The Psoriasis Treatment Pipeline: An Overview and Update.

Significant research advances in our understanding of psoriatic disease have led to the development of several highly selective, effective, and safe topical and systemic treatments. These treatments have led to unprecedented levels of disease clearance and control for most patients with psoriasis with cutaneous disease. However, there remains a need for improved treatments for those patients with recalcitrant disease, psoriatic arthritis, or nonplaque disease variants. Recently approved therapies and investigational products in ongoing clinical development programs that target IL-17A/F, IL-23, TYK2, PDE4, AhR or IL-36 cytokine signaling are improving the clinician's ability to care for a broader range of patients affected by psoriasis.

The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.

Quality of life after resection of a chordoma of the mobile spine.

AIMS: The aim of the study was to compare measures of the quality of life (QOL) after resection of a chordoma of the mobile spine with the national averages in the United States and to assess which factors influenced the QOL, symptoms of anxiety and depression, and coping with pain post-operatively in these patients. PATIENTS AND METHODS: A total of 48 consecutive patients who underwent resection of a primary or recurrent chordoma of the mobile spine between 2000 and 2015 were included. A total of 34 patients completed a survey at least 12 months post-operatively. The primary outcome was the EuroQol-5 Dimensions (EQ-5D-3L) questionnaire. Secondary outcomes were the Patient-Reported Outcome Measurement Information System (PROMIS) anxiety, depression and pain interference questionnaires. Data which were recorded included the indication for surgery, the region of the tumour, the number of levels resected, the status of the surgical margins, re-operations, complications, neurological deficit, length of stay in hospital and rate of re-admission. RESULTS: The median EQ-5D-3L score was 0.71 (interquartile range (IQR) 0.44 to 0.79) which is worse than the national average in the United States of 0.85 (p < 0.001). Anxiety (median: 55 (IQR 49 to 61), p = 0.031) and pain (median: 61 (IQR 56 to 68), p < 0.001) were also worse than the national average in the United States (50), while depression was not (median: 52 (IQR 38 to 57), p = 0.513). Patients who underwent a primary resection had better QOL and less anxiety, depression and pain compared with those who underwent resection for recurrent or residual disease. The one- and five-year probabilities were 0.96 and 0.74 for survival, 0.07 and 0.25 for tumour recurrence, and 0.02 and 0.16 for developing distant metastasis. A total of 25 local complications occurred in 20 patients (42%), and there were 50 systemic and other complications in 25 patients (52%) within 90 days. CONCLUSION: These patient reported outcomes and oncological and surgical outcomes can be used when counselling patients and to aid decision-making when planning surgery. Cite this article: Bone Joint J 2017;99-B:979-86.

Best practices for the management of local-regional recurrent chordoma: a position paper by the Chordoma Global Consensus Group.

Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.

Guidelines for time-to-event end point definitions in sarcomas and gastrointestinal stromal tumors (GIST) trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). METHODS: We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. RESULTS: Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. CONCLUSION: Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.

Relative accuracy and availability of an Irish National Database of dispensed medication as a source of medication history information: observational study and retrospective record analysis.

WHAT IS KNOWN AND OBJECTIVE: The medication reconciliation process begins by identifying which medicines a patient used before presentation to hospital. This is time-consuming, labour intensive and may involve interruption of clinicians. We sought to identify the availability and accuracy of data held in a national dispensing database, relative to other sources of medication history information. METHODS: For patients admitted to two acute hospitals in Ireland, a Gold Standard Pre-Admission Medication List (GSPAML) was identified and corroborated with the patient or carer. The GSPAML was compared for accuracy and availability to PAMLs from other sources, including the Health Service Executive Primary Care Reimbursement Scheme (HSE-PCRS) dispensing database. RESULTS: Some 1111 medication were assessed for 97 patients, who were median age 74 years (range 18-92 years), median four co-morbidities (range 1-9), used median 10 medications (range 3-25) and half (52%) were male. The HSE-PCRS PAML was the most accurate source compared to lists provided by the general practitioner, community pharmacist or cited in previous hospital documentation: the list agreed for 74% of the medications the patients actually used, representing complete agreement for all medications in 17% of patients. It was equally contemporaneous to other sources, but was less reliable for male than female patients, those using increasing numbers of medications and those using one or more item that was not reimbursable by the HSE. WHAT IS NEW AND CONCLUSION: The HSE-PCRS database is a relatively accurate, available and contemporaneous source of medication history information and could support acute hospital medication reconciliation.

Pleomorphic spindle cell sarcoma (PSCS) formerly known as malignant fibrous histiocytoma (MFH): a complex malignant soft-tissue tumor.

A presentation defining the nature, characteristics, causation, treatment and outcome of patients with lesions formerly known as malignant fibrous histiocytoma and now as pleomorphic spindle cell sarcoma is clearly a very difficult subject. Many authors do not believe that the tumor exists and instead describe them as forms of fibrosarcomas, fibromyxoid lesions, dedifferentiated chondrosarcomas or even leiomyosarcomas. The reasons for this confusion are presumably related to the fact that the malignant pleomorphic spindle cell sarcoma does not seem to be a distinct type of lesion with specific histologic and genetic characteristics. Instead, the tumor has at least four separate histologic variations and no specific gene signature and in fact does not seem to be either familial or ethnic in presentation. In view of the fact that the tumor was traditionally the most frequently encountered malignant soft-tissue neoplasm, the world of orthopedic oncology is clearly distressed by the problems that these patients have and is joined by the radiation oncologists and chemotherapists in seeking new solutions.

Thromboembolic Events Associated with Thalidomide and Multimodality Therapy for Soft Tissue Sarcomas: Results of RTOG 0330.

Introduction. RTOG 0330 was developed to address the toxicity of RTOG 9514 and to add thalidomide (THAL) to MAID chemoradiation for intermediate/high grade soft tissue sarcomas (STSs) and to preoperative radiation (XRT) for low-grade STS. Methods. Primary/locally recurrent extremity/trunk STS: ≥8 cm, intermediate/high grade (cohort A): >5 cm, low grade (cohort B). Cohort A: 3 cycles of neoadjuvant MAID, 2 cycles of interdigitated THAL (200 mg/day)/concurrent 22 Gy XRT, resection, 12 months of adjuvant THAL. Cohort B: neoadjuvant THAL/concurrent 50 Gy XRT, resection, 6 months of adjuvant THAL. Planned accrual 44 patients. Results. 22 primary STS patients (cohort A/B 15/7). Cohort A/B: median age of 49/47 years; median tumor size 12.8/10 cm. 100% preoperative THAL/XRT and surgical resection. Three cycles of MAID were delivered in 93% cohort A. Positive margins: 27% cohort A/29% cohort B. Adjuvant THAL: 60% cohort A/57% cohort B. Grade 3/4 venous thromboembolic (VTE) events: 40% cohort A (1 catheter thrombus and 5 DVT or PE) versus 0% cohort B. RTOG 0330 closed early due to cohort A VTE risk and cohort B poor accrual. Conclusion. Neoadjuvant MAID with THAL/XRT was associated with increased VTE events not seen with THAL/XRT alone or in RTOG 9514 with neoadjuvant MAID/XRT.

Survey of medication documentation at hospital discharge: implications for patient safety and continuity of care.

BACKGROUND: Medication discrepancies at the time of hospital discharge are common and can result in error, patient/carer inconvenience or patient harm. Providing accurate medication information to the next care provider is necessary to prevent adverse events. AIMS: To investigate the quality and consistency of medication details generated for such transfer from an Irish teaching hospital. METHODS: This was an observational study of 139 cardiology patients admitted over a 3 month period during which a pharmacist prospectively recorded details of medication inconsistencies. RESULTS: A discrepancy in medication documentation at discharge occurred in 10.8% of medication orders, affecting 65.5% of patients. While patient harm was assessed, it was only felt necessary to contact three (2%) patients. The most common inconsistency was drug omission (20.9%). CONCLUSIONS: Inaccuracy of medication information at hospital discharge is common and compromises quality of care.

Recurrent intravascular papillary endothelial hyperplasia of the right middle finger treated with radiation therapy.

We describe a case of recurrent intravascular papillary endothelial hyperplasia involving the middle finger which was successfully-treated with photon and proton radiotherapy following two previous surgical excisions.

Rapid onset and offset of circulatory adaptations to exercise training in men.

Chronic aerobic exercise lowers blood pressure (BP), peripheral resistance and cardiac work, and is used widely in antihypertensive and cardiac rehabilitation programmes. In this study, we tested the hypothesis that the cardiovascular benefits of training would occur progressively over several weeks and would diminish over a similar time course on termination of training. In all, 17 young, healthy men undertook a 4-week programme of cycle ergometry (30 min at 60% VO2peak 3-4 times/week) and 13 subjects matched for age, body mass index and fitness acted as controls. Resting BP and rate-pressure product (RPP) had fallen significantly after only 1 week's training and reached a nadir after 2 weeks training. At this time, BP had fallen from 121+/-7/66+/-6 to 110+/-5/57+/-7 mmHg and resting RPP had fallen from 85+/-10 to 71+/-9 (mmHg (beats min-1))-2 (P<0.001 each). In parallel, resting forearm conductance had risen from 0.026+/-0.010 to 0.052+/-0.029 (ml min-1) 100 ml-1 mmHg-1 and peak reactive hyperaemia following 3 min brachial artery occlusion was increased from 0.105+/-0.031 to 0.209+/-0.041 (ml min-1) 100 ml-1 mmHg-1 (P<0.001 each). No significant further circulatory changes occurred over weeks 3-4 of training. On cessation of training, all values returned to pretraining levels within between 1 (SBP, RPP, vascular conductance) and 2 (DBP, MAP, heart rate, reactive hyperaemia) weeks. The results indicate that the optimal cardiovascular benefits of moderate exercise occur rapidly. At least with short training programmes, the benefits regress once training stops just as quickly as they appeared.

Proton beam therapy.

Conventional radiation therapy directs photons (X-rays) and electrons at tumours with the intent of eradicating the neoplastic tissue while preserving adjacent normal tissue. Radiation-induced damage to healthy tissue and second malignancies are always a concern, however, when administering radiation. Proton beam radiotherapy, one form of charged particle therapy, allows for excellent dose distributions, with the added benefit of no exit dose. These characteristics make this form of radiotherapy an excellent choice for the treatment of tumours located next to critical structures such as the spinal cord, eyes, and brain, as well as for paediatric malignancies.

Severe acute enteritis in a multiple myeloma patient receiving bortezomib and spinal radiotherapy: case report.

Proteasome inhibitors have been reported to enhance radiosensitivity in vitro. A case of potential clinical interaction between bortezomib, a proteasome inhibitor, and spine radiation is reported. A woman undergoing palliative radiotherapy to the T12 -S2 spine with concurrent bortezomib developed unexpectedly severe, acute radiation enteritis requiring hospital admission. Clinicians are advised to consider the potential for interactions of bortezomib with radiotherapy when the two agents are used simultaneously in the clinic.

Predictors of successful labor induction with oral or vaginal misoprostol.

OBJECTIVE: To identify independent predictors of successful labor induction with oral or vaginal misoprostol. METHODS: Women enrolled in four previous randomized trials involving oral or vaginal misoprostol for cervical ripening and labor induction were included in the present cohort study, with dosing of 25-50 microg every 4 to 6 h vaginally (n = 574) or 50 microg every 4 h orally (n = 207). Multiple logistic regression was performed to identify factors independently associated with successful labor induction -- defined as vaginal delivery within 12 h, vaginal delivery within 24 h and spontaneous vaginal delivery. Predictors of Cesarean birth and the need for only one dose of misoprostol were also identified. Variables included in the models were maternal age, weight, height, parity, gravidity, membrane status, route of misoprostol, gestational age, birth weight, and Bishop score and its individual components. RESULTS: Maternal age, height, weight, parity, birth weight, dilatation, effacement and cervical station were associated with vaginal delivery within 24 h of induction. Maternal age, height, weight, nulliparity, birth weight and route of misoprostol were associated with Cesarean birth, with oral misoprostol being associated with a lower rate of Cesarean birth. The need for only one dose of misoprostol was predicted by maternal height, weight, parity, gestational age, Bishop score and route of misoprostol. CONCLUSION: Characteristics of the woman (height, weight, parity), the fetus (birth weight) and some of the individual components of the Bishop score, were associated with successful labor induction, with oral misoprostol being associated with a lower rate of Cesarean birth.

In vivo detection of experimental ulcerative colitis in rats using fiberoptic confocal imaging (FOCI).

Fiberoptic confocal imaging (FOCI) is a noninvasive microscopic technique that enables subsurface imaging of living tissue in vivo. The aim of the present study was to assess the suitability of FOCI for the in vivo detection of early subsurface changes in the mucosal architecture of the colon in a rat model of ulcerative colitis. Mild colitis was induced in Sprague-Dawley rats (180-250 g) by the oral ingestion of 5% (w/v) dextran sulfate sodium (DSS; Mr 40,000 Da) in drinking water. Control animals were provided with water ad libitum. After three, five or seven days of oral consumption of DSS, the mucosal surface of the colon of anesthetised rats was surgically exposed. Morphological changes in the mucosa were examined (Optiscan F900e personal confocal system with rigid endomicroscope attachment; excitation 488 nm argon ion laser, detection above 515 nm) following the topical application of a fluorescent dye (fluorescein, eosin, or acridine orange). Confocal images were correlated with conventional histology and clinical parameters including occult blood and stool consistency. Histological evaluation of colon sections demonstrated that DSS-induced colitis was characterized by focal loss of mucous crypts, loss of epithelial cells, and neutrophilic infiltration into the mucosa. The extent of mucosal damage was positively correlated with the time of ingestion of DSS. Morphological changes associated with disease activity could be detected microscopically in vivo using FOCI but were not evident by visual inspection of the colon surface. Acridine orange enabled imaging of the colonic crypts at the surface of the mucosa. Morphological changes associated with colitis, including inflammatory cell infiltrate, crypt loss, and crypt distortion, could be detected using this fluorophore. Application of fluorescein and eosin enabled subsurface imaging of the lamina propria surrounding the crypts; however, no change in structure was detected in association with colitic disease activity. This study has shown that the topical application of acridine orange enables in vivo imaging of early colitis in a rat model. FOCI may be suitable for the diagnosis and monitoring of human inflammatory bowel disease.

Salicylic acid and NIM1/NPR1-independent gene induction by incompatible Peronospora parasitica in arabidopsis.

To identify pathogen-induced genes distinct from those involved in systemic acquired resistance, we used cDNA-amplified fragment length polymorphism to examine RNA levels in Arabidopsis thaliana wild type, nim1-1, and salicylate hydroxylase-expressing plants after inoculation with an incompatible isolate of the downy mildew pathogen Peronospora parasitica. Fifteen genes are described, which define three response profiles on the basis of whether their induction requires salicylic acid (SA) accumulation and NIM1/NPR1 activity, SA alone, or neither. Sequence analysis shows that the genes include a calcium binding protein related to TCH3, a protein containing ankyrin repeats and potential transmembrane domains, three glutathione S-transferase gene family members, and a number of small, putatively secreted proteins. We further characterized this set of genes by assessing their expression patterns in each of the three plant lines after inoculation with a compatible P. parasitica isolate and after treatment with the SA analog 2,6-dichloroisonicotinic acid. Some of the genes within subclasses showed different requirements for SA accumulation and NIM1/NPR1 activity, depending upon which elicitor was used, indicating that those genes were not coordinately regulated and that the regulatory pathways are more complex than simple linear models would indicate.