Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies.

PURPOSE: Recruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer. METHODS: We used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala. Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala. RESULTS: We recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001). CONCLUSION: Guatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

Evaluation of traditional targeted axillary dissection eligibility criteria for node-positive breast cancer after neoadjuvant chemotherapy in a prospective multicenter registry.

INTRODUCTION: Targeted axillary dissection (TAD) is performed after neoadjuvant systemic therapy (NST) to decrease the rate of non-therapeutic axillary dissection (ALND) for patients with node-positive breast cancer. In order to ensure the oncologic safety of TAD, eligibility criteria resulting in a low false negative rate (FNR) have been proposed. The purpose of this study was to evaluate the utility of the traditional criteria. METHODS: Data was collected from a prospective multicenter registry. In order to ascertain FNRs, pathologic findings in the sentinel lymph nodes (LN)s, malignant clipped LN, and axillary contents were determined. The FNRs within TAD eligibility criterion groups were compared. RESULTS: A total of 110 patients underwent TAD and ALND, and were therefore eligible for analysis. TAD retained a low FNR in advanced clinical T-N stage compared with earlier disease (T stage: 95% CI 0.00-11.93, p = 0.42; N stage: 95% CI 0.00-8.76, p = 0.31). Presentation with ≥4 abnormal LNs on axillary ultrasound did not predict a high TAD FNR (95% CI 0.00-5.37, p = 0.16). No significant differences were noted in TAD FNR when single was compared with dual tracer (blue dye vs dual tracer 95% CI 0.72-52.49, p = 0.13; radiotracer vs dual tracer 0.04-20.11, p = 0.51). Excision of the clipped LN and only one SLN was as accurate as excision of the clipped LN and ≥2 SLNs (95% CI 0.00-10.61, p = 0.38). CONCLUSIONS: TAD retained a low FNR among patients traditionally considered ineligible for this technique. However, excision of the clipped LN and at least one SLN remained essential to a low FNR.

Utility of 68Ga-DOTATATE PET-MRI for Gamma Knife® stereotactic radiosurgery treatment planning for meningioma.

OBJECTIVES: To investigate the impact of adding 68Ga-DOTATATE PET/MRI to standard MRI for target volume delineation in Gamma Knife® stereotactic radiosurgery (GKSRS) for meningioma. METHODS: Seventeen patients with 18 lesions undergoing GKSRS for WHO grade 1 meningioma were enrolled in a prospective study. All patients underwent pre-treatment 68Ga-DOTATATE PET/MRI examination in addition to standard procedures. Five clinicians independently contoured the gross tumour volume (GTV) based on standard MRI (GTVMRI) and PET/MRI (GTVPET/MRI) on separate occasions. Interobserver agreement was evaluated using Cohen's Kappa statistic (CKS), Dice similarity coefficient (DC), and Hausdorff distance (HD). Statistical analysis was performed with paired t-test and Wilcoxon signed rank test. RESULTS: The addition of PET/MRI significantly increased GTV contour volume (mean GTVPET/MRI 3.59 cm3 versus mean GTVMRI 3.18 cm3, P = .008). Using the treating clinician's pre-treatment GTVMRI as the reference, median CKS (87.2 vs 77.5, P = .006) and DC (87.2 vs 77.4, P = .006) were significantly lower, and median HD (25.2 vs 31.0, P = .001) was significantly higher with the addition of PET/MRI. No significant difference was observed in interobserver contouring reproducibility between GTVMRI and GTVPET/MRI. CONCLUSION: The addition of 68Ga-DOTATATE PET/MRI for target volume delineation in GKSRS for meningioma is associated with an increase in GTV volume and greater interobserver variation. PET/MRI did not affect interobserver contouring reproducibility. ADVANCES IN KNOWLEDGE: This study provides novel insights into the impact of 68Ga-DOTATATE PET/MRI on GTV delineation and interobserver agreement in meningioma GKSRS, highlighting its potential for improving GKSRS treatment accuracy.

Somatic estrogen receptor α mutations that induce dimerization promote receptor activity and breast cancer proliferation.

Physiologic activation of estrogen receptor α (ERα) is mediated by estradiol (E2) binding in the ligand-binding pocket of the receptor, repositioning helix 12 (H12) to facilitate binding of coactivator proteins in the unoccupied coactivator binding groove. In breast cancer, activation of ERα is often observed through point mutations that lead to the same H12 repositioning in the absence of E2. Through expanded genetic sequencing of breast cancer patients, we identified a collection of mutations located far from H12 but nonetheless capable of promoting E2-independent transcription and breast cancer cell growth. Using machine learning and computational structure analyses, this set of mutants was inferred to act distinctly from the H12-repositioning mutants and instead was associated with conformational changes across the ERα dimer interface. Through both in vitro and in-cell assays of full-length ERα protein and isolated ligand-binding domain, we found that these mutants promoted ERα dimerization, stability, and nuclear localization. Point mutations that selectively disrupted dimerization abrogated E2-independent transcriptional activity of these dimer-promoting mutants. The results reveal a distinct mechanism for activation of ERα function through enforced receptor dimerization and suggest dimer disruption as a potential therapeutic strategy to treat ER-dependent cancers.

Common aquatic pollutants modify hemocyte immune responses in Biomphalaria glabrata.

Disruptions to reproductive health in wildlife species inhabiting polluted environments is often found to occur alongside compromised immunity. However, research on impacts of aquatic pollution on freshwater mollusc immune responses is limited despite their importance as vectors of disease (Schistosomiasis) in humans, cattle and wild mammals. We developed an in vitro 'tool-kit' of well-characterized quantitative immune tests using Biomphalaria glabrata hemocytes. We exposed hemocytes to environmentally-relevant concentrations of common aquatic pollutants (17ß-estradiol, Bisphenol-A and p,p'-DDE) and measured key innate immune responses including motility, phagocytosis and encapsulation. Additionally, we tested an extract of a typical domestic tertiary treated effluent as representative of a 'real-world' mixture of chemicals. Encapsulation responses were stimulated by p,p'-DDE at low doses but were suppressed at higher doses. Concentrations of BPA (above 200 ng/L) and p,p'-DDE (above 500 ng/L) significantly inhibited phagocytosis compared to controls, whilst hemocyte motility was reduced by all test chemicals and the effluent extract in a dose-dependent manner. All responses occurred at chemical concentrations considered to be below the cytotoxic thresholds of hemocytes. This is the first time a suite of in vitro tests has been developed specifically in B. glabrata with the purpose of investigating the impacts of chemical pollutants and an effluent extract on immunity. Our findings indicate that common aquatic pollutants alter innate immune responses in B. glabrata, suggesting that pollutants may be a critical, yet overlooked, factor impacting disease by modulating the dynamics of parasite transmission between molluscs and humans.

Recently approved treatment options for patients with metastatic triple-negative and HER2-neu-positive breast cancer.

Breast cancer (BC) is the most common cancer affecting women worldwide. In 2021, the estimated number of new breast cancer cases was 281 550 and about 43 500 women died from metastatic breast cancer (mBC). For women aged 20-59 years, mBC remains the leading cause of cancer death and is, therefore, an important public health concern. Only 5% of women initially present with metastatic disease. Approximately 20% of patients presenting with local or locoregional disease progress to mBC despite adjuvant therapy. Inspite of all the medicosurgical advancements, the overall prognosis for patients diagnosed with mBC remains poor, with median overall survival of approximately 31 months, although this varies based on tumor biology. In recent years, there has been significant progress in developing immunotargeted therapies such as antihuman epidermal growth factor receptor 2 (anti-HER2) or check point inhibitors that confirmed to have dramatically improve the prognosis of mBC, a historically unfavorable disease subset. Even with the major progress that has been made in understanding the biology of BC, challenges such as resistance frequency to therapies, unknown efficacy, concerns for safety of drug combination and toxicities still remain high. Therefore, a new targeted and more selective treatment approaches are the need of the hour. In this review, we aim to outline the most recently approved medications in treatment of Her2-positive and triple-negative breast cancers.

Use of GammaPlan convolution algorithm for dose calculation on CT and cone-beam CT images.

PURPOSE: The aim of this study was to assess the suitability of using cone-beam computed tomography images (CBCTs) produced in a Leksell Gamma Knife (LGK) Icon system to generate electron density information for the convolution algorithm in Leksell GammaPlan (LGP) Treatment Planning System (TPS). MATERIALS AND METHODS: A retrospective set of 30 LGK treatment plans generated for patients with multiple metastases was selected in this study. Both CBCTs and fan-beam CTs were used to provide electron density data for the convolution algorithm. Plan quality metrics such as coverage, selectivity, gradient index, and beam-on time were used to assess the changes introduced by convolution using CBCT (convCBCT) and planning CT (convCT) data compared to the homogeneous TMR10 algorithm. RESULTS: The mean beam-on time for TMR10 and convCBCT was found to be 18.9 ± 5.8 minutes and 21.7 ± 6.6 minutes, respectively. The absolute mean difference between TMR10 and convCBCT for coverage, selectivity, and gradient index were 0.001, 0.02, and 0.0002, respectively. The calculated beam-on times for convCBCT were higher than the time calculated for convCT treatment plans. This is attributed to the considerable variation in Hounsfield values (HU) dependent on the position within the field of view. CONCLUSION: The artifacts from the CBCT's limited field-of-view and considerable HU variation need to be taken into account before considering the use of convolution algorithm for dose calculation on CBCT image datasets, and electron data derived from the onboard CBCT should be used with caution.

Haploinsufficiency Interactions between RALBP1 and p53 in ERBB2 and PyVT Models of Mouse Mammary Carcinogenesis.

We recently reported that loss of one or both alleles of Ralbp1, which encodes the stress-protective protein RLIP76 (Rlip), exerts a strong dominant negative effect on both the inherent cancer susceptibility and the chemically inducible cancer susceptibility of mice lacking one or both alleles of the tumor suppressor p53. In this paper, we examined whether congenital Rlip deficiency could prevent genetically-driven breast cancer in two transgenic mouse models: the MMTV-PyVT model, which expresses the polyomavirus middle T antigen (PyVT) under control of the mouse mammary tumor virus promoter (MMTV) and the MMTV-Erbb2 model which expresses MMTV-driven erythroblastic leukemia viral oncogene homolog 2 (Erbb2, HER2/Neu) and frequently acquires p53 mutations. We found that loss of either one or two Rlip alleles had a suppressive effect on carcinogenesis in Erbb2 over-expressing mice. Interestingly, Rlip deficiency did not affect tumor growth but significantly reduced the lung metastatic burden of breast cancer in the viral PyVT model, which does not depend on either Ras or loss of p53. Furthermore, spontaneous tumors of MMTV-PyVT/Rlip+/+ mice showed no regression following Rlip knockdown. Finally, mice lacking one or both Rlip alleles differentially expressed markers for apoptotic signaling, proliferation, angiogenesis, and cell cycling in PyVT and Erbb2 breast tumors. Our results support the efficacy of Rlip depletion in suppressing p53 inactivated cancers, and our findings may yield novel methods for prevention or treatment of cancer in patients with HER2 mutations or tumor HER2 expression.

Effect of a comprehensive deep-learning model on the accuracy of chest x-ray interpretation by radiologists: a retrospective, multireader multicase study.

BACKGROUND: Chest x-rays are widely used in clinical practice; however, interpretation can be hindered by human error and a lack of experienced thoracic radiologists. Deep learning has the potential to improve the accuracy of chest x-ray interpretation. We therefore aimed to assess the accuracy of radiologists with and without the assistance of a deep-learning model. METHODS: In this retrospective study, a deep-learning model was trained on 821 681 images (284 649 patients) from five data sets from Australia, Europe, and the USA. 2568 enriched chest x-ray cases from adult patients (≥16 years) who had at least one frontal chest x-ray were included in the test dataset; cases were representative of inpatient, outpatient, and emergency settings. 20 radiologists reviewed cases with and without the assistance of the deep-learning model with a 3-month washout period. We assessed the change in accuracy of chest x-ray interpretation across 127 clinical findings when the deep-learning model was used as a decision support by calculating area under the receiver operating characteristic curve (AUC) for each radiologist with and without the deep-learning model. We also compared AUCs for the model alone with those of unassisted radiologists. If the lower bound of the adjusted 95% CI of the difference in AUC between the model and the unassisted radiologists was more than -0·05, the model was considered to be non-inferior for that finding. If the lower bound exceeded 0, the model was considered to be superior. FINDINGS: Unassisted radiologists had a macroaveraged AUC of 0·713 (95% CI 0·645-0·785) across the 127 clinical findings, compared with 0·808 (0·763-0·839) when assisted by the model. The deep-learning model statistically significantly improved the classification accuracy of radiologists for 102 (80%) of 127 clinical findings, was statistically non-inferior for 19 (15%) findings, and no findings showed a decrease in accuracy when radiologists used the deep-learning model. Unassisted radiologists had a macroaveraged mean AUC of 0·713 (0·645-0·785) across all findings, compared with 0·957 (0·954-0·959) for the model alone. Model classification alone was significantly more accurate than unassisted radiologists for 117 (94%) of 124 clinical findings predicted by the model and was non-inferior to unassisted radiologists for all other clinical findings. INTERPRETATION: This study shows the potential of a comprehensive deep-learning model to improve chest x-ray interpretation across a large breadth of clinical practice. FUNDING: Annalise.ai.

Relative Risk of Peripheral Neuropathy With Ado-Trastuzumab Emtansine (T-DM1) Compared to Taxane-Based Regimens in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Cancers: A Systematic Review and Meta-Analysis.

Background Peripheral neuropathy (PN), especially peripheral sensory neuropathy (PSN), is significant toxicity of taxanes, the most used class of microtubule inhibitors for human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. Ado-trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate, consisting of trastuzumab and a microtubule inhibitor DM1, which has been approved for HER2-positive breast cancer. T-DM1 has also been found to cause significant PN, including PSN. Methods We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials using T-DM1 in the experimental arm and a taxane-based regimen in the control arm to determine the relative risk of PN and PSN associated with T-DM1 as compared to taxanes. A total of 1,857 patients were included in the analysis. The Cochran-Mantel-Haenszel method and the random-effects model were used to calculate the pooled risk ratio (RR) with a 95% confidence interval (CI) for all-grade and grade ≥3 PN and PSN.  Results The relative risks of all-grade PN and all-grade PSN were lower with T-DM1 compared to taxanes. The pooled RR of all-grade PN was 0.59, 95% CI: 0.39-0.89, P = 0.01, and the pooled RR of all-grade PSN was 0.58, 95% CI: 0.46-0.74, P < 0.0001. Conclusions Our meta-analysis demonstrated that T-DM1 is associated with a relatively lower risk of all-grade PN and PSN than the taxane-based regimens for HER2-positive cancers. It could be an area of consideration in selecting therapy for HER2-positive breast cancer patients at high risk of developing or having pre-existing PN and PSN.

Chest radiographs and machine learning - Past, present and future.

Despite its simple acquisition technique, the chest X-ray remains the most common first-line imaging tool for chest assessment globally. Recent evidence for image analysis using modern machine learning points to possible improvements in both the efficiency and the accuracy of chest X-ray interpretation. While promising, these machine learning algorithms have not provided comprehensive assessment of findings in an image and do not account for clinical history or other relevant clinical information. However, the rapid evolution in technology and evidence base for its use suggests that the next generation of comprehensive, well-tested machine learning algorithms will be a revolution akin to early advances in X-ray technology. Current use cases, strengths, limitations and applications of chest X-ray machine learning systems are discussed.

Clinical impact of magnetic resonance imaging distortions on gamma knife radiosurgery.

INTRODUCTION: Magnetic resonance imaging (MRI) is the preferred imaging modality for Leksell Gamma Knife® (LGK) stereotactic radiosurgery (SRS) treatment planning (TP) due to superior soft tissue definition compared to computed tomography (CT). However, inherent distortions in MRI can affect treatment accuracy. The aim of this study was to develop a model to visualise the effect of MRI distortion on LGK SRS target coverage. METHODS: A model was developed using MR images of a QUASARTM GRID3D QA phantom. One hundred and twenty-five points were compared against known phantom geometry. Using linear interpolation, the model was applied retrospectively to 10 brain metastases patient data sets treated with LGK. The model estimated the corrected shot position accounting for distortion. A total of 44 metastases were investigated regarding the effects of MRI distortion on target coverage. RESULTS: The model indicated significantly reduced mean error by 0.30 mm and variance by 0.09 mm (P = 0.008). After model application, 23 (53%) metastases showed reduced coverage. Six of the 23 metastases were deemed to be potentially clinically significant changes. Results indicated MRI distortion had a greater effect on smaller targets (mean 0.06cc) located further away from the image isocentre (mean 64.88 mm). CONCLUSION: This study developed a model to visualise the effect of MRI distortion on LGK SRS target coverage. Results suggest that MRI distortion can affect target coverage and the developed model may be one method to assess its impact. These results indicate that MRI distortion may have a greater effect on smaller targets located at the image periphery.

Androgen receptor expression in breast cancer: Implications on prognosis and treatment, a brief review.

Approximately 70%-85% of breast cancers express androgen receptors (ARs). The role of AR in breast cancer pathogenesis is currently in exploration. Both androgens and anti-androgens have demonstrated variable inhibitory and stimulatory effects in AR-positive breast cancer depending on estrogen receptor and HER2 co-expression. Androgen signaling pathways interact with other critical cellular pathways, such as the PI3K/AKT/mTOR, Ras/Raf/MAPK/ERK, Wnt/ß-catenin, and estrogen signaling pathways. Therapeutic exploitation of AR has been the crux of management of prostate cancer for decades. In recent years there has been increasing interest in AR as a novel therapeutic target in breast cancer. There have been many early phase clinical trials evaluating the safety and efficacy of various AR-targeted agents in breast cancer. Some of these studies have shown promising clinical benefits. Studies of biomarkers to identify the patients likely to benefit from AR-targeted therapies are currently in progress. Besides, AR expression may be an important prognostic and predictive marker for breast cancer, which needs to be defined better in future studies.

Endocrine prevention of breast cancer.

Breast cancer (BC) is the most common non-cutaneous malignancy among women worldwide and is a significant cause of morbidity, mortality, and national health care expenditure. Unfortunately, with few exceptions like alcohol consumption, obesity, and physical activity, most BC risk factors are unmodifiable. Antiestrogen endocrine therapy, commonly known as BC chemoprevention, is an effective method of BC prevention. In multiple randomized trials, two selective estrogen receptor modulators - tamoxifen and raloxifene, and two aromatase inhibitors - exemestane and anastrozole have reduced BC incidence by 50%-65% in high-risk women. An estimated 15% of the US women between 35 and 79 years of age may qualify as high risk for BC, yet a small percentage of these women will ever have a formal BC risk assessment or a discussion of endocrine prevention options. The etiology of underutilization of endocrine prevention of BC is multifactorial - infrequent use of BC risk assessment tools in the primary care settings, insufficient knowledge of BC risk assessment tools and antiestrogen agents among primary care providers, concerns of side effects, inadequate time for counseling during primary care visit, and lack of predictive biomarkers may play significant roles. Many small studies incorporating risk assessment tools and decision-making aids showed minimal success in enhancing endocrine prevention. One critical factor for underutilization of endocrine prevention is low uptake of endocrine prevention by high-risk women even when appropriately recommended. Furthermore, adherence to BC endocrine prevention is unsatisfactorily low. Despite the current infrequent usage, endocrine prevention has the potential to reduce the public health burden of BC significantly. Innovative approaches like finding new agents, alternative dosing and schedule of currently available agents, transdermal medication delivery, increased public and professional awareness, and policymakers' commitments may bring the desired changes.

Analytical implications of different methods for preparing plant cell wall material.

Almost all plant cells are surrounded by a wall constructed of co-extensive networks of polysaccharides and proteoglycans. The capability to analyse cell wall components is essential for both understanding their complex biology and to fully exploit their numerous practical applications. Several biochemical and immunological techniques are used to analyse cell walls and in almost all cases the first step is the preparation of an alcohol insoluble residue (AIR). There is significant variation in the protocols used for AIR preparation, which can have a notable impact on the downstream extractability and detection of cell wall components. To explore these effects, we have formally compared ten AIR preparation methods and analysed polysaccharides subsequently extracted using high-performance anion exchange chromatography (HPAEC-PAD) and Micro Array Polymer Profiling (MAPP). Our results reveal the impact that AIR preparation has on downstream detection of cell wall components and the need for optimisation and consistency when preparing AIR.

Collaborative working in health and social care: Lessons learned from post-hoc preliminary findings of a young families' pregnancy to age 2 project in South Wales, United Kingdom.

Children of young and socially disadvantaged parents are more likely to experience adverse outcomes. In response to this, a unique young families' project in Swansea, UK, was created, which drew together a team of multi-agency professionals, to support people aged 16-24 from 17 weeks of pregnancy throughout 1,001 days of the child's life. The aim of the JIGSO (the Welsh word for Jigsaw) project is for young people to reach their potential as parents and to break the cycle of health and social inequality. This evaluation analysed routinely collected data held by the project from January 2017 to December 2018 exploring health and social outcomes, including smoking and alcohol use in pregnancy, breastfeeding, maternal diet and social services outcomes. Outcomes were compared to local and national averages, where available. Data relating to parenting knowledge and skills were available via records of 10-point Likert scales, one collected at the start of the JIGSO involvement and one around 4-6 months later. Findings showed higher than average levels of breastfeeding initiation and lower smoking and alcohol use in pregnancy. Parents also reported enhanced knowledge and confidence in their child care skills, as well as improved family relationships. Parents with high levels of engagement with JIGSO also appeared to have positive outcomes with Social Services (their child's name was removed from child protection register or their case was closed to social services). This was a post-hoc evaluation, not an intervention study or trial, and thus findings must be interpreted with caution. Despite this, the findings are promising and more prospective research exploring similar services is required.

Leksell Gamma Knife® - The first 1000 patients from the radiation therapist's perspective.

The Princess Alexandra Hospital (PAH) Gamma Knife® Centre of Queensland (GKCoQ) began operations in October of 2015 as a sub-specialty located within a larger radiation oncology service at PAH. It is uniquely positioned as the only Leksell Gamma Knife® (LGK) treatment unit available in the public hospital system in Australia, and the first and only service in Queensland. The GKCoQ treated the 1000th patient on 23 January 2019. LGK is a non-invasive alternative to neurosurgery which uses radioactive cobalt sources to treat a variety of intracranial conditions ranging from tumours and metastases to functional disorders. It is a platform for stereotactic radiosurgery, a highly precise form of radiotherapy utilising very high doses to the target while maximally sparing surrounding normal brain. LGK enables patient planning and treatment to be done in one day as an outpatient procedure. This paper will outline our LGK service and provide insight into the expanded role that radiation therapists have within the multidisciplinary team required to deliver radiosurgery in a timely manner. The training programme and radiation licensing pathway that have been established for radiation therapists will also be described.

Effect of chemoradiation on the size of the thyroid gland.

We aimed to evaluate changes in thyroid gland size during the treatment of malignancies outside the head and neck with chemotherapy and/or external beam radiation. We performed a retrospective review of records of adult patients treated at our institution with external beam radiation to the chest and/or chemotherapy with taxanes, alkylating agents, and/or a topoisomerase II inhibitor. Neck and chest computed tomography (CT) images were used to calculate thyroid gland volume before and after therapy, using Vitrea® software or the volumetric ellipsoid method. Thirty-seven patients were included. After treatment, there was a significant reduction in thyroid gland volume of 14.0% (P < 0.01) using Vitrea and 17.1% (P < 0.05) using the volumetric ellipsoid method. Exposure to radiation or chemotherapy was not found to be associated with the degree of thyroid gland reduction, nor was the number of days between CT scans or the stage of the malignancy being treated. Finally, the degree of thyroid gland size reduction did not predict mortality. Our results showed that the treatment of malignancies outside the head and neck with chemotherapy and/or external beam radiation results in a reduction in thyroid gland size. The impact on thyroid gland function remains unknown.

Stereotactic radiotherapy for large vestibular schwannomas: Volume change following single fraction versus hypofractionated approaches.

Hypofractionated stereotactic radiotherapy is a treatment option for large vestibular schwannomas supported by an increasing evidence. A single institution retrospective review of large (>3.5cc) vestibular schwannomas treated with hypofractionated stereotactic radiotherapy and single-session radiosurgery was conducted. Using serial follow up scans, a volumetric analysis of tumor volume change over time was performed. Vestibular schwannomas treated with hypofractionated stereotactic radiotherapy appeared to reduce in volume significantly faster than those treated with single-session radiosurgery. Cystic lesions reduced in volume faster than solid lesions. There was no significant difference in the rates of radiological and symptomatic oedema, nor subsequent dexamethasone requirement between the two treatment modalities.

Rlip Depletion Suppresses Growth of Breast Cancer.

RLIP76 (RAL-binding protein-1, Rlip) is a stress-protective mercapturic-acid-pathway transporter protein that also plays a key role in regulating clathrin-dependent endocytosis as a Ral effector. Targeted inhibition or depletion of Rlip causes regression of xenografts of many cancers and is capable of abrogating tumor formation in p53-null mice. This is associated with the reversion of the abnormal methylomic profile of p53-null mice to wild-type. In a query of The Cancer Genome Atlas (TCGA) databases, we found that Rlip expression was associated with poor survival and with significant differences in the frequencies of PIK3CA mutation, MYC amplification, and CDKN2A/B deletion, which were the most commonly mutated, amplified, and deleted genes, respectively, among TCGA breast cancer patients. We conducted the present study to further examine the effects of Rlip inhibition and to evaluate the in vitro and in vivo efficacy in breast cancer. Using immunogold electron microscopy, we found that plasma-membrane Rlip was accessible to cell-surface antibodies in the MCF7 (ER+) breast cancer cell line. Rlip depletion resulted in decreased survival of MCF7 and MDA-MB-231 cells and increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity and DNA laddering, indicating apoptotic cell death. Additionally, in vitro knockdown of Rlip inhibited EGF endocytosis and WNT/MAPK signaling. Xenograft studies in nude mice showed regression of breast cancer via antisense-mediated depletion of Rlip mRNA as well as by anti-Rlip antibody. Finally, knockdown of Rlip by antisense locked nucleic acid oligonucleotides increased markers for apoptotic signaling and decreased markers for proliferation, angiogenesis, and cell cycling in MCF7 and MDA-MB-231luc xenografts. Our findings validate Rlip as an attractive target in breast cancer.