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This cohort study examines the risk of anaplastic large cell lymphoma (ALCL) following postmastectomy implant reconstruction among US women with breast cancer and ductal carcinoma in situ (DCIS).

Dose computation using cone beam computed tomography (CBCT) images is inaccurate for the purpose of adaptive treatment planning. The main goal of this study is to assess the dosimetric accuracy of synthetic computed tomography (CT)-based calculation for adaptive planning in the upper abdominal region. We hypothesized that deep learning-based synthetically generated CT images will produce comparable results to a deformed CT (CTdef) in terms of dose calculation, while displaying a more accurate representation of the daily anatomy and therefore superior dosimetric accuracy.We have implemented a cycle-consistent generative adversarial networks (CycleGANs) architecture to synthesize CT images from the daily acquired CBCT image with minimal error. CBCT and CT images from 17 liver stereotactic body radiation therapy (SBRT) patients were used to train, test, and validate the algorithm.The synthetically generated images showed increased signal-to-noise ratio, contrast resolution, and reduced root mean square error, mean absolute error, noise, and artifact severity. Superior edge matching, sharpness, and preservation of anatomical structures from the CBCT images were observed for the synthetic images when compared to the CTdef registration method. Three verification plans (CBCT, CTdef, and synthetic) were created from the original treatment plan and dose volume histogram (DVH) statistics were calculated. The synthetic-based calculation shows comparatively similar results to the CTdef-based calculation with a maximum mean deviation of 1.5%.Our findings show that CycleGANs can produce reliable synthetic images for the adaptive delivery framework. Dose calculations can be performed on synthetic images with minimal error. Additionally, enhanced image quality should translate into better daily alignment, increasing treatment delivery accuracy.

Purpose/Objective(s) Standard of care for locally advanced anal carcinoma is definitive chemoradiation with IMRT. Currently, target and organ-at-risk (OAR) volumes are created using a pre-treatment CT-simulation scan. However, during the course of radiotherapy, there is often change in the size and/or position of the tumor and surrounding normal structures. Therefore, we hypothesize that the implementation of an adaptive radiation therapy treatment protocol in anal cancer may reduce radiation dose to critical surrounding normal structures, such as the bowel, through the use of anatomy-adapted replanning. Materials/Methods Retrospective daily adaptive CTs were created for 4 patients (54 Gy, 30 fraction VMAT) in an oncology imaging informatics system using the Adaptive Calculation and Tracking for Offline Plan Review (ACTOR) toolkit. Each adaptive CT was created by deformable image registration (dir) of the planning CT to the daily CBCT. The structure sets from the planning CT were deformed onto each adaptive CT and ultimately corrected and revised by two qualified radiation oncologists. The adaptive CTs were transferred to a treatment planning system for recalculation. The original treatment plan was recalculated on each fraction adaptive CT to establish the real dose received during treatment. A two-sample t-test was used to compare the average real dose received dosimetric values to the values obtained on trigger-based adaptive planning. Results Using dose prescriptions for target volumes and normal tissue dose constraints as defined in RTOG 0529 (Kachnic et al 2013), normal bowel dose metrics, including bowel V45 20cc as trigger 1, there was a significant reduction in bowel V45 for each patient (table), with an average reduction in bowel V45 of 86.7% (P = 0.0001) across all patients. Adapting only the 5 fractions with the highest values for bowel V45 (trigger 2), we also found a significant reduction for each patient (table), with an average reduction of 20.8 % (P = 0.0011) across all patients. Conclusion Our study demonstrated that triggered adaptive re-planning using bowel V45 > 20cc could likely achieve reductions in normal tissue dose. Adaptive planning during radiation treatment of anal cancer may therefore be beneficial for reduction of treatment-related GI toxicity. These results can help inform a future randomized trial of adaptive therapy vs. standard planning.

Background Currently, diagnosis with pancreatic ductal adenocarcinoma (PDAC) renders an almost intrinsically poor patient prognosis. Despite complete surgical resection and intense neoadjuvant and/or adjuvant treatment the great majority of patients will ultimately relapse and die from the disease. Further, PDAC has been characterized as highly immune resistant. It is speculated that radiation, chemotherapy, or chemoradiation cause the release of tumor antigens and inflammatory cytokines eventually leading to increased immunogenicity of PDAC. Methods We used computational quantitative multiplex immune fluorescence (qmIF) (n=31) and the NanoString assay (n=34) to quantitatively analyze the effect of neoadjuvant chemoradiation (CRT) on the tumor immune microenvironment (TIME) of PDAC. Results When comparing non-treated (NT) to neoadjuvant chemoradiation (CRT) tumors, the proportion of tumor within the overall tissue sample was markedly lower in treated tumors (figure 1; Mann Whitney U, U=25, p Conclusions We find that CRT greatly alters the TIME of PDAC, altering distributions of tumor cells within the microenvironment and inducing an overall influx of T cells, including cytotoxic, helper, and Treg T cell subsets. In patients receiving CRT, it appears as though the proportion of T cells infiltrating the tumor that are Tregs is closely associated with patient outcome, with a higher proportion of Treg infiltration correlating with a poor outcome. This data suggests that therapies targeting regulatory T cells should be explored in combination with chemo-radiotherapy in PDAC. Ethics Approval The study was approved by Columbia University’s Ethics Board, approval number AAAQ7337.

Locally advanced, unresectable pancreatic ductal adenocarcinoma has a poor prognosis with a median overall survival of 10-16 months. It is defined by tumor involvement of neighboring blood vessels that precludes resection. Standard doses of conventionally fractionated radiation have had little effect on overall survival in this setting, although they are associated with improved progression-free survival and time off chemotherapy. Evolving radiotherapy techniques have allowed for higher, ablative doses of radiotherapy to target tumor while also respecting normal tissue constraints of neighboring radiosensitive structures in the gastrointestinal tract. Moreover, advancements in image guidance, organ motion management, and the use of adaptive planning have enabled safe delivery of higher, ablative doses of radiation. This has resulted in improved survival. This review will summarize the expanding role of radiotherapy in the management of locally advanced, unresectable pancreatic cancer.

Purpose Intraoperative radiation therapy (IORT) as a form of accelerated partial breast irradiation (APBI) is controversial given the limited evidence to support its efficacy. However, it remains an attractive option for low-risk patients with ductal carcinoma in situ (DCIS), who derive a small absolute benefit in local control with standard whole breast irradiation (WBI). We examine how the American Society for Therapeutic Radiation Oncology (ASTRO) APBI consensus guidelines (CG) may be applied to the preoperative selection of patients with DCIS for IORT and determine treatment outcomes by CG group. Methods and Materials We identified patients with biopsy-proven pure DCIS enrolled in an institutional prospective registry IORT database using the Zeiss Intrabeam® device between September 2013 and February 2017. Based on available preoperative clinicopathologic information, patients were deemed suitable, cautionary, or unsuitable for IORT according to the ASTRO CG. Change in CG group based on final pathologic diagnosis was determined, and additional therapy was recommended for unsuitable patients. Outcome in terms of ipsilateral breast tumor recurrence was determined. Results A total of 61 DCIS lesions in 60 patients were treated with IORT. Preoperatively, 21 patients (35%) were suitable and 36 (59%) were cautionary. Four (6%) were unsuitable because of lesion size but declined WBI. Final pathologic diagnosis changed the CG grouping of 10 patients (16%) because of either occult high-grade disease in 2 (3%) or close/positive margins in 8 (13%). Ultimately 12 patients total were considered unsuitable, of whom 8 (66%) accepted additional WBI after IORT. At a median follow-up of 2.2 years, ipsilateral breast tumor recurrence was identified among 2 suitable, 1 cautionary, and no unsuitable patients. Conclusion Further investigation is necessary to refine selection of patients with DCIS who may be optimally treated with IORT alone. High acceptance of additional therapy among unsuitable patients resulted in excellent outcomes. The use of biomarkers in addition to traditional clinical and pathologic factors may help to better select patients for IORT.

The current study investigated the feasibility of telehealth-delivered diabetes self-management education and support (DSMES) for older adults with type 2 diabetes mellitus following hospital discharge. The intervention included one in-person home visit and follow-up weekly virtual DSMES for 4 additional weeks. Diabetes knowledge was measured at baseline and completion of the program. The Telehealth Usability Questionnaire was completed following the final session. Hemoglobin A1C (A1C) level was abstracted from the electronic health record at baseline and 3 months post hospital discharge. Hospital re-admissions were measured at 30 days post index hospital stay. Of the 20 patients enrolled, 12 completed the intervention. The most common reason for attrition was discharge to a skilled nursing facility (3/20). Participants who completed the intervention increased their diabetes knowledge scores. A1C values decreased by 1.1%, and there were no hospital readmissions for any patient who completed the program. Participants described the program as useful and were satisfied with the program. These results suggest that it is feasible to identify and enroll patients in a telehealth education program for diabetes during hospital admission. [ Research in Gerontological Nursing, 13 (3), 138–145.]

The aim of the current study was to compare outcomes for older adults with type 2 diabetes mellitus and obesity following participation in a transitional care intervention that included diabetes self-management education (DSME) and homecare. The three groups analyzed comprised an inpatient DSME plus homecare group ( n = 35); an inpatient DSME only group ( n = 100); and a group who received usual care ( n = 45). Outcomes of interest included rehospitalization rates and hemoglobin A1C (A1C) for up to 1-year post hospital discharge. Rates of rehospitalization and A1C improved for older adults who received nurse-led inpatient DSME and homecare during transitions of care from hospital to home. Rehospitalization rates up to 90 days were decreased for the DSME plus homecare group (10%) compared to DSME only (20%) and usual care groups (26.7%) ( p < 0.05). A decrease of −0.4 and −2.3 A1C units was observed for the DSME group and DSME plus homecare group, respectively, at 90 days. These results support a transitional care educational intervention for older adults with type 2 diabetes mellitus and obesity. Targets: Older adults with type 2 diabetes mellitus and obesity. Intervention Description: Transitional care intervention including diabetes self-management education and homecare. Mechanisms of Action: Inpatient diabetes education and homecare helps improve rates of rehospitalization and hemoglobin A1C during care transitions from hospital to home. Outcomes: Rehospitalization rates, glycemic control (i.e., A1C level). [Res Gerontol Nurs. 2018; 11(2):71–81.]

Male breast cancer (MBC) comprises

Brain metastases (BM) of pancreatic origin are extremely rare. We review the literature around BM of pancreatic origin and describe a 38-year-old woman who developed BM 10 months after pancreaticoduodenectomy for treatment of pancreatic adenocarcinoma. She underwent resection and fractionated stereotactic radiotherapy followed by re-resection and Gamma Knife radiosurgery (GKRS) when the lesion recurred. She then developed two new BM, and was treated with GKRS. The patient is alive without progression 38 months after her most recent GKRS.

With recent advances in imaging modalities and radiation therapy, stereotactic body radiotherapy (SBRT) has allowed for the delivery of high doses of radiation with accuracy and precision. As such, SBRT has generated favorable results in the treatment of several cancers. Although the role of radiation has been controversial for the treatment of pancreatic ductal adenocarcinoma (PDAC) due to rather lackluster results in clinical trials, SBRT may offer improved outcomes, enhance the quality of life, and aid in palliative care settings for PDAC patients. This review delineates the role of SBRT in the treatment of PDAC, presents the defining principles of radiation biology and the radiation oncology work flow, and discusses the prospects of new treatment regimens involving tumor immunology and radiation therapy.

Compared to older adults without type 2 diabetes (T2D) older adults with T2D have higher rates of hospital admission and readmission. Despite having a diagnosis of T2D, attendance of diabetes self-management education (DSME) classes by older adults is low. Hospitalizations are an opportune time to engage older adults with T2D, currently no interventions exist utilizing telehealth and DSME for this population during transitions. The purpose of this study is to demonstrate the feasibility of providing DSME through telehealth to older patients with T2D following a hospital admission. We conducted a qualitative study using semi-structured, face-to-face interviews with older adults with T2D engaged in a post-discharge DSME telehealth transitions intervention. Hospitalized older adults (≥ 55 years of age) with T2D were recruited. An advanced practice nurse certified diabetes educator provided one in-person home visit within 48 hours of discharge and weekly DSME sessions via electronic tablet for four additional weeks. After completion of the program, eight patients were asked to describe their experience using the tablet to receive DSME, describe any behavior changes, and if they would accept future education virtual visits. Interviews were audio-recorded, transcribed verbatim and content analyzed thematically. Participants (50% male, aged 57-73 years, 75% African American), cited inconvenience and lack of availability as the leading cause for prior DSME non-attendance. Participants described an increased awareness of dietary habits and more frequent monitoring of glucose. Seven out of 8 participants indicated they would participate in future virtual DSME sessions. Every participant indicated the technology was easy to use and would recommend sessions to others. Our findings support ADA recommendations to improve transitions and to evaluate DSME need at this critical time. Technology use is feasible to enhance availability and convenience for continued DSME in the home after a hospital admission. Disclosure C.R. Whitehouse: None. J.A. Long: None. L. McLeer Maloney: None. D.A. Horowitz: None. K. Bowles: None.

Traditionally, head and neck squamous cell carcinoma (HNSCC) has been considered to be a relatively homogeneous disease. However, recent data have demonstrated that human papillomavirus (HPV)-positive and HPV-negative disease are two different clinical entities associated with different outcomes. Preclinical and clinical studies have reported a divergence in treatment strategies as well as prognostic outcomes for HNSCCs that are HPV-positive versus HPV-negative. The present study describes the case of a 52-year-old man who presented with stage IVB cT2N3M0 right tonsillar HPV-positive squamous cell carcinoma. Induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF), followed by chemoradiation therapy with carboplatin and 70 Gray (Gy) radiation in daily fractions was recommended. The patient completed the TPF and carboplatin treatment; however, he was unable to tolerate the radiation course, receiving a final dose of 46 Gy. A 60-day follow-up right neck salvage dissection was subsequently performed. Despite having received a partial radiation treatment of 46 Gy, the patient had no pathological evidence of disease at 60 days post radiation treatment. Repeat positron emission tomography-computed tomography at 32 months after the right neck dissection revealed no evidence of disease. The present study also discusses the current preclinical in vitro and in vivo targets for HPV-positive HNSCC and the obstacles presented in advancing clinical treatment modalities. Previous preclinical models investigating radiation sensitivity have yielded mixed results. Thus, it is important to understand and establish representative preclinical models for studying HPV and HNSCC to improve clinical research and therapeutic development. This review may guide future understanding of the role of HPV in HNSCC.

A variety of technologies have been developed to assist decision-making during the management of patients with acute brain injury who require intensive care. A large body of research has been generated describing these various technologies. The Neurocritical Care Society (NCS) in collaboration with the European Society of Intensive Care Medicine (ESICM), the Society for Critical Care Medicine (SCCM), and the Latin America Brain Injury Consortium (LABIC) organized an international, multidisciplinary consensus conference to perform a systematic review of the published literature to help develop evidence-based practice recommendations on bedside physiologic monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews on physiologic processes important in the care of acute brain injury. In this article we provide the evidentiary tables for select topics including systemic hemodynamics, intracranial pressure, brain and systemic oxygenation, EEG, brain metabolism, biomarkers, processes of care and monitoring in emerging economies to provide the clinician ready access to evidence that supports recommendations about neuromonitoring.

Introduction Mastectomy is the current standard of care for ipsilateral breast tumor recurrences after prior whole breast irradiation (WBI). We report our single-institution experience with breast-conserving surgery (BCS) followed by intraoperative radiotherapy (IORT) as an alternative to salvage mastectomy for new or recurrent breast cancers that develop in the setting of prior thoracic radiation. Methods We performed an IRB-approved retrospective review of patients treated with breast IORT between September 2013 and November 2016. We identified 12 patients who declined salvage mastectomy for their breast cancer after prior thoracic radiation. IORT was delivered using the Intrabeam™ device (Carl Zeiss, Germany). A dose of 20 Gy was prescribed to the lumpectomy cavity surface using 50 kV X-rays. We graded both acute and late treatment-related breast toxicities using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Local control, mastectomy-free survival, distant metastasis, and overall survival were determined. Results Our study included nine patients who developed a new or recurrent ipsilateral breast cancer after prior WBI for early-stage breast cancer, two patients with primary breast cancer after mantle-field radiation for Hodgkin’s lymphoma, and one patient with a synchronous stage III non-small cell lung cancer treated with definitive radiation to the ipsilateral lung and mediastinum. The median time from prior radiation to presentation was 18 years (range: 2 months to 46 years). All patients successfully underwent partial breast reirradiation with IORT and were able to preserve their breast. At a median follow-up of 14 months (4–25 months), there were no local or distant recurrences. There was a single non-cancer-related death. In the acute setting, we observed grade 1 toxicity in 58% (n = 7), grade 2 toxicity in 17% (n = 2), and no grade 3 or higher toxicity. In the late setting, at least 3 months after IORT, we observed grade 1 hyperpigmentation and/or fibrosis in 50% (n = 6), symptomatic seroma requiring drainage in 33% (n = 4). A single patient developed an abscess requiring hospitalization and intravenous antibiotic therapy. Conclusion BCS with IORT is a feasible salvage option for patients who present with localized breast cancer after prior thoracic radiation treatment. Continued follow-up of these patients is warranted given the incidence of delayed toxicity.

Importance Appropriate informed consent processes are crucial to preservation of patient autonomy and shared decision making. Although half of patients with cancer receive radiotherapy, it is unknown whether current consent practices are comprehensible for patients. Objective To characterize use, specificity, and readability of clinical informed consent forms for radiotherapy, hypothesizing that forms would be higher than the recommended sixth- to eighth-grade readability level. Design, Setting, and Participants This nationwide cross-sectional survey study and readability analysis was conducted from 2016 to 2018 and included 89 academic radiation oncology departments that were part of the 2016 Electronic Residency Application Service. Department leaders (clinical directors, chairs, and personal contacts of study authors) at academic radiation oncology departments were contacted via email. Main Outcomes and Measures Readability levels were measured by 7 validated readability indices, including the Ford, Caylor, Sticht (FORCAST) index for nonnarrative texts. Difficult words were identified usingThe Living Word Vocabulary, which describes the readability grade levels of 40 000 common words. Results Of 89 departments, 67 (75%) responded to questions and 57 (64%) provided 113 forms for analysis. Departments providing forms did not differ substantially from others in terms of region, residency size, research output, rural vs urban location, or public vs private institution status. All departments obtained patient written informed consent before radiotherapy; 38 (57%) used body site–specific forms. Using the most conservative (low-score) estimate, mean form readability ranged from grade level 10.6 to 14.2. By 7 distinct indices, only 9 (8%) of 113 forms met the recommended eighth-grade readability level, and 4 (4%) forms met a sixth-grade level. Not a single form met either recommendation based on the FORCAST index. Forms used an average of 7.2 difficult words. Body site–specific forms had considerably better readability than general consent forms. Conclusions and Relevance This nationwide study of informed consent practices for cancer treatment with radiotherapy demonstrates that while all US academic radiotherapy departments use written consent forms, it is rare for templates to meet the recommended readability levels for patient materials. These data suggest the need for reevaluation and modification of the approach to radiotherapy consent, ideally with guidance and templates designed by national professional organizations.

Identifying a reliable method of rectal volume delineation (RVD) for prostate cancer treatment planning using intensity-modulated radiation therapy (IMRT) is invaluable for clinical and investigational purposes. We analyzed rectal dose constraint outcomes utilizing commonly used RVD methods. Sixty-two prostate cancer patients treated with IMRT from August 2008 to March 2010 were reviewed. RVD either included the entire rectal volume (ERV) or limited the volume to a 3 mm rectal wall (3 MM). V50 ,the percentage of rectal volume receiving 50 Gy, V65, V70, and V75.6 were determined and analyzed for differences. We analyzed factors including definitive and postoperative treatment, rectal volume, and length. For definitive treatment, using ERV, the mean rectal V50, V65, V70, and V75.6 was 41.3, 21.6, 15.1, and 7.0 %, respectively. Using 3 MM, the mean V50, V65, V70, and V75.6 was 37.3, 23.4, 18.5, and 10.3 %, respectively. The V65, V70, and V75.6 were significantly lower in ERV than 3 MM (p

BACKGROUND: Cervical cancer is common in the elderly. The authors examined the patterns of care, treatment, and outcomes of elderly women with cervical cancer. METHODS: Women with cervical cancer diagnosed between 1988 and 2005 and registered in the Surveillance, Epidemiology, and End Results database were analyzed. Patients were stratified by age

Two recent papers, one from the Staley laboratory (Koodathingal and colleagues) and the other from the Cheng laboratory (Tseng and colleagues), show that the RNA-dependent ATPase Prp16, which is required for the second step of splicing, acts to reject slowly splicing pre-mRNAs immediately before the first catalytic reaction in pre-mRNA splicing. The results answer long-investigated questions about the actions of Prp16 and provide a wealth of molecular details on the proofreading process in pre-mRNA splicing. The discussion here reviews and integrates the results of the two papers and describes the implications for proofreading in splicing.

Identification of splice sites is essential for the expression of most eukaryotic genes, allowing accurate splicing of pre-mRNAs. The splice sites are recognized by the splicing machinery based on sequences within the pre-mRNA. Here, we show that the exon sequences at the splice junctions play a significant, previously unrecognized role in the selection of 3′ splice sites during the second step of splicing. The influence of the exon sequences was enhanced by the Prp18 mutant Prp18ΔCR, and the strength of an exon sequence in Prp18ΔCR splicing predicted its effect in wild-type splicing. Analysis of the kinetics of splicing in vitro demonstrated that 3′ splice sites were chosen competitively during the second step, likely at the same time as exon ligation. In wild-type yeast, splice site selection for two genes studied was altered by point mutations in their exon bases, affecting splicing fidelity and alternative splicing. Finally, we note that the degeneracy of the genetic code allows competing 3′ splice sites to be eliminated from coding regions, and we suggest that the evolution of the splicing signals and the genetic code are connected.

We compared the effects of evidence-based disease management guidelines delivered to patients with heart failure and diabetes using three different modalities: in-person visits alone (Control), in-person visits and a telephone intervention (Telephone), and in-person visits and telemonitoring (Telemonitoring). Patients were randomized to the three groups. There were 112 patients in the Control group, 93 in the Telephone group and 98 in the Telemonitoring group. During the first 60 days, 10% of the Control group were rehospitalized, 17% of the Telephone group and 16% of the Telemonitoring group. Having heart failure and receiving more in-person visits were significantly related to readmission and time to readmission. However, after adjusting for diagnosis and visits, the differences between the three groups were non-significant. There was a trend for increased risk of readmission for the Telephone group compared to Control alone ( P = 0.07, risk ratio 2.2, 95% CI: 0.9 to 5.2) and for readmission sooner ( P = 0.02, risk ratio 2.3, 95% CI: 1.2 to 4.6). Patient rehospitalization and emergency department visit rates were lower than the national average, making it difficult to detect a difference between groups. Previous rehospitalization was a consistent predictor of those who were rehospitalized, suggesting that it may be a useful indicator for identifying patients likely to need additional attention.

Bloom syndrome is caused by homozygous mutations in BLM, which encodes a RecQ DNA helicase. Patient-derived cells deficient in BLM helicase activity exhibit genetic instability - apparent cytogenetically as sister chromatid exchanges - and activated DNA damage signaling. In this report, we show that BLM-knockout colorectal cancer cells exhibited endogenous, ATM-dependent double-strand DNA break responses similar to those recently observed in Bloom syndrome patient-derived cells. Xenograft tumors established from BLM-deficient cancer cells were not radiosensitive, but exhibited growth impairment that was comparable to that of wild type tumors treated with a single, high dose of ionizing radiation. These results suggest that pharmacological inhibitors of BLM would have a radiomimetic effect, and that transient inhibition of BLM activity might be a viable strategy for anticancer therapy.

After the second transesterification step of pre-mRNA splicing, the Prp22 helicase catalyzes release of spliced mRNA by disrupting contacts in the spliceosome that likely involve Prp8. Mutations at Arg1753 in Prp8, which suppress helicase-defective prp22 mutants, elicit temperature-sensitive growth phenotypes, indicating that interactions in the spliceosome involving Prp8-R1753 might be broken prematurely at 37°C. Here we report that mutations in loop I of the U5 snRNA or in Prp18 can suppress the temperature-sensitive prp8-R1753 mutants. The same gain-of-function PRP18 alleles can also alleviate the growth phenotypes of multiple slu7-ts mutants, indicating a functional link between Prp8 and the second step splicing factors Prp18 and Slu7. These findings, together with the demonstration that changes at Arg1753 in Prp8 impair step 2 of pre-mRNA splicing in vitro, are consistent with a model in which (1) Arg1753 plays a role in stabilizing U5/exon interactions prior to exon joining and (2) these contacts persist until they are broken by the helicase Prp22.

Background Breast cancer subtype, determined by expression of estrogen/progesterone receptor (ER/PR) and human epidermal growth factor receptor (HER)-2, is predictive for prognosis. The importance of subtype to locoregional recurrence (LRR) following neoadjuvant chemotherapy (NAC) is unknown, particularly after adjuvant radiotherapy (RT). Methods We retrospectively identified 160-breast cancer patients registered at Columbia University Medical Center from 1999 to 2012 treated with NAC, surgery and adjuvant RT. Results Patients were grouped by receptor status: hormone receptor positive (HR+) [(ER or PR+)/HER2−; n = 75], HER2+ (n = 46), or triple-negative (TNBC) [ER (−) PR (−) HER2 (−); n = 36]. The median follow-up was 28 months. 92.0% received an anthracycline-taxane based NAC and 80.4% of HER2+ patients received trastuzumab. All underwent surgical resection followed by RT. 15.6% had a pathologic complete response (pCR): 26% of HER2+, 5% of HR+, and 25% of TN. The actuarial rate of DM was 13.8% for the entire cohort, with equivalent rates by subtypes in non-pCR patients. The overall rate of LRR was 8%. However, the LRR rate was significantly higher for TNBC patients (22.2%) than HER2+ (5.6%) (p = 0.025) or HR+ (3.0%) (p = 0.037) in non-pCR group. In the pCR group, two patients had recurrence; one LRR and one a DM, both had TNBC. All LRR occurred in or near the radiation field. Conclusions TNBC patients with

Careful patient monitoring using a variety of techniques including clinical and laboratory evaluation, bedside physiological monitoring with continuous or non-continuous techniques and imaging is fundamental to the care of patients who require neurocritical care. How best to perform and use bedside monitoring is still being elucidated. To create a basic platform for care and a foundation for further research the Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to develop recommendations about physiologic bedside monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews as a background to the recommendations. In this article, we highlight the recommendations and provide additional conclusions as an aid to the reader and to facilitate bedside care.

Both the Prp18 protein and the U5 snRNA function in the second step of pre-mRNA splicing. We identified suppressors of mutant prp18 alleles in the gene for the U5 snRNA (SNR7). The suppressors’ U5 snRNAs have either a U4-to-A or an A8-to-C mutation in the evolutionarily invariant loop 1 of U5. Suppression is specific for prp18 alleles that encode proteins with mutations in a highly conserved region of Prp18 which forms an unstructured loop in crystals of Prp18. The snr7 suppressors partly restored the pre-mRNA splicing activity that was lost in the prp18 mutants. The close functional relationship of Prp18 and U5 is emphasized by the finding that two snr7 alleles, U5A and U6A, are dominant synthetic lethal with prp18 alleles. Our results support the idea that Prp18 and the U5 snRNA act in concert during the second step of pre-mRNA splicing and suggest a model in which the conserved loop of Prp18 acts to stabilize the interaction of loop 1 of the U5 snRNA with the splicing intermediates. Pre-mRNA is spliced in two sequential transesterification reactions within the spliceosome (5, 7, 34, 54). The active spliceosome is composed of the U2, U5, and U6 snRNPs together with a dynamic cast of proteins. The U2 and U6 snRNAs appear to form the catalytic core of the spliceosome

The spliceosomal cyclophilin H is a specific component of the human U4/U6 small nuclear ribonucleoprotein particle, interacting with homologous sequences in the proteins U4/U6-60K and hPrp18 during pre-mRNA splicing. We determined the crystal structure of the complex comprising cyclophilin H and the cognate domain of U4/U6-60K. The 31 amino acid fragment of U4/U6-60K is bound to a region remote from the cyclophilin active site. Residues Ile118-Phe121 of U4/U6-60K expand the central beta-sheet of cyclophilin H and the side-chain of Phe121 inserts into a hydrophobic cavity. Concomitantly, in the crystal the cyclophilin H active site is occupied by the N terminus of a neighboring cyclophilin H molecule in a substrate-like manner, indicating the capacity of joint binding to a substrate and to U4/U6-60K. Free and complexed cyclophilin H have virtually identical conformations suggesting that the U4/U6-60K binding site is pre-shaped and the peptidyl-prolyl-cis/trans isomerase activity is unaffected by complex formation. The complex defines a novel protein-protein interaction mode for a cyclophilin, allowing cyclophilin H to mediate interactions between different proteins inside the spliceosome or to initiate from its binding platforms isomerization or chaperoning activities.

Prp18 functions in the second step of pre-mRNA splicing, joining the spliceosome just prior to the transesterification reaction that creates the mature mRNA. Prp18 interacts with Slu7, and the functions of the two proteins are intertwined. Using the X-ray structure of Prp18, we have designed mutants in Prp18 that imply that Prp18 has two distinct roles in splicing. Deletion mutations were used to delineate the surface of Prp18 that interacts with Slu7, and point mutations in Prp18 were used to define amino acids that contact Slu7. Experiments in which Slu7 and mutant Prp18 proteins were expressed at different levels support a model in which interaction between the proteins is needed for stable binding of both proteins to the spliceosome. Mutations in an evolutionarily conserved region show that it is critical for Prp18 function but is not involved in binding Slu7. Alleles with mutations in the conserved region are dominant negative, suggesting that the resulting mutant prp18 proteins make proper contacts with the spliceosome, but fail to carry out a Prp18-specific function. Prp18 thus appears to have two separable roles in splicing, one in stabilizing interaction of Slu7 with the spliceosome, and a second that requires the conserved loop.

Multiple treatment modalities are available for MF, but most result in inevitable relapse. Therefore, new treatment strategies that improve response rate and prolong response duration are greatly needed. TSEBT is a highly effective therapy in MF. LD-TSEBT (12 Gy) is much more tolerable than the conventional 36+ Gy dose, thereby allowing for re-treatment; however, LD-TSEBT has a less favorable complete response rate and response duration. Combining LD-TSEBT with immunostimulatory modalities in MF has a strong biological rationale, since radiation-induced exposure of cancer-specific antigens should be synergistic with concomitant stimulation of anti-cancer immune responses. Interleukin-12 is a robust candidate for radioimmunotherapy, as IL-12 has significant anti-MF activity as monotherapy, is very well tolerated without overlapping toxicity with TSEBT, and is a potent stimulator of innate and adaptive immunity. We report on a single-arm open-label phase 2a trial of combination of LD-TSEBT and NM-IL-12. Ten patients are planned for enrollment. Eligibility includes MF-type CTCL stages IB-IIIB and patients must be eligible for LD-TSEBT. TSEBT is started on study day 1 (fractionated 4 Gy/week, up to 12 Gy). NM-IL-12 is administered subcutaneously at 150 ng/kg on days 2 and 15, followed by 6 maintenance doses q4w at 100 ng/kg. The primary endpoint is safety with secondary endpoints being response rate and PFS. Currently, 6 patients are enrolled, 5 evaluable for response; 4 male; median age 55; three have stage IB, one IIB and one IIIB. Median number of previous therapies is 2 (0-6). The treatment was well-tolerated with only grade 1 or 2 AEs; most common AEs include grade 1 headache and chills. One patient achieved CR, 2 PR, and 2 SD. Median follow-up is so far 15 weeks and 5 patients remain on study. One patient has been withdrawn from the study due to development of a suspected PLC (pityriasis lichenoides chronica)-like skin reaction requiring topical steroid therapy. PK and PD analysis was completed in the first 4 patients. It demonstrated measurable drug levels in all patients studied, Cmax being 10.8-56.1 pg/ml achieved at 5-24 hours post injection. Interferon-γ and IP-10 (hallmark PD markers of IL-12 activity) were measurable after the first and the second injections in all patients. Levels of the inhibitory cytokine IL-10 were generally measurable after NM-IL-12 injections, but were very low ( Total RNA was extracted from patient blood samples and subjected to qRT-PCR. Gene specific primers were used to analyse intracellular expression of the IL-12 receptor and immune cell markers. Ongoing work investigates an activated cellular phenotype at week 15 of LD-TSEBT and NM-IL-12 treatment compared with the respective baseline samples. Overall these early results demonstrate that NM-IL-12 can be safely administered together with LD-TSEBT in CTCL patients. Encouraging clinical activity is observed including a CR. Enrollment is currently ongoing and planned PD and correlative biomarker studies are in progress. A phase 2B randomized trial of NM-IL-12 and low dose TSEBT compared against low-dose TSEBT alone in patients with MF is being developed based on the apparent benign AE profile as compared to approved systemic therapies. Disclosures Kim: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Neumedicine: Research Funding; Merck: Research Funding; Kyowa Kirin Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; miRagen: Research Funding; Innate: Research Funding; Horizon Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Soligenix: Research Funding. Ma:Neumedicines: Employment. Kha:Neumedicines: Employment. Lawrence:Neumedicines: Employment, Patents & Royalties. Vainstein:Neumedicines: Employment. Basile:Neumedicines: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

We have identified a human splicing factor required for the second step of pre-mRNA splicing. This new protein, hPrp18, is 30% identical to the yeast splicing factor Prp18. In HeLa cell extracts immunodepleted of hPrp18, the second step of pre-mRNA splicing is abolished. Splicing activity is restored by the addition of recombinant hPrp18, demonstrating that hPrp18 is required for the second step. The hPrp18 protein is bound tightly to the spliceosome only during the second step of splicing. hPrp18 is required for the splicing of several pre-mRNAs, making it the first general second-step splicing factor found in humans. Splicing activity can be restored to hPrp18-depleted HeLa cell extracts by yeast Prp18, showing that important functional regions of the proteins have been conserved. A 90-amino-acid region near the carboxyl terminus of hPrp18 is strongly homologous to yeast Prp18 and is also conserved in rice and nematodes. The homology identifies one region important for the function of both proteins and may define a new protein motif. In contrast to yeast Prp18, hPrp18 is not stably associated with any of the snRNPs. A 55-kD protein that cross-reacts with antibodies against hPrp18 is a constituent of the U4/U6 and U4/U6 x U5 snRNP particles.