% (95% CI, 96%-100%). Aneuploidy was detected in 64% (95% CI, 41%-83%) of the patients in the test performance study with nondiagnostic cytologic testing and/or flow cytometry, and in 55% (95% CI, 23%-83%) of patients in the neuroinflammatory disease study who were ultimately diagnosed with a CNS malignant neoplasm. Of the patients in whom aneuploidy was detected, 38 (90.5%) had multiple copy number variations with tumor fractions ranging from 31% to 49%. Conclusions and Relevance: This case-control study showed that CSF mNGS, which has low specimen volume requirements, does not require the preservation of cell integrity, and was orginally developed to diagnose neurologic infections, can also detect genetic evidence of a CNS malignant neoplasm in patients in whom CSF cytologic testing and/or flow cytometry yielded negative results with a low risk of false-positive results.

Hypofractionated Stereotactic Radiotherapy for the Treatment of Benign Intracranial Meningiomas: Long-Term Safety and Efficacy.

INTRODUCTION: Hypofractionated stereotactic radiotherapy (hSRT) has emerged as an alternative to single-fraction stereotactic radiosurgery (SRS) and conventionally fractionated radiotherapy for the treatment of intracranial meningiomas (ICMs). However, there is a need for data showing long-term efficacy and complication rates, particularly for larger tumors in sensitive locations. METHODS: A retrospective review was conducted on adult patients with ICMs seen at a tertiary care center. Eligible patients were treated with the CyberKnife platform and had a planned treatment course of 3-5 fractions from 2011-2020. The local control was assessed based on radiographic stability and the late toxicity/radionecrosis rates were recorded. Radiographic progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: In total, 62 patients (age 26-87) with 67 treated tumors were included in this study with a median follow-up of 64.7 months. RT was delivered as the primary treatment in 62.7% of cases and for recurrence in 37.3%. The most common tumor locations were the convexity of the brain and the base of the skull. The tumor sizes ranged from 0.1-51.8 cc and the median planning target volume was 4.9 cc. The most common treatment schedule was 18 Gy in 3 fractions. The five-year PFS and OS were 85.2% and 91.0%, respectively. The late grade III/IV toxicity rate was 3.2% and the radionecrosis rate was 4.8%. CONCLUSIONS: Based on our data, hSRT remains an effective modality to treat low-grade ICMs with acceptable long-term toxicity and radionecrosis rates. hSRT should be offered to patients who are not ideal candidates for SRS while preserving the benefits of hypofractionation.

Stereotactic body radiotherapy for osseous low alpha-beta resistant metastases for pain relief-SOLAR-P.

BACKGROUND: Stereotactic Body Radiotherapy (SBRT) has shown effectiveness in treating bone metastases to alleviate pain. The benefit of SBRT may be further harnessed especially when radiating disease from primary malignancies with low alpha-beta ratios in order to maximize the magnitude and durability of pain relief. However, such an approach has not been studied in a prospective trial. We look to assess single-fraction SBRT for painful non-spinal bone metastases from radioresistant primaries. METHODS: Forty patients will be enrolled on an open label, phase II single arm trial to receive a single fraction of SBRT (15-20 Gray) to all sites of bone metastases requiring treatment for pain relief. Eligible patients will include those with primary malignancies consisting of prostate cancer, breast cancer, renal cell carcinoma, or melanoma. The primary endpoint is pain response at 3 months post-treatment using the Brief Pain Inventory. Secondary endpoints include pain response at 1 month and 6 months post-treatment, toxicity, patient-reported quality of life, re-irradiation or salvage surgery, and local control. DISCUSSION: This study will evaluate the efficacy of single-fraction SBRT on painful bone metastases from primary cancers with low alpha-beta ratios. These data will be valuable to promote future randomized trials and support clinical implementation. Trial registration Clinicaltrials.gov, NCT04177056. Date of registration: November 26, 2019. https://clinicaltrials.gov/ct2/show/NCT04177056.

An overview of leptomeningeal disease.

Leptomeningeal disease (LMD) is a poor prognosis pattern of disease progression in patients with metastatic malignancy with limited treatment options. Patients may be asymptomatic or present with non-specific neurologic deficits, therefore gadolinium-enhanced magnetic resonance imaging of the brain and spine is critical for establishing a diagnosis. Although the treatment intent is palliative in the context of LMD, a multidisciplinary approach is still important to ensure patients receive a timely diagnosis and appropriate treatment to maximize symptom control and preserve quality of life. Radiotherapy is typically delivered to the whole brain or focal spinal regions for the purposes of treating bulky disease, stabilizing symptoms, or relieving cerebrospinal fluid obstruction. Whole craniospinal irradiation (CSI) is generally avoided given its toxicity profile and should only be considered in carefully selected patients where the potential benefit may outweigh the adverse effects. CSI with proton radiotherapy (oppose to conventional photon radiotherapy) has shown promise with improved toxicity for patients with primary CNS tumors. This may be a preferred option for patients being considered for CSI at centres with the proton therapy capabilities. Focal hypofractionated stereotactic radiotherapy (SRT) to intracranial targets is an emerging approach to LMD that may be useful in select patients with limited disease particularly in the setting of reirradiation. Chemotherapies may be delivered intrathecally, although the evidence supporting its efficacy is limited and heterogeneous in regards to the tumor sites examined. Finally, targeted therapy and novel applications of immune checkpoint inhibitors are promising; however, further research is required to guide the use of these agents.

Complex context relationships between DNA methylation and accessibility, histone marks, and hTERT gene expression in acute promyelocytic leukemia cells: perspectives for all-trans retinoic acid in cancer therapy.

Telomerase (hTERT) reactivation and sustained expression is a key event in the process of cellular transformation. Therefore, the identification of the mechanisms regulating hTERT expression is of great interest for the development of new anticancer therapies. Although the epigenetic state of hTERT gene promoter is important, we still lack a clear understanding of the mechanisms by which epigenetic changes affect hTERT expression. Retinoids are well-known inducers of granulocytic maturation in acute promyelocytic leukemia (APL). We have previously shown that retinoids repressed hTERT expression in the absence of maturation leading to growth arrest and cell death. Exploring the mechanisms of this repression, we showed that transcription factor binding was dependent on the epigenetic status of hTERT promoter. In the present study, we used APL cells lines and publicly available datasets from APL patients to further investigate the integrated epigenetic events that promote hTERT promoter transition from its silent to its active state, and inversely. We showed, in APL patients, that the methylation of the distal domain of hTERT core promoter was altered and correlated with the outcome of the disease. Further studies combining complementary approaches carried out on APL cell lines highlighted the significance of a domain outside the minimal promoter, localized around 5 kb upstream from the transcription start site, in activating hTERT. This domain is characterized by DNA hypomethylation and H3K4Me3 deposition. Our findings suggest a cooperative interplay between hTERT promoter methylation, chromatin accessibility, and histone modifications that force the revisiting of previously proposed concepts regarding hTERT epigenetic regulation. They represent, therefore, a major advance in predicting sensitivity to retinoid-induced hTERT repression and, more generally, in the potential development of therapies targeting hTERT expression in cancers.

Anastomotic Breakdown Five Years After Neoadjuvant Radiochemotherapy and Ultralow Anterior Resection for Rectal Adenocarcinoma.

For carefully selected patients with low-lying rectal cancers, ultralow anterior resection (ULAR) can be an effective alternative to abdominal perineal resection, and together with neoadjuvant radiochemotherapy can provide the opportunity for sphincter preservation. However, ULAR is not without potential postoperative complications, particularly anastomotic dehiscence which increases in likelihood after receiving radiation therapy. While surveillance imaging is not indicated three years beyond initial surgical resection, changes in chronic symptoms refractory to conservative management may warrant further investigation. In this case report, we present an interesting case of late-onset stenosis and anastomotic breakdown following neoadjuvant radiochemotherapy, ULAR, and coloanal anastomosis for a low-lying rectal adenocarcinoma. Effective patient education, reliable symptom assessment, and multidisciplinary collaboration are essential to assessing for long-term treatment-related complications and providing appropriate treatment in a timely manner.

Outcomes of trimodality bladder-sparing therapy for muscle-invasive bladder cancer.

INTRODUCTION: Although radical cystectomy is considered the standard of care for muscle-invasive bladder cancer (MIBC), recent data has suggested comparable survival outcomes for bladder-sparing trimodality therapy (TMT). We conducted a retrospective, single-institution analysis of MIBC patients to evaluate the efficacy of TMT as an alternative, curative approach to surgical intervention. METHODS: We conducted a retrospective analysis of MIBC patients assessed by a multidisciplinary team at the Juravinski Cancer Centre from 2010-2016. Patients underwent transurethral resection of bladder tumor (TURBT) followed by radiotherapy with or without concurrent chemotherapy. Patients could receive neoadjuvant treatment. Clinical data and response rates were summarized, and overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. RESULTS: Our analytic cohort included 115 patients, of whom 53 underwent TMT and 62 underwent radiotherapy alone following TURBT. Median age at diagnosis was 79 years and median followup was 21 months. Complete response rates in those receiving TMT and radiation without chemotherapy were 84.4% and 66.7%, respectively. For TMT patients, three-year OS and DFS were 68.5% and 49.6%, respectively. Patients who received TMT had reduction in risk of mortality (hazard ratio [HR] 0.49; p=0.026) and disease recurrence (HR 0.55; p=0.017) compared to those who had radiation without chemotherapy. Overall, four patients had grade 3 or higher late toxicity. CONCLUSIONS: In this single-institution analysis, TMT appears to be a safe and effective approach in the short-term management of MIBC in appropriately selected patients. Extended followup and analysis are necessary to validate these results.

Hypofractionated stereotactic radiotherapy for intracranial meningioma: a systematic review.

BACKGROUND: The availability of image guidance and intensity modulation has led to the increasing use of hypofractionated stereotactic radiotherapy (hSRT) as an alternative to conventionally fractionated radiotherapy or radiosurgery for intracranial meningiomas (ICMs). As the safety and efficacy of this approach is not well characterized, we conducted a systematic review of the literature to assess the clinical outcomes of hSRT in the setting of ICMs. METHODS: A systematic review of Medline and EMBASE databases was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Included studies were retrospective or prospective series that examined an ICM population of ≥10 patients, delivered >1 fraction of photon hSRT (≥2.5 Gy per fraction), and had a median follow-up of ≥2 years. Descriptive statistics were generated for included studies. RESULTS: Of 1480 initial studies, 14 met eligibility criteria for inclusion, reporting on 630 patients (age range, 18-90) treated for 638 tumors. Primary radiotherapy was delivered in 37% of patients, 36% had radiation following surgery, and surgical details were unavailable for 27%. In 474 tumors assessed for radiologic response, 78% remained stable, 18% decreased in size, and 4% increased in size. Crude local control was 90%-100% as reported in 10 studies. The median late toxicity rate was 10%. The most common significant late toxicities were decreased visual acuity and new cranial neuropathy. CONCLUSIONS: With limited follow-up, the available literature suggests hSRT for ICMs has local control and toxicity profiles comparable to other radiotherapy approaches. Confirmation in larger patient cohorts with a longer duration of follow-up is required.

Early Mobilization Post-Hip Fracture Surgery.

INTRODUCTION: Early mobilization after hip fracture surgery is a widely practiced component of postoperative care. However, there is little evidence to suggest that early mobilization post-hip fracture surgery is beneficial in reducing postoperative complications. This study aims to investigate the effect of early mobilization following hip fracture surgery on postoperative complications. MATERIALS AND METHODS: This study retrospectively included 240 patients (female = 165, male = 75, mean age: 82.2 years) admitted to a level 1 trauma center in Adelaide, Australia, for hip fracture surgery. The effect of early mobilization on postoperative complications was assessed along with premorbid status. Subgroup analysis of patients stratified by premorbid health was subsequently analyzed to reduce confounding. RESULTS: The odds of developing a complication were 1.9 times higher if the patient remained bedbound compared to mobilizing. Early mobilization was favorable to delayed mobilization. On average, complication-free patients mobilized earlier (mean [M] = 29 hours) compared to patients who experienced complications (M = 38 hours). In particular, rates of delirium was significantly reduced in patients who mobilized compared to remaining bedbound. However, premorbid status varied greatly. Early mobilizers had significantly better premorbid health than patients who remained bedbound. Overall subgroup analysis of patients with similar premorbid health showed mobilization was not associated with a reduction in complications. With an exception of patients with poor premorbid health, who experienced a reduction in complications following early mobilization. DISCUSSION: In general, early mobilization was associated with the same complication rates as delayed mobilization and remaining bedbound. Patients with poor premorbid health benefited most from early mobilization with reduced complication rates. CONCLUSION: Postoperative delirium and premorbid health were better indicators of postoperative outcomes than time to mobilization.

Customizable biomaterials as tools for advanced anti-angiogenic drug discovery.

The inhibition of angiogenesis is a critical element of cancer therapy, as cancer vasculature contributes to tumor expansion. While numerous drugs have proven to be effective at disrupting cancer vasculature, patient survival has not significantly improved as a result of anti-angiogenic drug treatment. Emerging evidence suggests that this is due to a combination of unintended side effects resulting from the application of anti-angiogenic compounds, including angiogenic rebound after treatment and the activation of metastasis in the tumor. There is currently a need to better understand the far-reaching effects of anti-angiogenic drug treatments in the context of cancer. Numerous innovations and discoveries in biomaterials design and tissue engineering techniques are providing investigators with tools to develop physiologically relevant vascular models and gain insights into the holistic impact of drug treatments on tumors. This review examines recent advances in the design of pro-angiogenic biomaterials, specifically in controlling integrin-mediated cell adhesion, growth factor signaling, mechanical properties and oxygen tension, as well as the implementation of pro-angiogenic materials into sophisticated co-culture models of cancer vasculature.