PRMT5 supports multiple oncogenic pathways in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy with an overall poor prognosis, particularly for patients that progress on targeted therapies. Novel, more durable treatment options are needed for patients with MCL. Protein arginine methyltransferase 5 (PRMT5) is overexpressed in MCL and plays an important oncogenic role in this disease via epigenetic and posttranslational modification of cell cycle regulators, DNA repair genes, components of prosurvival pathways, and RNA splicing regulators. The mechanism of targeting PRMT5 in MCL remains incompletely characterized. Here, we report on the antitumor activity of PRMT5 inhibition in MCL using integrated transcriptomics of in vitro and in vivo models of MCL. Treatment with a selective small-molecule inhibitor of PRMT5, PRT-382, led to growth arrest and cell death and provided a therapeutic benefit in xenografts derived from patients with MCL. Transcriptional reprograming upon PRMT5 inhibition led to restored regulatory activity of the cell cycle (p-RB/E2F), apoptotic cell death (p53-dependent/p53-independent), and activation of negative regulators of B-cell receptor-PI3K/AKT signaling (PHLDA3, PTPROt, and PIK3IP1). We propose pharmacologic inhibition of PRMT5 for patients with relapsed/refractory MCL and identify MTAP/CDKN2A deletion and wild-type TP53 as biomarkers that predict a favorable response. Selective targeting of PRMT5 has significant activity in preclinical models of MCL and warrants further investigation in clinical trials.

Palliative care utilization and racial and ethnic disparities among women with de novo metastatic breast cancer in the United States.

PURPOSE: The potential disparities in palliative care delivery for underrepresented minorities with breast cancer are not well known. We sought to determine whether race and ethnicity impact the receipt of palliative care for patients with metastatic breast cancer (MBC). METHODS: We retrospectively reviewed the National Cancer Database for female patients diagnosed with stage IV breast cancer between 2010 and 2017 who received palliative care following diagnosis of MBC to assess the proportion of patients who received palliative care, including non-curative-intent local-regional or systemic therapy. Multivariable logistic regression analysis was performed to identify variables associated with receiving palliative care. RESULTS: 60,685 patients were diagnosed with de novo MBC. Of these, only 21.4% (n = 12,963) received a palliative care service. Overall, there was a positive trend in palliative care receipt from 18.2% in 2010 to 23.0% in 2017 (P < 0.001), which persisted when stratified by race and ethnicity. Relative to non-Hispanic White women, Asian/Pacific Islander women (aOR 0.80, 95% CI 0.71-0.90, P < 0.001), Hispanic women (adjusted odds ratio [aOR] 0.69, 95% CI 0.63-0.76, P < 0.001), and non-Hispanic Black women (aOR 0.94, 95% CI 0.88-0.99, P = 0.03) were less likely to receive palliative care. CONCLUSIONS: Fewer than 25% of women with MBC received palliative care between 2010 and 2017. While palliative care has significantly increased for all racial/ethnic groups, Hispanic White, Black, and Asian/Pacific Islander women with MBC still receive significantly less palliative care than non-Hispanic White women. Further research is needed to identify the socioeconomic and cultural barriers to palliative care utilization.

Five-Year Breast Surgeon Experience in LYMPHA at Time of ALND for Treatment of Clinical T1-4N1-3M0 Breast Cancer.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a source of postoperative morbidity for breast cancer survivors. Lymphatic microsurgical preventive healing approach (LYMPHA) is a technique used to prevent BCRL at the time of axillary lymph node dissection (ALND). We report the 5-year experience of a breast surgeon trained in LYMPHA and investigate the outcomes of patients who underwent LYMPHA following ALND for treatment of cT1-4N1-3M0 breast cancer. METHODS: A retrospective review of patients with cT1-4N1-3M0 breast cancer was performed in patients who underwent ALND with and without LYMPHA. Diagnosis of BCRL was made by certified lymphedema therapists. Descriptive statistics and lymphedema surveillance data were analyzed using results of Fisher's exact or Wilcoxon rank-sum tests. Logistic regression and propensity matching were performed to assess the reduction of BCRL occurrence following LYMPHA. RESULTS: In a 5-year period, 132 patients met inclusion criteria with 76 patients undergoing LYMPHA at the time of ALND and 56 patients undergoing ALND alone. Patients who underwent LYMPHA at the time of ALND were significantly less likely to develop BCRL than those who underwent ALND alone (p = 0.045). Risk factors associated with BCRL development were increased patient age (p = 0.007), body mass index (BMI) (p = 0.003), and, in patients undergoing LYMPHA, number of positive nodes (p = 0.026). CONCLUSIONS: LYMPHA may be successfully employed by breast surgeons trained in lymphatic-venous anastomosis at the time of ALND. While research efforts should continue to focus on prevention and surveillance of BCRL, LYMPHA remains an option to reduce BCRL and improve patient quality of life.

Functional Network Development in Sagittal Craniosynostosis Treated With Whole Vault Cranioplasty.

INTRODUCTION: In this study, the authors seek to clarify the neurological changes before and after whole vault cranioplasty (WVC) in patients born with sagittal craniosynostosis. METHODS: A case control study design was performed that included thirty functional MRI scans, from 25 individual patients. Functional MRI and diffusion tension imaging data were analyzed with BioImageSuite (Yale University, USA). 9 functional brain networks were analyzed, with appropriate correlated functional regions of the brain and utilized for analysis. RESULTS: Comparing functional MRI the infants after WVC versus infants before WVC group, the after WVC group demonstrated an increased connectivity in the left frontoparietal, secondary (V2), and third (V3) visual networks (P < 0.001). The right frontoparietal (RFPN) had decreased connectivity (P < 0.001). There is also a decrease and increase in anisotropy in the cingulum and precuneus despite surgery, respectively (P < 0.05). Adolescents treated with WVC compared to controls, demonstrated an increased connectivity in the salience and decreased connectivity in the RFPN relative to adolescent controls. CONCLUSIONS: Patients born with sagittal craniosynostosis have different connections in infancy in most of the defined cerebral networks compared to controls. After surgery, there are specific connectivity changes that occur in the RFPN, left frontoparietal, V2, and V3 networks, which are areas associated with executive function and emotional control. Changes identified in white matter tract microstructure connections could be influential in changes in functional connectivity. Although, as a child with sagittal craniosynostosis develops, much of the abnormal network connections, seen in infancy preoperatively, corrects to some degree after surgery. However, some aberrancies in the salience and RFPN networks remain potentially affecting executive functioning.

Understanding the Learning Disabilities Linked to Sagittal Craniosynostosis.

OBJECTIVE: The purpose of this study is to investigate further findings that corroborate similarities between corrected sagittal craniosynostosis and attention deficit hyperactivity disorder (ADHD). The aim is to further characterize the neurocognitive deficits seen in adolescents with corrected craniosynostosis by comparing it to established learning deficits such as ADHD. METHODS: A total of 30 functional magnetic resonance imaging (fMRI) of 10 sagittal nonsyndromic craniosynostosis (sNSC), 10 ADHD-combined, and 10 control adolescents were studied. The fMRI scans were analyzed utilizing Statistical Parametric Mapping (University College London, UK) and analyzed with BioImageSuite (Yale University, New Haven, CT). RESULTS: The ADHD has lower connectivity to Brodmann area (BA) 11 (Montreal Neurological Institution [MNI]: -12,26,-21), BA20 (MNI: 62,-24,-25), and BA21 (MNI: 62,-32,-23) compared to sNSC and controls (P < 0.001). The sNSC has a unique visuospatial defect, compared to ADHD, created by decreased connectivity to BA31 (MNI: -3,-68,37), BA7 (MNI: -4,-68,41), BA19 (MNI: 0,-83,31), visual association cortex (MNI: -4,-78,22), and primary visual cortex (MNI: 7,-74,21) (P < 0.001). CONCLUSION: Patients born with sNSC have different neural connections than children born with ADHD. Patients born with sNSC have decreased connections in areas of visual processing and increased connections in areas of attention and auditory processing than patients with ADHD. Therefore, children with sagittal craniosynsotosis may have learning difficulties that, similar, yet different from ADHD.

An Investigation of Brain Functional Connectivity by Form of Craniosynostosis.

PURPOSE: Long-term neurocognitive sequelae of nonsyndromic craniosynostosis (NSC) patients are just beginning to be clarified. This study uses functional MRI (fMRI) to determine if there is evidence of altered brain functional connectivity in NSC, and whether these aberrations vary by form of synostosis. METHODS: Twenty adolescent participants with surgically treated NSC (10 sagittal synostosis, 5 right unilateral coronal synostosis [UCS], 5 metopic synostosis [MSO]) were individually matched to controls by age, gender, and handedness. A subgroup of MSO was classified as severe metopic synostosis (SMS) based on the endocranial bifrontal angle. Resting state fMRI was acquired in a 3T Siemens TIM Trio scanner (Erlangen, Germany), and data were motion corrected and then analyzed with BioImage Suite (Yale School of Medicine). Resulting group-level t-maps were cluster corrected with nonparametric permutation tests. A region of interest analysis was performed based on the left Brodmann's Areas 7, 39, and 40. RESULTS: Sagittal synostosis had decreased whole-brain intrinsic connectivity compared to controls in the superior parietal lobules and the angular gyrus (P = 0.071). Unilateral coronal synostosis had decreased intrinsic connectivity throughout the prefrontal cortex (P = 0.031). The MSO cohort did not have significant findings on intrinsic connectivity, but the SMS subgroup had significantly decreased connectivity among multiple subcortical structures. CONCLUSION: Sagittal synostosis had decreased connectivity in regions associated with visuomotor integration and attention, while UCS had decreased connectivity in circuits crucial in executive function and cognition. Finally, severity of metopic synostosis may influence the degree of neurocognitive aberration. This study provides data suggestive of long-term sequelae of NSC that varies by suture type, which may underlie different phenotypes of neurocognitive impairment.

What is the Functional Difference Between Sagittal With Metopic and Isolated Sagittal Craniosynotosis?

INTRODUCTION: The purpose of this study is to understand the neurological differences between patients born with combined sagittal and metopic craniosynostosis (SMc) and isolated sagittal craniosynostosis (ISc) by studying aberrations in functional brain connectivity and white matter microstructure, before surgery, utilizing functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). METHODS: The authors collected DTI and resting-state (ie, no sedation and asleep) functional connectivity MRI data in 10 infant patients preoperatively: 5 in the SMc group (4.3 ±â€Š1 months) and 5 in the ISc group (4.8 ±â€Š1.1 months). Resting state fMRI imaging and DTI data were acquired using a 3-T Siemens Trio MRI system (Erlangen, Germany) while the infant patients slept. fMRI data were corrected for movement using SPM, underwent cerebrospinal fluid and white matter signal regression and further analyzed with BioImageSuite. For the DTI data, 3 diffusion runs were averaged, processed utilizing FMRIB Software Library, and analyzed statistically using BioImageSuite. RESULTS: Comparing the SMc versus ISc groups, SMc demonstrated that there was increased connectivity, statistically significant differences, in neural networks between children with sagittal synostosis alone versus those with sagittal with metopic synostosis, in the right BA 31 and BA 23 (corresponding to the posterior cingulate cortex (PCC) (P < 0.001). Analysis of the DTI revealed increased fractional anisotropy (normal maturation of white tracts) in the SMc group in the cingulum compared to the ISc group (P < 0.05). Differences in the functional networks include increased connectivity right frontoparietal network (RFPN) in ISc and increased connectivity in the primary visual network (V1) in SMc (P < 0.001). CONCLUSION: The SMc had increased connectivity as measured by fMR in the PCC, an area associated with attention deficit hyperactivity disorder. The DTI analysis demonstrated an increase in fractional anisotropy of the cingulum in the SMc group, a white matter tract projecting from the cingulate cortex; connections of the limbic (emotional regulation) system are instrumental. In SMc, increase of connectivity in the PCC correlates with an increase in maturation of the cingulum compared to ISc. There is increased connectivity of the RFPN network in the ISc and increased connectivity of the V1 network in the SMc patients. The SMc group has increased connectivity in the PCC, the original seed of the DMN network, and decreased connectivity to the RFPN network. The pattern of increased connectivity in the area of the DMN and decreased connectivity in the RFPN network is similar to the trend when comparing ADHD patients to normal controls. SMc has more similar functional network connectivity to ADHD as compared to ISc.

Chemoradiotherapy Versus Chemotherapy Alone for Unresected Nonmetastatic Gallbladder Cancer: National Practice Patterns and Outcomes.

Purpose: Current guidelines recommend chemotherapy (CT) with or without radiotherapy for unresected nonmetastatic gallbladder cancer (GC), with little consensus. However, several small-volume, single-institution studies have documented the efficacy of local therapy for this population. This is the largest study to date evaluating outcomes of chemoradiotherapy (CRT) versus CT alone in unresected nonmetastatic GC. Methods: The National Cancer Database was queried for primary GC cases (2004-2013) receiving CT alone or CRT. Patients receiving resection or lack of CT were excluded, as were those with metastatic disease or unknown M classification. Logistic regression analysis ascertained factors associated with CRT delivery. Kaplan-Meier analysis evaluated overall survival (OS) between both cohorts. Cox proportional hazards modeling determined variables associated with OS. Results: In total, 1,199 patients were analyzed (CRT: n=327, 27%; CT: n=872, 73%). Groups were evenly balanced, with no factor on multivariate logistic regression analysis statistically predicting for receipt of a particular paradigm. Median OS in the CRT and CT groups was 12.9 versus 7.8 months, respectively (P=.001). On multivariate analysis, OS was associated with age and years of treatment (P=.001 each). Notably, receipt of CRT independently predicted for improved OS (P=.001). Conclusions: CRT, compared with CT alone, was independently associated with improved survival in unresected nonmetastatic GC. Although causation is not implied, these results support the necessity for prospective CRT evaluation.

The Etiology of Neuronal Development in Craniosynostosis: A Working Hypothesis.

Craniosynostosis is one of the most common craniofacial conditions treated by neurologic and plastic surgeons. In addition to disfigurement, children with craniosynostosis experience significant cognitive dysfunction later in life. Surgery is performed in infancy to correct skull deformity; however, the field is at a crossroads regarding the best approach for correction. Since the cause of brain dysfunction in these patients has remained uncertain, the role and type of surgery might have in attenuating the later-observed cognitive deficits through impact on the brain has been unclear. Recently, however, advances in imaging such as event-related potentials, diffusion tensor imaging, and functional MRI, in conjunction with more robust clinical studies, are providing important insight into the potential etiologies of brain dysfunction in syndromic and nonsyndromic craniosynostosis patients. This review aims to outline the cause(s) of such brain dysfunction including the role extrinsic vault constriction might have on brain development and the current evidence for an intrinsic modular developmental error in brain development. Illuminating the cause of brain dysfunction will identify the role of surgery can play in improving observed functional deficits and thus direct optimal primary and adjuvant treatment.

Normalization of Speech Processing After Whole-Vault Cranioplasty in Sagittal Synostosis.

BACKGROUND: Neurocognitive studies have found impairments in language-related abilities in nonsyndromic craniosynostosis, highlighting clinical importance of early language processing. In this study, neural response to speech sounds in infants with nonsyndromic sagittal craniosynostosis (NSC) is compared, preoperatively and postoperatively, using event-related potentials (ERPs) to objectively characterize development in language processing. METHODS: Electroencephalogram was recorded while 39 infants (12 NSC and 27 controls; ages 73-283 days) listened to the Hindi dental /(Equation is included in full-text article.)a/ and retroflex /da/ phonemes (non-native phonemic discrimination task). The mismatch negativity (MMN) ERP was extracted as the peak amplitude of the largest negative deflection in the difference wave over 80 to 300 milliseconds poststimulus. Differences in MMN were analyzed using repeated measures analysis of variance. RESULTS: The MMN amplitude was attenuated in the infants with NSC preoperatively compared with controls (P = 0.047). A significant region by group interaction (P = 0.045) was observed, and infants with NSC displayed attenuated MMN in the frontal electrodes compared with controls (P = 0.010). Comparing the preoperative and postoperative MMN, a time by group interaction trend (P = 0.070) was observed. Pair-wise comparisons showed a trend for increase in MMN amplitude from preoperatively to postoperatively in the infants with NSC (P = 0.059). At the postoperative time point, infants with NSC showed no significant difference in MMN from controls (P = 0.344). CONCLUSION: Infants with NSC demonstrated atypical neural response to language preoperatively. After undergoing surgery, infants with NSC showed increased MMN amplitude which was not significantly different from controls. These findings support the idea that whole vault cranioplasty may improve neurocognitive outcomes in sagittal craniosynostosis.

7-year follow-up after stereotactic ablative radiotherapy for patients with stage I non-small cell lung cancer: Results of a phase 2 clinical trial.

BACKGROUND: The authors evaluated the efficacy, patterns of failure, and toxicity of stereotactic ablative radiotherapy (SABR) for patients with medically inoperable, clinical stage I non-small cell lung cancer (NSCLC) in a prospective clinical trial with 7 years of follow-up. Clinical staging was performed according to the seventh edition of the American Joint Committee on Cancer TNM staging system. METHODS: Eligible patients with histologically confirmed NSCLC of clinical stage I as determined using positron emission tomography staging were treated with SABR (50 grays in 4 fractions). The primary endpoint was progression-free survival. Patients were followed with computed tomography and/or positron emission tomography/computed tomography every 3 months for the first 2 years, every 6 months for the next 3 years, and then annually thereafter. RESULTS: A total of 65 patients were eligible for analysis. The median age of the patients was 71 years, and the median follow-up was 7.2 years. A total of 18 patients (27.7%) developed disease recurrence at a median of 14.5 months (range, 4.3-71.5 months) after SABR. Estimated incidences of local, regional, and distant disease recurrence using competing risk analysis were 8.1%, 10.9%, and 11.0%, respectively, at 5 years and 8.1%, 13.6%, and 13.8%, respectively, at 7 years. A second primary lung carcinoma developed in 12 patients (18.5%) at a median of 35 months (range, 5-67 months) after SABR. Estimated 5-year and 7-year progression-free survival rates were 49.5% and 38.2%, respectively; the corresponding overall survival rates were 55.7% and 47.5%, respectively. Three patients (4.6%) experienced grade 3 treatment-related adverse events. No patients developed grade 4 or 5 adverse events (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]). CONCLUSIONS: With long-term follow-up, the results of the current prospective study demonstrated outstanding local control and low toxicity after SABR in patients with clinical stage I NSCLC. Regional disease recurrence and distant metastases were the dominant manifestations of failure. Surveillance for second primary lung carcinoma is recommended. Cancer 2017;123:3031-39. © 2017 American Cancer Society.

Direct brain recordings reveal impaired neural function in infants with single-suture craniosynostosis: a future modality for guiding management?

BACKGROUND: Patients with single-suture craniosynostosis (SSC) are at an elevated risk for long-term learning disabilities. Such adverse outcomes indicate that the early development of neural processing in SSC may be abnormal. At present, however, the precise functional derangements of the developing brain remain largely unknown. Event-related potentials (ERPs) are a form of noninvasive neuroimaging that provide direct measurements of cortical activity and have shown value in predicting long-term cognitive functioning. The current study used ERPs to examine auditory processing in infants with SSC to help clarify the developmental onset of delays in this population. METHODS: Fifteen infants with untreated SSC and 23 typically developing controls were evaluated. ERPs were recorded during the presentation of speech sounds. Analyses focused on the P150 and N450 components of auditory processing. RESULTS: Infants with SSC demonstrated attenuated P150 amplitudes relative to typically developing controls. No differences in the N450 component were identified between untreated SSC and controls. CONCLUSIONS: Infants with untreated SSC demonstrate abnormal speech sound processing. Atypicalities are detectable as early as 6 months of age and may represent precursors to long-term language delay. Electrophysiological assessments provide a precise examination of neural processing in SSC and hold potential as a future modality to examine the effects of surgical treatment on brain development.

Radiation Toxicity in MDA5+ and PL7-Positive Dermatomyositis: Heightened Risk in Autoimmune Subtypes.

Purpose: To increase awareness of peri-radiation therapy (RT) intervention that may unduly heighten the risk of toxicity in lung cancer patients and encourage molecular testing and pretreatment consultation with rheumatology for patients with active autoimmune conditions. Materials and Methods: A 42-year-old male with an autoimmune disease was diagnosed with non-small cell lung cancer. He received 4 cycles of pemetrexed/cisplatin with proton therapy (PT) delivered halfway through for a bronchial stump positive margin. After completing the first cycle of adjuvant chemotherapy, he was given 61.6 Gy in 28 fractionations of PT. Before restarting chemotherapy, he experienced a dry cough and later shortness of breath (SOB), which resolved with an aggressive steroid taper. After completing his third cycle of cisplatin/pemetrexed, his SOB and cough worsened. He was admitted for an urgent bronchoscopy with debridement of the distal trachea and proximal left main bronchus. He received high-dose steroids again and another bronchoscopy, revealing a tracheoesophageal fistula. Rheumatology identified an MDA5+ and PL7-positive dermatomyositis subtype at this time, known to be associated with rare ulcerative symptoms. Results: A rare MDA5+ and PL7-positive dermatomyositis subtype, discovered post treatment, most likely contributed to SOB and cough following chemotherapy and PT, resulting in bronchoscopy of the irradiated field. A combination of these factors may have contributed to the tracheoesophageal fistula. Conclusion: Patients with autoimmune disease should be carefully evaluated for rare underlying subtypes that could pose a danger to treatment. Oncologists should continue to be vigilant about underlying genetic predisposing factors that lead to exacerbated toxicity. Immunosuppressive agents given with RT may be considered for patients with autoimmune disease. Avoidance of biopsy, tissue manipulation, debridement, or any form of soft-tissue or hard-tissue violation needs to be discussed across the multidisciplinary spectrum to avoid nonhealing lesions shortly after RT.

A single-cell atlas of spatial and temporal gene expression in the mouse cranial neural plate.

The formation of the mammalian brain requires regionalization and morphogenesis of the cranial neural plate, which transforms from an epithelial sheet into a closed tube that provides the structural foundation for neural patterning and circuit formation. Sonic hedgehog (SHH) signaling is important for cranial neural plate patterning and closure, but the transcriptional changes that give rise to the spatially regulated cell fates and behaviors that build the cranial neural tube have not been systematically analyzed. Here we used single-cell RNA sequencing to generate an atlas of gene expression at six consecutive stages of cranial neural tube closure in the mouse embryo. Ordering transcriptional profiles relative to the major axes of gene expression predicted spatially regulated expression of 870 genes along the anterior-posterior and mediolateral axes of the cranial neural plate and reproduced known expression patterns with over 85% accuracy. Single-cell RNA sequencing of embryos with activated SHH signaling revealed distinct SHH-regulated transcriptional programs in the developing forebrain, midbrain, and hindbrain, suggesting a complex interplay between anterior-posterior and mediolateral patterning systems. These results define a spatiotemporally resolved map of gene expression during cranial neural tube closure and provide a resource for investigating the transcriptional events that drive early mammalian brain development.

Navigating Complexities: Leadless Pacemaker Management in Proton Therapy for a Pacemaker-Dependent Bilateral Breast Cancer Patient.

This case study explores the strategic decision-making and safety considerations in managing a unique scenario where a pacemaker dependent patient, requiring adjuvant radiotherapy for bilateral breast cancer. The conventional pacemaker was located entirely within the treatment target, without the option for transposition because of the bilateral chest treatment, resulting in significant risk of malfunction caused by exposing it to the full prescribed dose. Consequently, the decision was made to replace the conventional pacemaker with a leadless device Micra implanted directly into the heart to mitigate direct device radiation and potential adverse effects of proton therapy on the cardiac device. Following Micra implantation, the patient underwent the proton treatment without complications or serious device malfunctions. This study explores solutions to address the challenges posed by within-the-field cardiac devices and highlights the use of pencil beam proton therapy for individuals with leadless cardiac devices while acknowledging the potential for neutron production and the associated risk of single-event upsets (SEU) in cardiac implantable electronic devices (CIEDs). The findings underscore the significance of strategic decision-making, risk assessment, and continuous monitoring for successful outcomes, particularly in the context of proton therapy for patients with advanced cardiac considerations.

Effects on Lung Tissue After Breast Cancer Radiation: Comparing Photon and Proton Therapies.

Purpose: In breast cancer, improved treatment approaches that reduce injury to lung tissue and early diagnosis and intervention for lung toxicity are increasingly important in survivorship. The aims of this study are to (1) compare lung tissue radiographic changes in women treated with conventional photon radiation therapy and those treated with proton therapy (PT), (2) assess the volume of lung irradiated to 5 Gy (V5) and 20 Gy (V20) by treatment modality, and (3) quantify the effects of V5, V20, time, and smoking history on the severity of tissue radiographic changes. Patients and Methods: A prospective observational study of female breast cancer patients was conducted to monitor postradiation subclinical lung tissue radiographic changes. Repeated follow-up x-ray computed tomography scans were acquired through 2 years after treatment. In-house software was used to quantify an internally normalized measure of pulmonary tissue density change over time from the computed tomography scans, emphasizing the 6- and 12-month time points. Results: Compared with photon therapy, PT was associated with significantly lower lung V5 and V20. Lung V20 (but not V5) correlated significantly with increased subclinical lung tissue radiographic changes 6 months after treatment, and neither correlated with lung effects at 12 months. Significant lung tissue density changes were present in photon therapy patients at 6 and 12 months but not in PT patients. Significant lung tissue density change persisted at 12 months in ever-smokers but not in never-smokers. Conclusion: Patients treated with PT had significantly lower radiation exposure to the lungs and less statistically significant tissue density change, suggesting decreased injury and/or improved recovery compared to photon therapy. These findings motivate additional studies in larger, randomized, and more diverse cohorts to further investigate the contributions of treatment modality and smoking regarding the short- and long-term radiographic effects of radiation on lung tissue.

Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination.

Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including SRY, RSPO1, SOX9, NR5A1, WT1, NR0B1, and WNT4. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in MAP3K1 segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg)-18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination.

Updated ultrasound criteria for polycystic ovary syndrome: reliable thresholds for elevated follicle population and ovarian volume.

STUDY QUESTION: Do the ultrasonographic criteria for polycystic ovaries supported by the 2003 Rotterdam consensus adequately discriminate between the normal and polycystic ovary syndrome (PCOS) condition in light of recent advancements in imaging technology and reliable methods for estimating follicle populations in PCOS? STUDY ANSWER: Using newer ultrasound technology and a reliable grid system approach to count follicles, we concluded that a substantially higher threshold of follicle counts throughout the entire ovary (FNPO)-26 versus 12 follicles-is required to distinguish among women with PCOS and healthy women from the general population. WHAT IS KNOWN ALREADY: The Rotterdam consensus defined the polycystic ovary as having 12 or more follicles, measuring between 2 and 9 mm (FNPO), and/or an ovarian volume (OV) >10 cm(3). Since their initial proposal in 2003, a heightened prevalence of polycystic ovaries has been described in healthy women with regular menstrual cycles, which has questioned the accuracy of these criteria and marginalized the specificity of polycystic ovaries as a diagnostic criterion for PCOS. STUDY DESIGN, SIZE, DURATION: A diagnostic test study was performed using cross-sectional data, collected from 2006 to 2011, from 168 women prospectively evaluated by transvaginal ultrasonography. Receiver operating characteristic (ROC) curve analyses were performed to determine the appropriate diagnostic thresholds for: (i) FNPO, (ii) follicle counts in a single cross section (FNPS) and (iii) OV. The levels of intra- and inter-observer reliability when five observers used the proposed criteria on 100 ultrasound cases were also determined. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ninety-eight women diagnosed with PCOS by the National Institutes of Health criteria as having both oligo-amenorrhea and hyperandrogenism and 70 healthy female volunteers recruited from the general population. Participants were evaluated by transvaginal ultrasonography at the Royal University Hospital within the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Saskatchewan (Saskatoon, SK, Canada) and in the Division of Nutritional Sciences' Human Metabolic Research Unit, Cornell University (Ithaca, NY, USA). MAIN RESULTS: Diagnostic potential for PCOS was highest for FNPO (0.969), followed by FNPS (0.880) and OV (0.873) as judged by the area under the ROC curve. An FNPO threshold of 26 follicles had the best compromise between sensitivity (85%) and specificity (94%) when discriminating between controls and PCOS. Similarly, an FNPS threshold of nine follicles had a 69% sensitivity and 90% specificity, and an OV of 10 cm(3) had a 81% sensitivity and 84% specificity. Levels of intra-observer reliability were 0.81, 0.80 and 0.86 when assessing FNPO, FNPS and OV, respectively. Inter-observer reliability was 0.71, 0.72 and 0.82, respectively. LIMITATIONS, REASONS FOR CAUTION: Thresholds proposed by this study should be limited to use in women aged between 18 and 35 years. WIDER IMPLICATIONS OF THE FINDINGS: Polycystic ovarian morphology has excellent diagnostic potential for detecting PCOS. FNPO have better diagnostic potential and yield greater diagnostic confidence compared with assessments of FNPS or OV. Whenever possible, images throughout the entire ovary should be collected for the ultrasonographic evaluation of PCOS. STUDY FUNDING AND COMPETING INTEREST: This study was funded by Cornell University and fellowship awards from the Saskatchewan Health Research Foundation and Canadian Institutes of Health Research. The authors have no conflict of interests to disclose.

Proton Therapy in the Treatment of Men with Breast Cancer.

Purpose: Male breast cancer treatment involves multimodality therapy, including radiation therapy; nevertheless, few men have received proton therapy (PT) for it. Further, heart disease is an established leading cause of death in men, and radiation therapy heart dose correlates with cardiac toxicity, highlighting the need for cardiac-sparing radiation techniques. Thus, we provide a descriptive analysis of PT in a male breast cancer cohort. Patients and Methods: Men who received PT for localized breast cancer between 2012 and 2022 were identified from a prospective database. Toxicities were prospectively recorded by using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Results: Five male patients were identified. All had estrogen receptor (ER)-positive, Her2neu-negative disease and received adjuvant endocrine therapy. One had genetic testing positive for BRCA2, one had a variant of unknown significance (VUS) in the APC gene, and one had a VUS in MSH2. Median age was 73 years (range, 41-80). Baseline comorbidities included obesity (n = 1), diabetes (n = 1), hypertension (n = 4), history of deep vein thrombosis (n = 1), personal history of myocardial infarction (n = 3; 1 with a pacemaker), and a history of lung cancer (n = 1). All received PT to the left chest wall and comprehensive regional lymphatics. One received passive-scattering PT, and 4 received pencil beam scanning. One patient received a boost to the mastectomy incision via electrons. Median heart dose was 1 GyRBE (range, 0-1.0), median 0.1-cm3 dose to the left anterior descending artery was 7.5 GyRBE (range, 0-14.2), and median follow-up was 2 years (range, 0.75-6.5); no patient experienced a new cardiac event, and all remain free from breast cancer recurrence and progression. Conclusion: In a small case series for a rare diagnosis, PT to the chest wall and regional lymphatics, including internal mammary nodes, resulted in low cardiac exposure, high local regional disease control rates, and minimal toxicity. Proton therapy should be considered for treating men with breast cancer to achieve cardiac sparing.