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Neurocritical care depends, in part, on careful patient monitoring but as yet there are little data on what processes are the most important to monitor, how these should be monitored, and whether monitoring these processes is cost-effective and impacts outcome. At the same time, bioinformatics is a rapidly emerging field in critical care but as yet there is little agreement or standardization on what information is important and how it should be displayed and analyzed. 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 begin to address these needs. International experts from neurosurgery, neurocritical care, neurology, critical care, neuroanesthesiology, nursing, pharmacy, and informatics were recruited on the basis of their research, publication record, and expertise. They undertook a systematic literature review to develop recommendations about specific topics on physiologic processes important to the care of patients with disorders that require neurocritical care. This review does not make recommendations about treatment, imaging, and intraoperative monitoring. A multidisciplinary jury, selected for their expertise in clinical investigation and development of practice guidelines, guided this process. The GRADE system was used to develop recommendations based on literature review, discussion, integrating the literature with the participants' collective experience, and critical review by an impartial jury. Emphasis was placed on the principle that recommendations should be based on both data quality and on trade-offs and translation into clinical practice. Strong consideration was given to providing pragmatic guidance and recommendations for bedside neuromonitoring, even in the absence of high quality data.

Acinar cell carcinoma (ACC) is an extremely rare cancer of the pancreas, accounting for less than 1 % of non-endocrine pancreatic tumors. The role for adjuvant radiation therapy (RT) in the management of this disease is unknown. The Survival, Epidemiology, and End Results 18 database, November 2012 submission, was queried for ACC of the pancreas reported between the years of 1998 and 2010. Baseline characteristics were compared with the chi-squared test. Overall survival (OS) and cause-specific survival (CSS) were estimated using the Kaplan–Meier method. Cox proportional hazard modeling was performed for multivariate analysis of factors associated with OS and CSS. Analyses were performed using SPSS, version 20. Two hundred nineteen patients with acinar cell carcinoma were identified. Median follow-up was 11 months. Median patient age was 66 (range 4–92). One hundred fourteen patients (52.1 %) had locoregional disease, while 105 patients (47.9 %) had metastatic disease at diagnosis. Median OS for all patients was 14 months (95 % confidence interval (CI) 9.24–18.77 months), and median CSS was 17 months (95 % CI 10.37–23.63 months). For patients with non-metastatic disease, median OS was 38 months (95 % CI 28.43–47.57). Among patients with non-metastatic disease, the use of adjuvant radiation was associated with increased median OS (56 months [95 % CI 21.67–90.33]), compared to patients not treated with radiation (27 months [95 % CI 4.06–49.94]), p = 0.046. Use of adjuvant radiation was associated with increased cause-specific survival (66 vs. 40 months), but this was not statistically significant (p = 0.104). On multivariate analysis, use of surgery and adjuvant radiation were both associated with improved OS for patients with non-metastatic disease (hazard ratio (HR) 0.517, p = 0.034 and HR 0.423, p = 0.009, respectively). Both surgery and radiation were associated with non-statistically significant improvement in ACC cause-specific survival, HR = 0.606 (95 % CI = 0.314–1.170), p = 0.136 and HR = 0.501 (95 % CI = 0.249–1.009), p = 0.053, respectively. Surgical resection with curative intent followed by adjuvant RT is associated with excellent long-term overall survival in patients with non-metastatic local-regional acinar cell carcinoma of the pancreas.

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

The molecular mechanisms of the second step of pre-mRNA splicing in yeast and higher eukaryotes are reviewed. The important elements in the pre-mRNA, the participating proteins, and the proposed secondary structures and roles of the snRNAs are described. The sequence of events in the second step is presented, focusing on the actions of the proteins in setting up and facilitating the second reaction. Mechanisms for avoiding errors in splicing are discussed. WIREs RNA 2012, 3:331–350. doi: 10.1002/wrna.112 For further resources related to this article, please visit the WIREs website. This article is a U.S. Government work, and as such, is in the public domain in the United States of America.

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.

Immunotherapy has altered the therapeutic landscape in several malignancies but to date has not been effective in treatment of pancreatic ductal adenocarcinoma (PDAC). Patients with advanced PDAC continue to have median survival under one year and thus new therapeutic approaches for this daunting disease are urgently needed. It is well known that radiation therapy causes the release of tumor antigens and pro-inflammatory cytokines leading to stimulation of anti-tumor immunity. In our study, we sought to quantify this effect by comparing immune cell infiltration in tissues of PDAC treated with chemoradiation to untreated tumors. Slides obtained from surgical resection specimens were stained using quantitative multiplex immunofluorescence (qmIF) for: CD3, CD4, CD8, FOXP3, CD68, and Ki-67. Nuclei were labeled using DAPI. Slides with tumor tissue were then imaged (15-20 images per slide) using automated imaging system VECTRA and they were analyzed using inForm software to evaluate cell density in tumor and stroma compartments. Overall, slides were obtained and analyzed from 6 different patients who underwent chemoradiation therapy and from 5 patients who did not receive neoadjuvant treatment. When comparing treated vs. untreated tumors, CD3+ densities were significantly higher in the stromal tissue of the treated tumors vs. untreated tumors (P = 0.0095). CD3+CD4+FOXP3- T helper cells were similarly significantly higher in treated tumors (P = 0.0095), while there was a trend towards increase in CD3+CD8+ cytotoxic T cells (P = 0.0667). Conversely, CD4+FOXP3+ cells were increased in untreated tumors although significance was not reached (P = 0.15). No clear differences in infiltrating CD68+ macrophages were observed between treated and untreated tumors. To our knowledge this is the first time that immune cell infiltrates of PDAC were characterized using qmIF. The higher counts of CD3+CD4+ T helper cells and of CD3+CD8+ cytotoxic T cells found in tumors treated with chemoradiation can be explained by the increased immunogenicity caused by treatment. A tendency towards a higher density of CD4+FOXP3+ cells in untreated tumors may contribute to immunosuppression in the tumor microenvironment as there were less CD3+CD8+ cytotoxic T cells and CD3+CD4+ T helper cells found in those tumors. We are in the process of collecting and staining additional samples to build on these findings. We will correlate our data with survival data to identify biomarkers predictive of outcome and provide rationale for the development of new treatment strategies for this challenging disease. Citation Format: Thomas Enzler, Robyn Gartrell, Ladan Fazlollahi, Subha Perni, Pan Kim, Thomas Hart, Christian Monsalve, Samuel Green, Yvonne Saenger, David P. Horowitz. Quantitative multiplex immunofluorescence reveals that chemoradiation therapy favorably modulates the tumor immune microenvironment of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B51.

4122Background: Patients with advanced pancreatic ductal adenocarcinoma (PDA) continue to have median survival under one year and to date immunotherapy has largely been unsuccessful. Radiation or c...

e22152Background: Given the importance of informed consent in cancer care, we sought to characterize readability and specificity of consent forms for radiation therapy, hypothesizing that readabili...

A disease management study conducted in home care with 303 patients with diabetes, heart failure, or both revealed information deficits that make disease and quality management difficult. Nurses used a guideline checklist to indicate the amount and type of information available to them on admission and by the end of the episode of care. Nurses reported having data on 7% to 94% of the data elements. Whether a lipid profile had been done, the HbA1C (glycosolated hemoglobin test, also called a hemoglobin A1C) levels, or ejection fractions were known for 7%, 17%, and 18%, respectively. When nurses reported information related to ACE-I use (N = 183), they reported that 76% of patients were on ACE-I (angiotensin-converting enzyme inhibitor) or acceptable alternative for heart failure. But no information was reported on ACE-I use for 12% of the patients (N = 24). Potential solutions to these deficits in information and quality include increased use of guidelines in home care, guideline checklists, information transfer forms, nurse activism to request information, and the adoption of the electronic health record.

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.

Most depressed patients are seen and treated exclusively by primary care clinicians. However, primary care patients with depression are often not adequately treated. The aims of this pilot study were to measure the impact of a telephone disease management program on patient outcome and clinician adherence to practice guidelines, measure the relationship of clinician adherence to patient outcome, and explore the measurement of patient adherence to clinician recommendations and its impact on patient outcomes. Thirty-five primary care practices in the University of Pennsylvania Health System were randomized to telephone disease management (TDM) or "usual care" (UC). All patients received a baseline and a 16-week follow-up clinical evaluation performed over the telephone. Those from TDM practices also received follow-up contact at least every 3 weeks, with formal evaluations at weeks 6 and 12. These interval contacts were designed to facilitate patient and clinician adherence to a treatment algorithm based on the Agency for Health Research and Quality (AHRQ) practice guidelines. Depressive symptoms evaluated with the Community Epidemiologic Survey of Depression (CES-D) scale as well as guideline adherence were the primary outcome measures. Sixty-one patients were enrolled in this pilot project. The overall effect for CES-D scores over time was significant, (P

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.

436 Background: Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis, with significant morbidity and mortality from local progression. Radiotherapy can be administered for local control, with stereotactic body radiotherapy (SBRT) increasingly being utilized. We aim to compare the toxicity of SBRT with intensity-modulated radiotherapy (IMRT) in this setting. Methods: A retrospective analysis of patients with PDAC receiving IMRT or SBRT at our institution between April 2011 and November 2015 was performed. 81 patients were identified. Clinical notes were reviewed for treatment details and acute and late toxicities. Late toxicity data was available for 62 patients. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 4.0. Radiology reports were reviewed to assess for the presence of recurrence and/or progression. Results: Median follow-up from RT was 29 months (95% CI 22-36 months), and median survival from RT was 25 months (95% CI 22-34 months). IMRT patients received 37.5-54 Gy in 15-30 fractions. SRBT patients received 19.8-39.6 Gy in 3-6 fractions. 45% of IMRT and 29% of SBRT patients had local failure (p = 0.1329). IMRT patients were significantly more likely to have Grade ≥2 acute gastrointestinal (GI) toxicity than SBRT patients (RR 1.70; 95% CI 0.98-2.96, p = 0.0489), although one SBRT patient had to have treatment stopped due to extrahepatic stricture. There were no significant differences in late GI toxicity (67% Grade 2 or higher vs. 57%, respectively, p = 0.4244), although one IMRT patient died due to late GI bleeding.IMRT patients were more likely to lose weight during RT(Median -0.03% vs. -0.004%, p = 0.0001) and have moreEmergency Department (ED) visits after RT (Range 0-8 vs. 0-3, p = 0.0019). There were no significant differences in dermatitis, fatigue, or hematologic toxicity. Conclusions: Patients with locally advanced PDAC treated with IMRT versus SBRT had significantly more acute gastrointestinal toxicity, median weight loss, and ED visits after RT, but no significant differences in late gastrointestinal toxicity, dermatitis, fatigue, or hematologic toxicity. SBRT is a relatively tolerable and more convenient alternative for patients with pancreatic cancer.

We examined the fetal dose from irradiation of glioblastoma during pregnancy using intensity modulated radiation therapy (IMRT), and describe fetal dose minimization using mobile shielding devices. A case report is described of a pregnant woman with glioblastoma who was treated during the third trimester of gestation with 60 Gy of radiation delivered via a 6 MV photon IMRT plan. Fetal dose without shielding was estimated using an anthropomorphic phantom with ion chamber and diode measurements. Clinical fetal dose with shielding was determined with optically stimulated luminescent dosimeters and ion chamber. Clinical target volume (CTV) and planning target volume (PTV) coverage was 100 and 98 % receiving 95 % of the prescription dose, respectively. Normal tissue tolerances were kept below quantitative analysis of normal tissue effects in the clinic (QUANTEC) recommendations. Without shielding, anthropomorphic phantom measurements showed a cumulative fetal dose of 0.024 Gy. In vivo measurements with shielding in place demonstrated a cumulative fetal dose of 0.016 Gy. The fetal dose estimated without shielding was 0.04 % and with shielding was 0.026 % of the target dose. In vivo estimation of dose equivalent received by the fetus was 24.21 mSv. Using modern techniques, brain irradiation can be delivered to pregnant patients in the third trimester with very low measured doses to the fetus, without compromising target coverage or normal tissue dose constraints. Fetal dose can further be reduced with the use of shielding devices, in keeping with the principle of as low as reasonably achievable.

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.

Identification of 5' splice sites requires that limited and dispersed sequence information be interpreted precisely. Both snRNAs and proteins are required for this process. The selection of 5' splice sites in alternative splicing is closely related to that in constitutive splicing, and uses the same components in somewhat different ways.

Background Secretory carcinoma of the breast is a rare breast cancer that is associated with incidence at a young age and an indolent course. The role for breast conservation and adjuvant radiation is unknown. Methods The SEER database was reviewed and 83 patients were identified with secretory carcinoma of the breast between the years 1983 and 2007. Baseline characteristics were compared with χ2 or Fisher’s exact test. Overall survival (OS) and cause-specific survival (CSS) were estimated using the Kaplan–Meier method. Analyses were performed using PASW Statistics, version 18. Results Median follow-up was 70 months. Median patient age was 53 years (range 11–86 years). 29 patients (34.9%) had involved regional lymph nodes. 39 patients (47.0%) underwent lumpectomy and 44 patients (53.0%) underwent mastectomy. 35 patients (42.2%) received radiation. Patients receiving radiation were more likely to have undergone lumpectomy, and the use of radiation increased over time. 5-year OS was 87.2%; 10-year OS was 76.5%. 5-year CSS was 94.4%; 10-year CSS was 91.4%. Among the lumpectomy patients, 25 patients (64.1%) received radiation. For lumpectomy patients, those who did not receive radiation had a 5-year OS of 92.9% and 10-year OS of 72.2% while patients who did receive radiation had a 5-year OS of 95.5% and 10-year OS of 85.9%. Only 1 patient treated with lumpectomy only died of cancer (92.9% CSS) and no patients treated with lumpectomy and radiation died of cancer (100% CSS). Conclusions Secretory carcinoma of the breast commonly occurs at a later age than previously recognized, and is associated with good long-term survival.

Cervical cancer is common in the elderly. The authors examined the patterns of care, treatment, and outcomes of elderly women with cervical cancer.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:50, 50 to 59, 60 to 69, 70 to 79, and ≥80 years. Multivariate logistic regression models were constructed to examine treatment; cancer-specific survival was examined using Cox proportional hazards models.A total of 28,902 women were identified, including 2543 women 70 to 79 years old and 1364 ≥80 years. For women with early stage (IB1-IIA) tumors, primary surgery was performed in 82.0% of women50 years old compared with 54.5% of those 70 to 79 years old and 33.2% of those ≥80 years old (P.0001). For women treated surgically, lymphadenectomy was performed in 66.8% of women50 years old versus 9.1% of patients ≥80 years old (P.0001). Compared with patients50 years old, those80 years old were less likely to undergo radical hysterectomy (odds ratio [OR], 0.10; 95% confidence interval [CI], 0.07-0.14) and lymphadenectomy (OR, 0.11; 95% CI, 0.08-0.16) and to receive adjuvant radiation therapy (OR, 0.06; 95% CI, 0.01-0.35). Among women with stage IIB-IVA disease, use of brachytherapy declined with age (P.0001). For women with stage IB1-IIA tumors, the hazard ratio for death from cancer was 1.35 (95% CI, 1.16-1.58) for women 70 to 79 years old and 2.08 (95% CI, 1.72-2.48) for those ≥80 years old compared with younger women.Elderly women with cervical cancer are less likely to undergo surgery, receive adjuvant radiation, and receive brachytherapy. After adjusting for treatment disparities, cancer-specific mortality is higher in older women.