Measuring Emergency Department Patient Population Acuity

Abstract

Background

Emergency department (ED) acuity is the general level of patient illness, urgency for clinical intervention, and intensity of resource use in an ED environment. The relative strength of commonly used measures of ED acuity is not well understood.

Methods

We performed a retrospective cross-sectional analysis of ED-level data to evaluate the relative strength of association between commonly used proxy measures with a full spectrum measure of ED acuity. Common measures included the percentage of patients with Emergency Severity Index (ESI) scores of 1 or 2, case mix index (CMI), academic status, annual ED volume, inpatient admission rate, percentage of Medicare patients, and patients-seen-per-attending-hour. Our reference standard for acuity is the percentage of high acuity charts (PHAC) coded and billed according to the Centers for Medicare and Medicaid Service's Ambulatory Payment Classification (APC) system. High acuity charts included those APC 4, 5 or critical care. PHAC was represented as a fractional response variable. We examined the strength of associations between common acuity measures and PHAC using Spearman's rank correlation coefficients (r_s) and regression models including a quasi-binomial generalized linear model and linear regression.

Results

In our univariate analysis, the percentage of patients ESI 1or 2, CMI, academic status and annual ED volume had statistically significant associations with PHAC. None explained more than 16% of PHAC variation. For regression models including all common acuity measures, academic status was the only variable significantly associated with PHAC.

Conclusion

ESI had the strongest association with PHAC followed by CMI and annual ED volume. Academic status captures variability outside of that explained by ESI, CMI, annual ED volume, percentage Medicare patients, or patients-per-attending-per-hour. All measures combined only explained only 42.6% of PHAC variation.

This article is protected by copyright. All rights reserved.

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Decision Making in Orthopaedic Trauma

Abstract

The first edition of Decision Making in Orthopaedic Trauma, is a uniquely formatted textbook intended to guide medical students, resident physicians-in-training, and practicing clinicians in the acute management of a comprehensive range of orthopedic emergencies. The authors of the individual algorithms are members of the faculty at the University of California, San Francisco (UCSF) / Zuckerberg San Francisco General (ZSFG) Orthopaedic Trauma Institute. Relying on their extensive professional experience and relevant evidence based publications, they created an easy to access format that provides a quick, simple to use reference for the critical decision points for a variety of traumatic orthopedic conditions. Using an algorithm-based approach, clinicians are guided through critical decision trees to assist decision making in the evaluation and treatment of a wide variety of orthopedic emergencies, from simple fractures through complex life and limb threatening conditions. The text includes 80 chapters, each composed of a 1-page, beautifully styled and easy to follow flow diagram for decision making, followed by a page listing relevant evidence-based references.

This article is protected by copyright. All rights reserved.

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Feasibility of tongue strength measurements during (chemo)radiotherapy in head and neck cancer patients

Abstract

Purpose

The aim of this study was to investigate the feasibility of tongue strength measures (TSMs) and the influence of bulb location, sex, and self-perceived pain and mucositis in head and neck cancer (HNC) patients during chemoradiotherapy (CRT).

Methods

Twenty-six newly diagnosed HNC patients treated with CRT performed anterior and posterior maximal isometric tongue pressures by means of the Iowa Oral Performance Instrument (IOPI). The Oral Mucositis Weekly Questionnaire (OMWQ) and a Visual Analogue Scale (VAS) for pain during swallowing were completed weekly from baseline to 1 week post CRT.

Results

Feasibility of TSMs during CRT declines significantly from 96 to 100% at baseline to 46% after 6 weeks of CRT. But post-hoc analyses reveal only significant differences in feasibility between baseline and measurements after 4 weeks of treatment. No effect of gender or bulb location was established, but feasibility is influenced by pain and mucositis.

Conclusions

Feasibility of TSMs declines during CRT and is influenced by mucositis and pain. For the majority of subjects, TSMs were feasible within the first 4 weeks, which provides a window of scientific and clinical opportunities in this patient population.

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Dyadic interdependence of psychosocial outcomes among haematological cancer survivors and their support persons

Abstract

Purpose

This study aimed to explore the dyadic relationships between unmet need, depression, and anxiety in people diagnosed with haematological cancer and their support persons.

Methods

Adult survivors (18 years+) who had been diagnosed with a haematological cancer were recruited to a cross-sectional mailed survey via five state cancer registries in Australia. Participating survivors invited a support person to also complete a survey. Structural equation modelling was used to explore the relationships among survivor and support person self-reported depression, anxiety, and unmet needs.

Results

Of the 4299 eligible haematological cancer survivors contacted by the registries, 1511 (35%) returned a completed survey as did 1004 support persons. There were 787 dyads with complete data. After adjusting for age, gender, rurality, cancer type, and whether the support person was a relative, positive correlations were found between survivor and support person scores for depression (p = 0.0029) and unmet needs (p < 0.001), but not anxiety scores (p = 0.075). Survivor unmet needs were significantly related to support person depression (p = 0.0036). Support person unmet needs were significantly related to a higher depression score for survivors (p = 0.0067). Greater support person unmet needs were significantly related to a higher anxiety score for survivors (p = 0.0083). Survivor unmet needs did not have a significant relationship to support person anxiety (p = 0.78).

Conclusion

Unmet needs may mediate the interdependence of psychosocial experiences for survivors and support persons, although a longitudinal study is required to confirm causality. Addressing unmet needs may be a potential target for improving outcomes for both groups.

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Association between bone scan index and activities of daily living in patients with advanced non-small cell lung cancer: methodological issues in cross-sectional study

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Changes in light-, moderate-, and vigorous-intensity physical activity and changes in depressive symptoms in breast cancer survivors: a prospective observational study

Abstract

Purpose

Despite the recommendations for cancer survivors to engage in either moderate or vigorous physical activity, light-intensity physical activity may also have beneficial effects on mental health. The purpose of this study was to examine the associations between light, moderate, and vigorous physical activity and depressive symptoms in breast cancer survivors over 1 year post-treatment.

Methods

Participants (N = 201) were a sample of breast cancer survivors who self-reported depressive symptoms and wore an accelerometer for seven consecutive days to measure physical activity, on five occasions every 3 months post-treatment for cancer.

Results

Based on the results of hierarchical linear modeling, relative to others (i.e., between-person effects) and to oneself (i.e., within-person effects), higher levels of light- and moderate-intensity physical activity, but not vigorous-intensity physical activity, were associated with lower scores of depressive symptoms.

Conclusions

In the first year post-treatment, increases in light- and moderate-intensity physical activity, but not vigorous-intensity physical activity, were associated with lower scores of depressive symptoms in relation to other study participants (i.e., between-person effects) and when participants were compared to their own typical levels of physical activity (i.e., within-person effects). The findings may have implications for physical activity recommendations following treatment for breast cancer as light-intensity physical activity may play a role in mitigating depressive symptoms over the first year.

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Longitudinal perceptions of the side effects of chemotherapy in patients with gynecological cancer

Abstract

Purpose

This study aimed to assess the incidence and difference of side effects among six courses of chemotherapy (C/T) in gynecological cancer patients.

Methods

The study period was from Sep. 2010 to Dec. 2011 at the Kaohsiung Veterans General Hospital in Taiwan. The treating protocols, courses, and drugs of C/T in patient were considered according to the different malignant cancers and clinical conditions. The patient data of age, marriage status, education, religion, and experiences of C/T were collected. The patients' or their families' reported side effects of C/T were recorded daily from the beginning of C/T to the 10th day after C/T in each cycle and every course of C/T.

Results

Total 89 patients enrolled into the study received total 450 courses of C/T. The mean age was 54.52 ± 11.02. Ovarian cancer was the most common malignant disease (64.0%). The most often combination of drugs used was Taxol and carboplatin (40.9%). Patients complained peripheral numbness of limbs, with the highest incidence of 58.6%. The side effects with incidence about 50% were decreased fatigue (55.0%) and hair loss (49.9%). Other side effects with different levels of incidence were also noticed, such as lack of appetite, changes in taste, and muscle ache. The incidences of peripheral limb numbness and hair loss were increased with following courses of C/T. The high incidence of fatigue did not show variation between different courses of C/T.

Conclusion

This study revealed the incidence of side effects and occurrence timing during C/T in patients with gynecological cancer. These data provide substantial information to patients and their families to understand the potential side effects of C/T courses, which might increase their compliance in receiving adjuvant C/T. Relieving the side effects in C/T would be important to improve their quality of daily life and treatment willingness.

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Can complications in febrile neutropenia be predicted? Report from a developing country

Abstract

Purpose

Febrile neutropenia (FN) is an important cause of morbidity and mortality in children with acute lymphoblastic leukemia (ALL). We aimed to look at complications in febrile neutropenia and to derive a risk model for developing complications from the variables predicting complications.

Methods

Children on treatment for ALL, presenting with FN, were prospectively enrolled over a period of 1 year. Their clinical presentation, course during hospital stay, and outcomes were recorded. Complications recorded included septic shock, pneumonia requiring invasive or non-invasive ventilation, renal failure, neutropenic enterocolitis, encephalopathy, congestive heart failure, and bleeding manifestations.

Results

There were 320 episodes of FN among 176 patients. Complications occurred during 73 (22.8%) episodes. Time since last chemotherapy ≤7 days [OR 2.2 (1–4.5)], clinical focus of infection [OR 2.7 (1.3–5.5)], undernutrition [OR 2.5 (1.1–5.5)], absolute neutrophil count (ANC) ≤ 100/μL [OR 2.8 (1.3–5.9)], and C-reactive protein (CRP) > 60 mg/L at admission [OR 13.3 (5.2–33.8)] were independent predictors of complications. A risk model (total score = 13) was developed based on these predictors. Children with score of ≥7 had 17.2 (7.7–38.6) odds of developing complications as compared to those with score <7. Score of <7 predicted children at lower risk of complications [sensitivity 88% (78.2–93.8%), specificity 72.5% (65.7–78.4%), PPV 53.6% (44.3–62.6%), NPV 94.4% (89.3–97.1%)].

Conclusions

Complications during febrile neutropenia are high in a developing country setup. A risk score model based on identified risk factors can possibly help in recognizing low-risk febrile neutropenic children at admission.

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Management of infection during chemotherapy for acute leukemia in Japan: a nationwide questionnaire-based survey by the Japan Adult Leukemia Study Group

Abstract

Purpose

We performed a nationwide questionnaire-based survey to evaluate the current clinical practices of infectious complications during chemotherapy for acute leukemia in Japan.

Methods

We e-mailed a questionnaire to member institutions of the Japan Adult Leukemia Study Group in September, 2013. The questionnaire consisted of 50 multiple-choice questions covering therapeutic environment, antimicrobial prophylaxis, screening test during neutropenia, empirical therapy for febrile neutropenia, and the use of granulocyte-colony stimulating factor. The results were compared to those of previous surveys conducted in 2001 and 2007, and also to the recommendations described in the guidelines.

Results

Usable responses were received from 141 out of 222 (63.5%) institutions. Chemotherapy for acute myeloid leukemia was performed in protective environment in 90% of the institutions, which increased compared to previous survey (76%). Fluoroquinolones and fluconazole were the most commonly used antimicrobial agents for antibacterial and antifungal prophylaxis, followed by sulfamethoxazole-trimethoprim and itraconazole, respectively. In empirical therapy for febrile neutropenia, monotherapy with β-lactum antibiotics was the first-line therapy in most of the institutions. While empirical antifungal therapy was adopted for persistent fever in more than half of the institutions, preemptive/presumptive therapy was also used in approximately 40% of the institutions. Most of the clinicians were reluctant to use granulocyte-colony stimulating factor routinely in chemotherapy for acute myeloid leukemia.

Conclusions

This study clarified the current clinical practices of infectious complications during chemotherapy for acute leukemia and would provide important information for the development of a suitable guideline in Japan.

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Incidence and risk factors of febrile neutropenia in patients with non-Hodgkin B-cell lymphoma receiving R-CHOP in a single center in Japan

Abstract

Purpose

The incidence of and risk factors for febrile neutropenia (FN) in Japanese non-Hodgkin B-cell lymphoma (B-NHL) patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and predonisolone (R-CHOP) chemotherapy are unknown. We conducted this study to address this issue.

Methods

In this single-center, retrospective, observational study, 466 patients with B-NHL who completed an R-CHOP regimen within a 7-year period and who planned to undergo at least three cycles of this regimen were analyzed. The following FN-related factors were assessed: fever, infection, disease state, neutrophil count, and prophylactic interventions such as use of antibiotics and/or granulocyte colony-stimulating factor (G-CSF). We simulated the FN incidence and 95% confidence interval (CI) of patients without prophylaxis with G-CSF (cycle 1) using bootstrap sampling.

Results

The incidence of FN was 9.1% (42 of 462) in cycle 1 and 12.3% (57 of 462 patients) throughout all cycles, with 73.7% (42/57) developing FN during cycle 1. Risk factors for FN among patients with B-NHL treated with R-CHOP were albumin <35 g/L (p = 0.0047), relative dose intensity <85% (p = 0.0007), and lack of prophylaxis with G-CSF (p = 0.0006) in cycle 1. In the simulation analysis, the estimated FN incidence in cycle 1 was 16.2% (95% CI [10.9–22.2]).

Conclusions

At 9.1% in cycle 1 and 12.3% throughout all cycles, the incidence of FN was lower than previously reported, possibly reflecting the appropriate use of G-CSF in this clinical setting. For patients with risk factors, the prophylaxis with G-CSF may decrease the occurrence of FN.

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Illness perception is a strong parameter on anxiety and depression scores in early-stage breast cancer survivors: a single-center cross-sectional study of Turkish patients

Abstract

Background

Illness perception has been suggested to have a significant effect on anxiety and depression in cancer patients. In this cross-sectional study, we aimed to evaluate this on Turkish breast cancer patients with follow-up periods up to 12 years.

Patients and methods

A total of 225 patients (with 6 months to 12 years follow-up) were recruited in this cross-sectional study. The patients were divided into three groups of follow-up: 6 months–2 years, 2–5 years, and >5 years. Beck Depression Inventory, Beck Anxiety Inventory, Duke–University of North Carolina Functional Social Support Questionnaire, and Brief Illness Perception Questionnaire were used to assess the depression, anxiety, functional social support (FSS), and illness perception, respectively. Statistical significance of the associations was analyzed using Spearman correlation, Student's t, Mann–Whitney U, and ANOVA tests.

Results

Rates of moderate–severe anxiety and depression scores were not correlated with follow-up period and disease stage, whereas all these parameters were associated significantly with FSS and age. Parameters of illness perception were also not correlated with follow-up period and stage of disease. However, illness perception scores were noticeably better with increments in FSS. Also, the parameters of illness perception were strongly associated with the depression/anxiety score.

Conclusion

Illness perception is an important determinant of the depression/anxiety score in Turkish breast cancer patients.

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Author’s response

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Prevention of palmoplantar erythrodysesthesia in patients treated with pegylated liposomal doxorubicin (Caelyx®)

Abstract

Purpose

Palmoplantar erythrodysesthesia (PPE) is one of the most frequent side effects during systemic treatment with pegylated liposomal doxorubicin (PLD, Caelyx®). PPE lesions show a range of symptoms, from numbness to painful erosions, and can have a major impact on the quality of life in affected patients. Previously, a possible pathomechanism of PPE was found in doxorubicin-treated patients based on radical formation in the skin. Here, a preventive strategy using a topically applied ointment with a high radical protection factor was investigated.

Methods

In this randomized placebo-controlled double-blind study the antioxidant-containing ointment was compared with a placebo ointment regarding PPE grade III occurrence, overall PPE grade I–III occurrence and PPE severity in PLD patients. The verum or placebo cream was topically applied for a period of 16 weeks, starting 3 days prior to the first cycle of chemotherapy. Clinical evaluations were carried out by a dermatologist prior to the first cycle of chemotherapy and every 4 weeks for the duration of 16 weeks.

Results

Thirty-two patients were enrolled in total, of which 17 (66%) completed the study. No PPE grade III was found in the verum group, while five out of seven patients (71%) had to be unblinded in the placebo arm due to PPE grade III (p = 0.003). General PPE occurrence of all grades was 60% under verum and 86% under placebo treatment.

Conclusions

The preventive application of an antioxidant-containing ointment was shown to be significantly more effective in the prevention of PPE grade III compared to placebo treatment.

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Effectiveness of a standardized patient education program on therapy-related side effects and unplanned therapy interruptions in oral cancer therapy: a cluster-randomized controlled trial

Abstract

Purpose

Oral agents for cancer treatment are increasingly prescribed due to their benefits. However, oral cancer medications are difficult to handle and have a considerable potential for side effects. This type of therapy requires a high level of self-management competence by the patient. A standardized patient education program provided by physicians and oncology nurses may positively influence the handling of oral agents. The aim of the study was to evaluate the impact of a standardized patient education program provided by specially trained oncology nurses on therapy management regarding side effects and unplanned therapy interruptions.

Methods

One hundred sixty-five patients from 28 office-based oncology practices from all over Germany participated in this cluster-randomized controlled study. Patients of both intervention (n = 111) and standard care groups (n = 54) received the usual oncologist counseling; in addition, the patients from the intervention group (k = 17 practices) received an education from specially trained oncology nurses. The time of observation was 3 months per patient.

Results

The patients of the intervention group reported fewer side effects (skin rash, pain, fatigue, nausea, vomiting). Patients in the standard care group interrupted the therapy more frequently without informing their oncologist, compared to the intervention group.

Conclusions

Patients benefit from a standardized patient education program provided by specially trained oncology nurses. They tend to handle side effects and critical situations better.

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A pilot study of minocycline for the prevention of paclitaxel-associated neuropathy: ACCRU study RU221408I

Abstract

Purpose

Paclitaxel is associated with both an acute pain syndrome (P-APS) and chronic chemotherapy-induced peripheral neuropathy (CIPN). Given that extensive animal data suggest that minocycline may prevent chemotherapy-induced neurotoxicity, the purpose of this pilot study was to investigate the efficacy of minocycline for the prevention of CIPN and the P-APS.

Methods

Patients with breast cancer were enrolled prior to initiating neoadjuvant or adjuvant weekly paclitaxel for 12 weeks and were randomized to receive minocycline 200 mg on day 1 followed by 100 mg twice daily or a matching placebo. Patients completed (1) an acute pain syndrome questionnaire daily during chemotherapy to measure P-APS and (2) the EORTC QLQ-CIPN20 questionnaire at baseline, prior to each dose of paclitaxel, and monthly for 6 months post treatment, to measure CIPN.

Results

Forty-seven patients were randomized. There were no remarkable differences noted between the minocycline and placebo groups for the overall sensory neuropathy score of the EORTC QLQ-CIPN20 or its individual components, which evaluate tingling, numbness and shooting/burning pain in hands and feet. However, patients taking minocycline had a significant reduction in the daily average pain score attributed to P-APS (p = 0.02). Not only were no increased toxicities reported with minocycline, but there was a significant reduction in fatigue (p = 0.02).

Conclusions

Results of this pilot study do not support the use of minocycline to prevent CIPN, but suggest that it may reduce P-APS and decrease fatigue; further study of the impact of this agent on those endpoints may be warranted.

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Timing to antibiotic therapy in septic oncologic patients presenting without hypotension

Abstract

Purpose

Sepsis accounts for only 2% of the hospitalizations worldwide but more than 17% of total in-hospital mortality. Inappropriate antimicrobial selection and delays in appropriate therapy have been associated with reduced survival in severe sepsis and septic shock. No studies to date have exclusively targeted septic oncologic patients without hypotension.

Methods

This study was a retrospective chart review of 100 adult cancer patients presenting to the emergency department with sepsis without hypotension. We investigated the effect of time to appropriate antibiotics on in-hospital mortality and hospital length of stay. It was hypothesized that increased time to antibiotic administration would worsen patient outcomes including in-hospital mortality and length of stay.

Results

Each 1-h delay in administration of appropriate antibiotic therapy increased the odds of in-hospital mortality by 16% (adjusted OR 1.16. 95% CI 1.04–1.34, p = 0.04). Time to appropriate antibiotics had no effect on hospital length of stay.

Conclusions

Time to appropriate antibiotics and in-hospital mortality were associated in this population of adult oncologic patients with sepsis without hypotension. Clinicians in the emergency department should strive to ensure the timely administration of a complete and appropriate empiric antibiotic regimen in septic patients with active cancer even in the absence of hypotension.

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The influence of unmet supportive care needs on anxiety and depression during cancer treatment and beyond: a longitudinal study of survivors of haematological cancers

Abstract

Objectives

This paper aims to examine the cross-sectional and longitudinal associations between patient-reported unmet needs and anxiety and depression for survivors of diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM).

Methods

In a longitudinal study design, self-reported data were collected through telephone interviews at two time points approximately 7 (T1) and 15 (T2) months post-diagnosis. The sample was recruited through the population-based Victorian Cancer Registry. At T1 and T2, the study outcomes, anxiety and depression, were assessed using the Hospital Anxiety and Depression Scale (HADS) and unmet needs were measured using the Supportive Care Needs Survey (SCNS-SF34). Questions related to social/family problems, relationship problems and financial problems were also asked. A three-step multivariable hierarchical logistic regression analysis examined the relative role of T1 anxiety and depression, T1 and T2 unmet needs and other psychosocial factors with T2 anxiety and depression.

Results

Both cross-sectional and longitudinal associations were observed between unmet needs and psychological distress. T2 anxiety was associated with T1 anxiety (OR 4.75, 95% CI 1.86–11.09), T2 psychological needs (OR 1.68, 95% CI 1.34–2.11) and with T1 social problems (OR 2.33, 95% CI 1.03–5.05) in multivariate analysis. T2 depression was associated with both T1 (OR 1.28, 95% CI 1.06–1.57) and T2 psychological needs (OR 1.35, 95% CI 1.06–1.70), T2 physical needs (OR 1.89, 95% CI 1.27–2.81) and T1 depression (OR 4.52, 95% CI 1.88–10.86).

Conclusions

Unmet needs that manifest following diagnosis and treatment may persist into early survivorship and contribute to psychological distress. Addressing these needs during treatment may diminish the risk of current and future anxiety and depression.

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Critical review of current clinical practice guidelines for antifungal therapy in paediatric haematology and oncology

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Optimal clinical assessment strategies for chemotherapy-induced peripheral neuropathy (CIPN): a systematic review and Delphi survey

Abstract

Background/purpose

Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent side effect of the treatment of cancer. Despite this frequent complication, there has been no comprehensive review and quality appraisal of CIPN assessments. The purpose of this study is to provide a definitive quality appraisal of CIPN assessment strategies for clinical use.

Methods

Relevant studies were identified through database searches of Medline, Embase, CINAHL, and Cochrane. CIPN assessment strategies from included articles were extracted and initially rated by an oncologist and neurophysiologist according to criteria related to assessment depth, comprehensiveness, appropriateness, and reliability. The six highest scoring assessment strategies were the focus of a two-round Delphi survey of a working party of 32 physicians, nurses, and consumers to achieve consensus on the highest rated assessments for each criterion.

Results

The database search yielded 117 distinct CIPN assessments that were extracted from 2373 articles. Three patient-reported outcome surveys and three clinician-based assessments were included in the Delphi survey. No consensus was generated regarding the best overall CIPN assessment, although good (≥70%) consensus was achieved regarding the best assessment within each criterion. The Participant Neurotoxicity Questionnaire (PNQ) was rated the highest overall and patient-reported outcome (PRO) assessment, while the Total Neuropathy Score clinical version (TNSc) was the highest rated clinician-based assessment.

Conclusions

A diverse range of CIPN assessments currently exists. While several assessments assess CIPN symptoms with adequate comprehensiveness, depth, language, and feasibility, the consensus 'gold standard' clinical assessment remains to be established.

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Needs assessment of primary care physicians in the management of chronic pain in cancer survivors

Abstract

Introduction

Cancer patients live longer with effective anti-cancer therapy and supportive care. About 30% of cancer survivors (non-palliative cancer patients who completed treatment) suffer from chronic pain, which will be managed by their primary care physician (PCP). The aim of this study was to assess practice patterns and treatment barriers in the management of chronic pain in cancer survivors among PCPs.

Methods

A survey using a 16-item questionnaire was sent to PCPs across Canada.

Results

A total of 162 responses were collected. The majority of participants were in group (59%) or solo (33%) practice, with an average of 25 years of clinical experience. Seventy-one percent of PCPs were practicing in communities of 10,000 to 100,000 people. Respondents were treating approximately 10 cancer survivors with chronic pain per month. The majority of PCPs (59%) reported having "little knowledge" or "some understanding" of chronic pain management in cancer survivors. They did not usually refer these patients to other specialists. Patient comorbidities (79%), pain medication side effects (78%), previous pain treatment (76%), effect of pain on daily functioning (75%), and drug interactions (71%) were identified as factors that guided PCP treatment choices. Major barriers included medication cost (54%), concerns about opioid abuse (51%), and patient non-compliance (46%). PCPs indicated that treatment guidelines (74%) and knowledge of pharmacological (64%) and non-pharmacological (62%) treatment options would help their chronic pain management.

Conclusion

Most PCPs report a lack of knowledge in the management of chronic pain in cancer survivors but are keen to receive medical education on treatment options and clinical practice guidelines.

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An update in symptom clusters using the Edmonton Symptom Assessment System in a palliative radiotherapy clinic

Abstract

Purpose

To identify symptom clusters in advanced cancer patients attending a palliative radiotherapy clinic using the Edmonton Symptom Assessment System (ESAS).

Methods

Principal component analysis (PCA), exploratory factor analysis (EFA), and hierarchical cluster analysis (HCA) were used to identify symptom clusters among the nine ESAS items using scores from each patient's first visit.

Results

ESAS scores from 182 patients were analyzed. The PCA identified three symptom clusters (cluster 1: depression-anxiety-well-being, cluster 2: pain-tiredness-drowsiness, cluster 3: nausea-dyspnea-loss of appetite). The EFA identified two clusters (cluster 1: tiredness-drowsiness-loss of appetite-well-being-pain-nausea-dyspnea, cluster 2: depression-anxiety). The HCA identified three clusters similar to the PCA with an exception of the loss of appetite item being classified under cluster 1 rather than 3. Two to three symptom clusters were identified using three analytical methods, with similar patterns reported in the literature. Particular groups of items co-occurred consistently across all three analyses: depression and anxiety; nausea and dyspnea; as well as pain, tiredness, and drowsiness.

Conclusion

Three similar symptom clusters were identified in our patient population using the PCA and HCA; whereas, the EFA produced two clusters: one physical and one psychological cluster. Given the implications of symptom clusters in the management of quality of life, clinicians should be aware of these clusters to aid in the palliative treatment of patients.

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Long-term follow-up of the potential benefits of early nutritional intervention in adults with upper gastrointestinal cancer: a pilot randomised trial

Abstract

Purpose

This study aimed to evaluate the long-term survival of all patients who participated in a pilot randomised trial of an early nutritional intervention for adults with upper gastrointestinal cancer. It also sought to identify factors that predicted patient mortality.

Methods

All participants (n = 21) who were randomised into the original study were followed for a maximum of 5 years and 2 months (final follow-up April 2016). The primary outcome measure was time from date of recruitment until date of death, ascertained by the Victorian Cancer Registry and/or Monash Health Scanned Medical Records. Secondary analyses were conducted to identify factors that adversely affected survival.

Results

At the end of the follow-up period, three patients were alive in the nutrition intervention group whilst only two patients were living from the standard care group. Visual evaluation of the Kaplan-Meier survival curves demonstrated a possible survival benefit from being exposed to the intervention between 6 months and 1.4 years post-recruitment, though this benefit dissipated soon after. The intervention was not associated with increased survival in univariate analyses, but was after adjustment for other factors found to adversely impact on survival (adjusted hazard ratio 0.12 (95% CI 0.02–0.72) p = 0.02). These factors were being a smoker (14.2 (1.43 to 140.67), p = 0.02); low baseline physical functioning (1.11 (1.01 to 1.21), p = 0.03); high baseline fatigue (1.09 (1.02–1.16), p = 0.007); and high baseline dyspnoea (1.08 (1.02–1.13), p = 0.003).

Conclusion

Early and intensive nutrition intervention may increase the survival of people with upper gastrointestinal cancer.

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Mutations in DNM1L , as in OPA1 , result indominant optic atrophy despite opposite effectson mitochondrial fusion and fission

Abstract

Dominant optic atrophy is a blinding disease due to the degeneration of the retinal ganglion cells, the axons of which form the optic nerves. In most cases, the disease is caused by mutations in OPA1, a gene encoding a mitochondrial large GTPase involved in cristae structure and mitochondrial network fusion. Using exome sequencing, we identified dominant mutations in DNM1L on chromosome 12p11.21 in three large families with isolated optic atrophy, including the two families that defined the OPA5 locus on chromosome 19q12.1-13.1, the existence of which is denied by the present study. Analyses of patient fibroblasts revealed physiological abundance and homo-polymerization of DNM1L, forming aggregates in the cytoplasm and on highly tubulated mitochondrial network, whereas neither structural difference of the peroxisome network, nor alteration of the respiratory machinery was noticed. Fluorescence microscopy of wild-type mouse retina disclosed a strong DNM1L expression in the ganglion cell layer and axons, and comparison between 3-month-old wild-type and Dnm1l^+/− mice revealed increased mitochondrial length in retinal ganglion cell soma and axon, but no degeneration. Thus, our results disclose that in addition to OPA1, OPA3, MFN2, AFG3L2 and SPG7, dominant mutations in DNM1L jeopardize the integrity of the optic nerve, suggesting that alterations of the opposing forces governing mitochondrial fusion and fission, similarly affect retinal ganglion cell survival.

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Long Cold Ischemia Times in Same Hospital Deceased Donor Transplants.

Background: Recent changes in deceased donor organ allocation for livers (Share-35) and kidneys (KAS) have resulted in broader sharing of organs and increased cold ischemia time (CIT). Broader organ sharing however is not the only cause of increased CIT. Methods: This was a retrospective registry study of CIT in same-hospital liver transplants (SHLT, n=4,347) and kidney transplants (SHKT, n=9,707) between 2004 and 2014. Results: In SHLT, median (IQR) CIT was 5.0 (3.5-6.5) hours versus 6.6 (5.1-8.4) hours in other-hospital LT. DCD donors, donor biopsy, male recipient, recipient obesity, and previous transplant were associated with increased CIT. MELD at transplant of 29+ or status 1a was associated with decreased CIT. SHLT CIT varied by OPO and transplant-center (p

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Feasibility of Monotherapy by Rituximab Without Additional Desensitization in ABO-incompatible Living Donor Liver Transplantation.

Background: Rituximab is a cornerstone in the regimens of desensitization for ABO-incompatible living donor liver transplantation (ABO-i LT) that makes this modality an acceptable option for liver transplantation. Plasmapheresis (PP) to reduce anti-ABO antibody titer and local infusion therapy (LI) were practiced as the strategies for desensitization before the application of rituximab and were reported as additional treatments. The aim of this study was to clarify the feasibility of monotherapy by rituximab without any additional desensitization treatments in ABO-i LT. Methods: Forty patients receiving ABO-i LDLT with Rituximab were enrolled in this retrospective study. The patients were divided into 2 groups: the rituximab with pretransplant PP and posttransplant LI (RPL) group (n=20) and the rituximab monotherapy without any additional treatment (RM) group (n=20). The groups were then compared in terms of the rates of patient survival, antibody-mediated rejection (AMR), and infection. Results: The 1-, 3-, and 5-year patient survival rates were 85%, 85%, and 85% in the RPL group and 89%, 80%, and 80% in the RM group, respectively. There was no significant difference in patient survival between the 2 groups. There were no episodes of AMR in either group. The RM group had a lower rate of fungal and viral infections than the RPL group. Conclusions: Pretransplant rituximab without additional treatments yielded satisfactory outcomes comparable to that with additional treatments such as PP and LI. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Validation of salivary oxytocin and vasopressin as biomarkers in domestic dogs

Publication date: 1 January 2018
Source:Journal of Neuroscience Methods, Volume 293
Author(s): Evan L. MacLean, Laurence R. Gesquiere, Nancy Gee, Kerinne Levy, W. Lance Martin, C. Sue Carter
BackgroundOxytocin (OT) and Vasopressin (AVP) are phylogenetically conserved neuropeptides with effects on social behavior, cognition and stress responses. Although OT and AVP are most commonly measured in blood, urine and cerebrospinal fluid (CSF), these approaches present an array of challenges including concerns related to the invasiveness of sample collection, the potential for matrix interference in immunoassays, and whether samples can be collected at precise time points to assess event-linked endocrine responses.New methodWe validated enzyme-linked immunosorbent assays (ELISAs) for the measurement of salivary OT and AVP in domestic dogs.ResultsBoth OT and AVP were present in dog saliva and detectable by ELISA and high performance liquid chromatography – mass spectrometry (HPLC–MS). OT concentrations in dog saliva were much higher than those typically detected in humans. OT concentrations in the same samples analyzed with and without sample extraction were highly correlated, but this was not true for AVP. ELISA validation studies revealed good accuracy and parallelism, both with and without solid phase extraction. Collection of salivary samples with different synthetic swabs, or following salivary stimulation or the consumption of food led to variance in results. However, samples collected from the same dogs using different techniques tended to be positively correlated. We detected concurrent elevations in salivary and plasma OT during nursing.Comparison with existing methodsThere are currently no other validated methods for measuring OT/AVP in dog saliva.ConclusionsOT and AVP are present in dog saliva, and ELISAs for their detection are methodologically valid.



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An interpretation of the new international MAP guideline for the management of Milk Allergy in Primary Care

General Practitioners suffer from guideline fatigue. They come fast and furious in many complicated forms. Cow's milk allergy (CMA) is one of the most common presentations of food allergy seen in early childho...

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Patterns of care and impact of brachytherapy boost utilization for squamous cell carcinoma of the base of tongue in a large, national cohort

Publication date: Available online 22 September 2017
Source:Brachytherapy
Author(s): Anna Lee, Babak Givi, S. Peter Wu, Moses M. Tam, Naamit K. Gerber, Kenneth S. Hu, Peter Han, David Schreiber
PurposeThe National Cancer Data Base was analyzed to evaluate the patterns of care and impact of brachytherapy (BT) boost on overall survival (OS) for patients with squamous cell carcinoma of the base of tongue.Methods and MaterialsPatients with nonmetastatic squamous cell carcinoma of the base of tongue between 2004 and 2012 who received concurrent external beam radiation therapy (EBRT) and chemotherapy with or without BT boost in the definitive setting were queried. Overall survival was assessed by the Kaplan-Meier method. Cox regression analysis was used to identify covariates that affected OS.ResultsThere were 15,934 patients included in this study; 137 (0.9%) received EBRT + BT and the remaining received EBRT only. Median followup was 41.2 months. The utilization of BT boost declined from 2.1% in 2004 to 0.2% in 2012 (p < 0.0001), whereas intensity-modulated radiation therapy use increased from 22.8% in 2004 to 69.2% in 2012 (p < 0.0001). The three- and 5-year OS was 83.2% and 78.3% for patients receiving EBRT + BT compared with 77.4% and 69.0% for those receiving EBRT only (p = 0.03). The difference in survival was significantly better among patients with T3-4 tumors with EBRT + BT boost (p = 0.009) however, there was no survival benefit among patients with T1-2 tumors (p = 0.72). The analysis was repeated with patients who received intensity-modulated radiation therapy vs. EBRT with BT boost and the survival difference was sustained only for those with T3-4 tumors (p = 0.02).ConclusionsBrachytherapy boost has decreased in its utilization even though it was associated with favorable survival outcomes particularly among patients with higher T-stage tumors.



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An integrated system for clinical treatment verification of HDR prostate brachytherapy combining source tracking with pretreatment imaging

Publication date: Available online 22 September 2017
Source:Brachytherapy
Author(s): Ryan L. Smith, Max Hanlon, Vanessa Panettieri, Jeremy L. Millar, Bronwyn Matheson, Annette Haworth, Rick D. Franich
PurposeHigh-dose-rate (HDR) prostate brachytherapy treatment is usually delivered in one or a few large dose fractions. Poor execution of a planned treatment could have significant clinical impact, as high doses are delivered in seconds, and mistakes in an individual fraction cannot be easily rectified. Given that most potential errors in HDR brachytherapy ultimately lead to a geographical miss, a more direct approach to verification of correct treatment delivery is to directly monitor the position of the source throughout the treatment. In this work, we report on the clinical implementation of our treatment verification system that uniquely combines the 2D source-tracking capability with 2D pretreatment imaging, using a single flat panel detector (FPD).Methods and MaterialsThe clinical brachytherapy treatment couch was modified to allow integration of the FPD into the couch. This enabled the patient to be set up in the brachytherapy bunker in a position that closely matched that at treatment planning imaging. An anteroposterior image was acquired of the patient immediately before treatment delivery and was assessed by the Radiation Oncologist online, to reestablish the positions of the catheters relative to the prostate. Assessment of catheter positions was performed in the left-right and superior-inferior directions along the entire catheter length and throughout the treatment volume. Source tracking was then performed during treatment delivery, and the measured position of the source dwells were directly compared to the treatment plan for verification.ResultsThe treatment verification system was integrated into the clinical environment without significant change to workflow. Two patient cases are presented in this work to provide clinical examples of this system, which is now in routine use for all patient treatments in our clinic. The catheter positions were visualized relative to the prostate, immediately before treatment delivery. For one of the patient cases presented in this work, they agreed with the treatment plan on average by 1.5 mm and were identifiable as a predominantly inferior shift. The source tracking was performed during treatment delivery, and for the same case, the mean deviation from the planned dwell positions was 1.9 mm (max = 4.9 mm) for 280 positions across all catheters.ConclusionWe have implemented our noninvasive treatment verification system based on an FPD in the clinical environment. The device is integrated into a patient treatment couch, and the process is now included in the routine clinical treatment procedure with minor impact on workflow. The system which combines both 2D pretreatment imaging and HDR 2D source tracking provides a range of information that can be used for comprehensive treatment verification. The system has the potential to meaningfully improve safety standards by allowing widespread adoption of routine treatment verification in HDR brachytherapy.



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Time-resolved in vivo dosimetry for source tracking in brachytherapy

Publication date: Available online 22 September 2017
Source:Brachytherapy
Author(s): Jacob Graversen Johansen, Susanne Rylander, Simon Buus, Lise Bentzen, Steffen Bjerre Hokland, Christian Skou Søndergaard, Anders Karl Mikael With, Gustavo Kertzscher, Kari Tanderup
PurposeThe purpose of this article is to demonstrate that brachytherapy source tracking can be realized with in vivo dosimetry. This concept could enable real-time treatment monitoring.MethodsIn vivo dosimetry was incorporated in the clinical routine during high-dose-rate prostate brachytherapy at Aarhus University Hospital. The dosimetry was performed with a radioluminescent crystal positioned in a dedicated brachytherapy needle in the prostate. The dose rate was recorded every 50–100 ms during treatment and analyzed retrospectively. The measured total delivered dose and dose rates for each dwell position with dwell times >0.7 s were compared with expected values. Furthermore, the distance between the source and dosimeter, which was derived from the measured dose rates, was compared with expected values. The measured dose rate pattern in each needle was used to determine the most likely position of the needle relative to the dosimeter.ResultsIn total, 305 needles and 3239 dwell positions were analyzed based on 20 treatments. The measured total doses differed from the expected values by −4.7 ± 8.4% (1SD) with range (−17% to 12%). It was possible to determine needle shifts for 304 out of 305 needles. The mean radial needle shift between imaging and treatment was 0.2 ± 1.1 mm (1SD), and the mean longitudinal shift was 0.3 ± 2.0 mm (1SD).ConclusionTime-resolved in vivo dosimetry can be used to provide geometric information about the treatment progression of afterloading brachytherapy. This information may provide a clear indication of errors and uncertainties during a treatment and, therefore, enables real-time treatment monitoring.



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Image-guided high-dose-rate intracavitary brachytherapy in the treatment of medically inoperable early-stage endometrioid type endometrial adenocarcinoma

Publication date: Available online 22 September 2017
Source:Brachytherapy
Author(s): Scott E. Jordan, Ida Micaily, Enrique Hernandez, J. Stuart Ferriss, Curtis T. Miyamoto, Shidong Li, Bizhan Micaily
PurposeThe purpose of this case series is to describe the treatment and outcomes of a cohort of patients with inoperable early-stage endometrioid endometrial cancer with 3D image-guided high-dose-rate (HDR) intracavitary brachytherapy.MATERIALS AND METHODSA review was performed of patients with early-stage endometrial cancer who underwent primary radiation treatment between 2010 and 2016. Staging and treatment planning were performed CT, pelvic ultrasound, and pelvic MRI. Gross tumor volume (GTV) was defined as the MRI or ultrasound demonstrated endometrial stripe width, with the entire uterine corpus, cervix, and proximal vagina representing the clinical target volume (CTV). Dosimetry calculations were performed in each fraction of HDR brachytherapy.RESULTSEight patients received external beam radiation therapy followed by intracavitary HDR brachytherapy. Seven patients underwent intracavitary HDR brachytherapy alone. In all patients, mean cumulative dose to 90% (D90) of GTV was 95.99 Gy in equivalent dose in 2 Gy fractions (EQD2, α/β = 10). Mean cumulative D90 EQD2 to CTV was 51.64 Gy. Average follow-up was 29 months. Four patients died from concurrent disease(s) at an average of 2.83 years after completion of treatment. Except for 1 (6.6%) patient who recurred at 9 months following completion of treatment, all patients remained disease-free for the remainder of follow-up.ConclusionsIn patients who are poor surgical candidates and have early-stage endometrioid type endometrial carcinoma, image-guided HDR intracavitary brachytherapy carries minimal side effects and a high response rate.



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Physical Activity in Preventing Alzheimer’s Disease and Cognitive Decline: A Narrative Review

Abstract

A large body of epidemiological and experimental data exploring the relationship between physical activity (PA) and Alzheimer's disease (AD) are now available. Despite observational evidence supporting a role for PA in delaying the onset of AD, randomised controlled trials have reported mixed findings, likely due to the heterogeneity in study cohorts, outcome measures, and the adopted PA intervention. The primary objective of this narrative review is to evaluate the extant evidence on the relationship between PA, cognitive decline and AD in older populations. The interaction between PA and the putative mechanisms underlying AD progression, including genetic factors and amyloid-β levels will be explored. In this context, particular attention will be given to studies assessing PA in the early clinical and preclinical, asymptomatic stages of AD. Based on current evidence, clinical considerations for implementation of exercise-based interventions are discussed, along with limitations of previous research and directions for future studies.

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Socio-Economics Perspectives of Healthcare in Sleep Apnea

Publication date: Available online 22 September 2017
Source:Sleep Medicine
Author(s): Ana C. Krieger




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Does CO-MORBID obstructive sleep apnea impair the effectiveness of cognitive and behavioral therapy for insomnia?

Publication date: Available online 22 September 2017
Source:Sleep Medicine
Author(s): Alexander Sweetman, Leon Lack, Sky Lambert, Michael Gradisar, Jodie Harris
AimsCo-morbid insomnia and obstructive sleep apnea (OSA) represents a highly prevalent and debilitating condition, however physicians and researchers are still uncertain as to the most effective treatment approach. Several research groups have suggested that these patients should initially receive treatment for their insomnia before the sleep apnea is targeted. The current study aims to determine whether cognitive and behavioral therapy for insomnia (CBT-i) can effectively treat insomnia in patients with co-morbid OSA, and whether its effectiveness is impaired by the presence of OSA.MethodsA retrospective chart review was conducted to examine 455 insomnia patients entering a CBT-i treatment program in a hospital outpatient setting. 314 patients were diagnosed with insomnia-alone, and 141 with insomnia and co-morbid obstructive sleep apnea. Improvements in average sleep diary parameters, global insomnia severity, and several daytime functioning questionnaires from baseline, to post-treatment, to 3-month follow-up were compared between insomnia patients with- and without co-morbid sleep apnea.ResultsInsomnia patients with co-morbid OSA experienced significant improvements in insomnia symptoms, global insomnia severity, and other daytime functioning measures during and following treatment. Furthermore, improvements were no different between patients with or without co-morbid OSA. Sleep apnea presence and severity were not related to rates of insomnia-remission or treatment-resistance following treatment.ConclusionsCBT-i is an effective treatment in the presence of co-morbid OSA. This information offers support for the suggestion that patients with co-morbid insomnia and obstructive sleep apnea should be treated with CBT-i prior to treatment of the OSA.



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Sleep apneas trigger epilepsy

Publication date: Available online 22 September 2017
Source:Sleep Medicine
Author(s): Valerio Brunetti, Michela Ada Noris Ferilli, Catello Vollono, Giacomo Della Marca




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Need for Positive Airway Pressure Re-titration with Changes in Mask Style

Publication date: Available online 22 September 2017
Source:Sleep Medicine
Author(s): Matthew R. Ebben




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The St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017: the point of view of an International Panel of Experts in Radiation Oncology

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Overall survival analysis of EXAM, a phase 3 trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma

Abstract

Background

Primary analysis of the double-blind, phase 3 EXAM trial demonstrated significant improvement in progression-free survival (PFS) with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was performed after long-term follow-up.

Patients and Methods

EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.

Results

Minimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 v 21.1 months), although the difference did not reach statistical significance (stratified hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.64 to 1.12; P = 0.24). In an exploratory assessment of OS, PFS, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation–positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo (HR, 0.60; 95% CI, 0.38 to 0.94; P = 0.03 [not adjusted for multiple subgroup analyses]), with correspoding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70–1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.

Conclusion

The secondary endpoint was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically non-significant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest patients with RET M918T–positive tumors may experience a greater treatment benefit with cabozantinib.

Trial Registration Number

NCT00704730

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Role of adjuvant chemotherapy in early stage endometrioid and clear cell ovarian cancer

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Toxicity Adjustment in the ESMO-MCBS: A Gestalt Approach?

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Checkpoint blockade for metastatic melanoma and Merkel cell carcinoma in HIV-positive patients

nivolumabpembrolizumabipilimumabmelanomaHIVAIDS

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A prospective evaluation of plasma phospholipid fatty acids and breast cancer risk in the EPIC study

Abstract

Background Intakes of specific fatty acids have been postulated to impact breast cancer risk but epidemiological data based on dietary questionnaires remain conflicting.Material and methods We assessed the association between plasma phospholipid fatty acids and breast cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Sixty fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 2,982 incident breast cancer cases matched to 2,982 controls. Conditional logistic regression models were used to estimate relative risk of breast cancer by fatty acid level. The false discovery rate (q-values) was computed to control for multiple comparisons. Subgroup analyses were performed by estrogen receptor (ER) and progesterone receptor (PR) expression in the tumours.Results A high level of palmitoleic acid (odds ratio, OR for the highest quartile compared with the lowest OR[Q4-Q1]=1.37; 95%CI=1.14-1.64; p for trend=0.0001, q-value=0.004) as well as a high desaturation index (DI₁₆) (16:1n-7/16:0) (OR[Q4-Q1]=1.28; 95%CI=1.07-1.54; p for trend=0.002, q-value=0.037), as biomarkers of de novo lipogenesis, were significantly associated with increased risk of breast cancer. Levels of industrial trans-fatty acids were positively associated with ER-negative tumors (OR for the highest tertile compared with the lowest [T3-T1]=2.01; 95% CI = 1.03-3.90; p for trend=0.047), while no association was found for ER-positive tumors (P-heterogeneity =0.01). No significant association was found between n-3 polyunsaturated fatty acids and breast cancer risk, overall or by hormonal receptor.Conclusion These findings suggest that increased de novo lipogenesis, acting through increased synthesis of palmitoleic acid, could be a relevant metabolic pathway for breast tumorigenesis. Dietary trans fatty acids derived from industrial processes may specifically increase ER-negative breast cancer risk.

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Combined high dose radiation and pazopanib in metastatic renal cell carcinoma: a phase I dose escalation trial

The primary objective was to determine maximum tolerated radiation dose in patients with metastatic renal cell carcinoma on pazopanib treatment.

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Hair Transplantation in Migraine Headache Patients.

Background: Migraine headache is a primary neurologic disease affecting millions of people worldwide. As a consequence, quality of life is diminished, productivity suffers (through loss of work force), and treatment costs are substantial. The occurrence rate in the general population is quite high, with women accounting for 3 of every 4 cases. Methods: Between January 2011 and May 2012, a total of 221 patients received hair transplants. Another 590 patients underwent hair transplantation between June 2012 and December 2016. Initially (first interval), patients were not questioned on migraine headaches in preoperative visits, but questioning was regularly done thereafter. Overall, 150 patients given transplants in the first period were surveyed by phone regarding preoperative migraine headaches. Aside from the 1 incidental discovery, no other instances of migraine emerged. Headache origins were occipital-frontal in 2 patients, occipital-temporal in 2 patients, and occipital-temporal-frontal in the 2 others. Donor/receiver areas in hair transplantation and migraine trigger zones shared locations. Headache frequencies ranged from 4 to 8 days per month (average, 6 days), and pain scores were 5-8 (10 being highest). Duration of pain was 3-5 hours (average, 4 hours). All six patients had used various medications, such as triptans, ergot, and nonsteroidal anti-inflammatory drugs, before hair transplantation. The 1 female patient was a 32-year-old seeking treatment for alopecia, with a 6-year history of migraine headaches. The male patients presenting with androgenetic alopecia (grade 4-5 by Norwood classification) had 6- to 20-year migrainous histories. Results: After hair transplantation, each migraine sufferer was checked once in the first month and then once every 3 months. Those who could not appear in person after the first year were evaluated by phone every 3 months. Migraine headaches had ceased in all 6 patients, none of whom used medical treatments for migraines thereafter. The postoperative improvement each patient experienced was dramatic (P

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Enabling Remote Monitoring Using Free Apps and Smart Devices for a Free-Flap Adjunct Monitor.

Summary: Remote monitoring capability does not currently exist for Periflux (Perimed AB, Jarfalla, Sweden) laser Doppler and other perfusion monitors. Two simple adaptations using free apps (applications) and smart devices can enable transmission of the perfusion readout to the surgeon's smartphone. A literature review was conducted to identify reports relating to remote free flap monitoring. In addition, 2 wireless methodologies are devised: One method uses a free app that converts a smart device into a camera, stationed next to the perfusion monitor, to stream live video of the laser Doppler readout to the surgeon's smartphone; a second method uses a free app installed on a bedside laptop computer, which is connected to the laser Doppler flowmeter via a data cord. A live feed of the computer's desktop as a teleconference host is transmitted to the surgeon's smart device over the Internet. These 2 methodologies were employed on 9 and 8 free flaps, respectively, as a pilot study. All free flaps were monitored remotely for 4-6 days with near 100% reliability. The Internet connectivity became disrupted only on several occasions, requiring simple Wi-Fi and software reset. Minor mechanical issues were encountered with the video streaming method. Literature review identified very few articles describing remote monitoring of free flaps. The 2 methodologies reported here provided reliable continuous transmission of quantitative data of flap perfusion to smart devices via Internet connection, which can revolutionize the microsurgeon's practice if his/her adjunctive perfusion monitor with display does not yet have Wi-Fi capability. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright (C) 2017 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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10 Years Later: Lessons Learned from an Academic Multidisciplinary Cosmetic Center.

Background: In 2006, a Centers for Medicare and Medicaid Services-accredited multidisciplinary academic ambulatory surgery center was established with the goal of delivering high-quality, efficient reconstructive, and cosmetic services in an academic setting. We review our decade-long experience since its establishment. Methods: Clinical and financial data from 2006 to 2016 are reviewed. All cosmetic procedures, including both minimally invasive and operative cases, are included. Data are compared to nationally published reports. Results: Nearly 3,500 cosmetic surgeries and 10,000 minimally invasive procedures were performed. Compared with national averages, surgical volume in abdominoplasty is high, whereas rhinoplasty and breast augmentation is low. Regarding trend data, breast augmentation volume has decreased by 25%, whereas minimally invasive procedural volume continues to grow and is comparable with national reports. Similarly, where surgical revenue remains steady, minimally invasive revenue has increased significantly. The majority of surgical cases (70%) are reconstructive in nature and insurance-based. Payer mix is 71% private insurance, 18% Medicare and Medicaid, and 11% self-pay. Despite year-over-year revenue increases, net profit in 2015 was $6,120. Rent and anesthesia costs exceed national averages, and employee salary and wages are the highest expenditure. Conclusion: Although the creation of our academic cosmetic ambulatory surgery center has greatly increased the overall volume of cosmetic surgery performed at the University of Wisconsin, the majority of surgical volume and revenue is reconstructive. As is seen nationwide, minimally invasive cosmetic procedures represent our most rapidly expanding revenue stream. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright (C) 2017 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

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Two-Stage Prosthetic Breast Reconstruction after Mastectomy with or without Prior Postmastectomy Radiotherapy.

Background: Two-stage prosthetic breast reconstruction with initial insertion of a tissue expander followed by an implant after a period of inflation is a well-established breast reconstruction option. Most of the current literature concentrates on the immediate setting, and there are only a few reports into delayed cases, especially after postmastectomy radiotherapy (RT). We performed a retrospective review of our experience over a 12.5-year period. Methods: Between June 1998 and December 2010, a total of 671 patients received prosthetic-only breast reconstruction. Of these, 170 (25.3%) underwent delayed 2-stage prosthetic breast reconstruction after mastectomy for cancer. Patients were divided into group A, no postmastectomy RT (n = 150), and group B, postmastectomy RT (n = 20). The primary factor examined was the failure of the reconstruction from loss of prosthesis with or without smoking. Other complications, as well as rates of revisional surgery were also recorded. Results: Expander or implant loss occurred in 3 of 150 patients in group A (2.0%) and 3 of 20 patients in group B (15%; P = 0.02). For nonsmokers, implant loss was 1.6% and 5.6%, respectively (P = NS). Smoking was associated with 1 of the 3 losses in group A and 2 of the 3 in group B (smokers, n = 2; P

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Recruiting primary care physicians to qualitative research: Experiences and recommendations from a childhood cancer survivorship study

Abstract

Background

Primary care physicians (PCPs) are essential for healthcare delivery but can be difficult to recruit to health research. Low response rates may impact the quality and value of data collected. This paper outlines participant and study design factors associated with increased response rates among PCPs invited to participate in a qualitative study at Sydney Children's Hospital, Australia.

Procedure

We invited 160 PCPs by post, who were nominated by their childhood cancer patients in a survey study. We followed-up by telephone, email, or fax 2 weeks later.

Results

Without any follow-up, 32 PCPs opted in to the study. With follow-up, a further 42 PCPs opted in, with email appearing to be the most effective method, yielding a total of 74 PCPs opting in (46.3%). We reached data saturation after 51 interviews. On average, it took 34.6 days from mail-out to interview completion. Nonrespondents were more likely to be male (P = 0.013). No survivor-related factors significantly influenced PCPs' likelihood of participating. Almost double the number of interviews were successfully completed if scheduled via email versus phone. Those requiring no follow-up did not differ significantly to late respondents in demographic/survivor-related characteristics.

Conclusion

PCP factors associated with higher opt in rates, and early responses, may be of interest to others considering engaging PCPs and/or their patients in cancer-related research, particularly qualitative or mixed-methods studies. Study resources may be best allocated to email follow-up, incentives, and personalization of study documents linking PCPs to patients. These efforts may improve PCP participation and the representativeness of study findings.

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Recurrent desmoplastic small round cell tumor responding to an mTOR inhibitor containing regimen

Abstract

Desmoplastic small round cell tumor (DSRCT) is a rare mesenchymal tumor that typically presents with multiple abdominal masses. Initial treatment is multimodal in nature. Patients with relapsed DSRCT have a poor prognosis, and there are no standard therapies. We report our experience with five patients treated with vinorelbine, cyclophosphamide, and temsirolimus (VCT). Median number of VCT courses delivered was 7 (range 4–14 courses), and partial response was observed in all patients. Median time to progression or relapse was 8.5 months (range 7–16 months). Neutropenia and mucositis were most common toxicities (n = 4 each).

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Palonosetron is nonsuperior to ondansetron in acute phase but provides superior antiemetic control in delayed phase for pediatric patients administered highly emetogenic chemotherapy

Abstract

Purpose

Chemotherapy-induced nausea and vomiting (CINV) in children remains to be a major side effect despite antiemetic treatment. Palonosetron is a new generation 5-HT₃ receptor antagonists effective against acute and delayed nausea and vomiting. This study aimed to compare the therapeutic values of palonosetron and ondansetron in preventing pediatric CINV.

Methods

A prospective, randomized, double-blind, parallel controlled study was conducted in 0–18 years old cancer patients administered highly emetogenic chemotherapy, with different dosage of palonosetron or ondansetron, both followed by dexamethasone. The patients were observed for vomiting and nausea from 0 to 120 hr after chemotherapy initiation. All adverse events (AEs) during the study period were recorded. This study was registered with the Chinese Clinical Trial Registry, number ChiCTR-TRC-14004891.

Results

Between August 2014 and July 2016, 565 patients were randomly assigned to receive 5 μg/kg palonosetron (n = 185), 10 μg/kg palonosetron (n = 186), and 3 × 150 μg/kg ondansetron (n = 194), of whom 181, 185, and 189, respectively, were included in the efficacy analysis. Complete response (CR) rates during the acute phase were 69.1, 69.7, and 64.6%, respectively, in the 5 μg/kg palonosetron, 10 μg/kg palonosetron, and ondansetron groups. In the delayed phase, 10 μg/kg palonosetron (CR, 53.5%) showed superiority to 5 μg/kg palonosetron (CR, 39.8%) and ondansetron (CR, 32.8%) groups (P < 0.05). The most frequently observed drug-related AEs were nervous system disorders, mainly headache, with an incidence of 2.8, 2.2, and 2.6% in each group, respectively.

Conclusion

Combination of palonosetron plus dexamethasone is highly effective in controlling acute and delayed CINV, with palonosetron superior to ondansetron.

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A phase II study of radioimmunotherapy with intraventricular 131I-3F8 for medulloblastoma

Abstract

Background

High-risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular ¹³¹I-labeled 3F8 in patients with MB on a phase II clinical trial.

Methods

Patients with histopathologically confirmed high-risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) ¹²⁴I-3F8 or ¹³¹I-3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) ¹³¹I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6–12 months thereafter.

Results

Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0–2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3–55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18–0.88, P = 0.024).

Conclusions

cRIT with ¹³¹I-3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent MB.

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Targeting Phosphatidylserine with Calcium-dependent Protein-Drug Conjugates for the Treatment of Cancer

In response to cellular stress, phosphatidylserine (PS) is exposed on the outer membrane leaflet of tumor blood vessels and cancer cells, motivating the development of PS-specific therapies. The generation of drug-conjugated PS-targeting agents represents an unexplored therapeutic approach, for which anti-tumor effects are critically dependent on efficient internalization and lysosomal delivery of the cytotoxic drug. In the current study, we have generated PS-targeting agents by fusing PS-binding domains to a human IgG1-derived Fc fragment. The tumor localization and pharmacokinetics of several PS-specific Fc fusions have been analyzed in mice and demonstrate that Fc-Syt1, a fusion containing the synaptotagmin 1 C2A domain, effectively targets tumor tissue. Conjugation of Fc-Syt1 to the cytotoxic drug, monomethyl auristatin E, results in a protein-drug conjugate (PDC) that is internalized into target cells and, due to the Ca²⁺-dependence of PS binding, dissociates from PS in early endosomes. The released PDC is efficiently delivered to lysosomes and has potent anti-tumor effects in mouse xenograft tumor models. Interestingly, whilst an engineered, tetravalent Fc-Syt1 fusion shows increased binding to target cells, this higher avidity variant demonstrates reduced persistence and therapeutic effects compared with bivalent Fc-Syt1. Collectively, these studies show that finely tuned, Ca²⁺-switched PS-targeting agents can be therapeutically efficacious.

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Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (ulixertinib)

Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF- and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic anti-proliferative effects in a BRAFV600E mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to single-agent and combination BRAF/MEK targeted therapy. Based on these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway (NCT01781429, NCT02296242 and NCT02608229).

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A novel therapeutic strategy for pancreatic cancer: targeting cell surface glycan using rBC2LC-N lectin-drug conjugate (LDC).

Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumour-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin-glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin-drug conjugate (LDC), and its safety and anti-tumour effects were evaluated. A specific affinity between rBC2LC-N (a recombinant bacterial C-type lectin) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. In contrast to the belief that all lectins mediate harmful haemagglutination, rBC2LC-N did not cause haemagglutination with human erythrocytes and was safely administered to mice. The 50% inhibitory concentration of LDC to Capan-1 (1.04 pg/ml=0.0195 pmol/l) was 1/1000 lower than that reported for conventional immunotoxins. The intraperitoneal administration of LDC reduced the tumour weight from 390 mg to 130.8 mg (P<0.01) in an orthotopic model, and reduced the number of nodules from 48 to 3 (P<0.001) and improved survival from 62 to 105 days in a peritoneal dissemination model (P<0.0001). In addition, the effect of LDC was reproduced in nodules from patient-derived PDAC xenografts through intravenous injection. Herein, we show the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments.

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A chemical modulator of p53 transactivation that acts as a radioprotective agonist

Inhibiting p53-dependent apoptosis by inhibitors of p53 is an effective strategy for preventing radiation-induced damage in hematopoietic lineages, while p53 and p21 also play radioprotective roles in the gastrointestinal epithelium. We previously identified some zinc(II) chelators, including 8-quinolinol derivatives that suppress apoptosis in attempts to discover compounds that target the zinc-binding site in p53. We found that 5-chloro-8-quinolinol (5CHQ) has a unique p53-modulating activity that shifts its transactivation from proapoptotic to protective responses including enhancing p21 induction and suppressing PUMA induction. This p53-modulating activity also influenced p53 and p53-target gene expression in unirradiated cells without inducing DNA damage. The specificity of 5CHQ for p53 and p21 was demonstrated by silencing the expression of each protein. These effects seems to be attributable to the sequence-specific alteration of p53 DNA-binding, as evaluated by chromatin immunoprecipitation and electrophoretic mobility shift assays. In addition, 5-chloro-8-methoxyquinoline itself had no antiapoptotic activity, indicating that the hydroxyl group at the 8-position is required for its antiapoptotic activity. We applied this remarkable agonistic activity to protecting the hematopoietic and gastrointestinal system in mouse irradiation models. The dose-reduction factors of 5CHQ in total-body and abdominally irradiated mice were about 1.2 and 1.3, respectively. 5CHQ effectively protected mouse epithelial stem cells from a lethal dose of abdominal irradiation. Furthermore, the specificity of 5CHQ for p53 in reducing the lethality induced by abdominal irradiation was revealed in Trp53-KO mice. These results indicate that the pharmacological upregulation of radioprotective p53-target genes is an effective strategy for addressing the gastrointestinal syndrome.

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ABC294640, a novel sphingosine kinase 2 inhibitor induces oncogenic virus infected cell autophagic death and represses tumor growth

Kaposi's Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several malignancies, including Kaposi's Sarcoma (KS) and primary effusion lymphoma (PEL), which preferentially arise in HIV+ patients and lack effective treatment. Sphingosine kinase 2 (SphK2) is a key factor within sphingolipid metabolism, responsible for the conversion of pro-apoptotic ceramides to anti-apoptotic sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to the accumulation of intracellular ceramides and induces apoptosis in KSHV-infected primary endothelial cells and PEL tumor cells but not in uninfected cells. In the current study, we found that ABC294640 induces autophagic death instead of apoptosis in a KSHV long-term-infected immortalized endothelial cell-line, TIVE-LTC, but not in uninfected TIVE cells, through the up-regulation of LC3B protein. Transcriptomic analysis indicates that many genes related to cellular stress responses, cell cycle/proliferation, and cellular metabolic process are altered in TIVE-LTC exposed to ABC294640. One of the candidates, Egr-1, was found to directly regulate LC3B expression and required for the ABC294640-induced autophagic death. By using a KS-like nude mice model with TIVE-LTC, we found that ABC294640 treatment significantly suppressed KSHV-induced tumor growth in vivo, which indicates that targeting sphingolipid metabolism especially SphK2 may represent a promising therapeutic strategy against KSHV-related malignancies.

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Infiltrating Lobular Breast Cancer Presenting as Isolated Gastric Metastasis: a Case Report

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A novel Breast Cancer Index for prediction of distant recurrence in HR+ early stage breast cancer with 1 to 3 positive nodes

Purpose: Study objective was to characterize the prognostic performance of a novel Breast Cancer Index model (BCIN+), an integration of BCI gene expression, tumor size, and grade, specifically developed for assessment of distant recurrence (DR) risk in HR+ breast cancer patients with 1-3 positive lymph nodes (pN1). <br><br> Experimental Design: Analysis was conducted in a well-annotated retrospective series of pN1 patients (N=402) treated with adjuvant endocrine therapy with or without chemotherapy using a pre-specified model. The primary endpoint was time-to-DR. Results were determined blinded to clinical outcome. Kaplan-Meier estimates of overall (0-15y) and late (≥5y) DR, hazard ratios and 95% CIs were estimated. Likelihood ratio statistics assessed relative contributions of prognostic information. <br><br> Results: BCIN+ classified 81 patients (20%) as low risk with a 15-year DR rate of 1.3% (95%CI: 0.0-3.7%) vs 321 patients as high risk with a DR rate of 29.0% (23.2-34.4%). In patients DR-free for ≥5y (n=349), the late DR rate was 1.3% (95%CI: 0.0-3.7%) and 16.1% (10.6-21.3%) in low- and high-risk groups, respectively. BCI gene expression alone was significantly prognostic (LR-2=20.12, P<0.0001). Addition of tumor size (LR-2=13.29, P=0.0003) and grade (LR-2=12.72, P=0.0004) significantly improved prognostic performance. BCI added significant prognostic information to tumor size (LR-2=17.55, P<0.0001); addition to tumor grade was incremental (LR-2=2.38, P=0.1) with considerable overlap between prognostic values (LR-2=17.74). <br><br> Conclusions: The integrated BCIN+ identified 20% of pN1 patients with limited risk of recurrence over 15y, in whom extended endocrine treatment may be spared. Ongoing studies will characterize combined clinical-genomic risk assessment in node-positive patients.

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Phase III clinical trial (RERISE study) results of Efficacy and safety of radotinib compared with imatinib in newly diagnosed chronic phase chronic myeloid leukemia

Purpose: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for CML-CP in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. Methods: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily (bid) radotinib doses, or imatinib daily (qd). The primary endpoint was major molecular response (MMR) by 12 months. Results: Two hundred forty-one patients were randomized to receive radotinib 300 mg (n = 79) or 400 mg bid (n = 81), or imatinib 400 mg qd (n = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg bid (46%) versus imatinib (30%; P = 0.0044 and P = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; P = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction. Conclusion: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome-positive CML-CP. This trial was registered at http://ift.tt/PmpYKN as NCT01511289.

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In-depth genetic analysis of sclerosing epithelioid fibrosarcoma reveals recurrent genomic alterations and potential treatment targets

Purpose: Sclerosing epithelioid fibrosarcoma (SEF) is a highly aggressive soft tissue sarcoma closely related to low-grade fibromyxoid sarcoma (LGFMS). Some tumors display morphological characteristics of both SEF and LGFMS, so called hybrid SEF/LGFMS. Despite the overlap of gene fusion variants between these two tumor types, SEF is much more aggressive. The present study aimed to further characterize SEF and hybrid SEF/LGFMS genetically in order to better understand the role of the characteristic fusion genes and possible additional genetic alterations in tumorigenesis. Experimental Design: We performed whole exome sequencing, single nucleotide polymorphism (SNP) array analysis, RNA-sequencing (RNA-seq), global gene expression analyses and/or IHC on a series of 13 SEFs and 6 hybrid SEF/LGFMS. We also expressed the FUS-CREB3L2 and EWSR1-CREB3L1 fusion genes conditionally in a fibroblast cell line; these cells were subsequently analyzed by RNA-seq and expression of the CD24 protein was assessed by FACS analysis. Results: The SNP array analysis detected a large number of structural aberrations in SEF and SEF/LGFMS, many of which were recurrent, notably DMD microdeletions. RNA-seq identified FUS-CREM and PAX5-CREB3L1 as alternative fusion genes in one SEF each. CD24 was strongly upregulated, presumably a direct target of the fusion proteins. This was further confirmed by the gene expression analysis and FACS analysis on Tet-On 3G cells expressing EWSR1-CREB3L1. Conclusions: While gene fusions are the primary tumorigenic events in both SEF and LGFMS, additional genomic changes explain the differences in aggressiveness and clinical outcome between the two types. CD24 and DMD constitute potential therapeutic targets.

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Phospholipase D1 inhibition linked to upregulation of ICAT blocks colorectal cancer growth hyperactivated by Wnt/{beta}-catenin and PI3K/Akt Signaling

Purpose: Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer (CRC), which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of CRC. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via ICAT, a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of CRC hyperactivated by Wnt/β-catenin and PI3K/Akt signaling. Experimental design: Expression of ICAT via targeting of PLD1 was assessed in vivo in ApcMin/+ mice, an AOM/DSS model, and in vitro using various CRC cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 CRC patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying APC and PI3K mutations. Results: PLD1 promoted the Wnt/β-catenin signaling pathway by selectively down-regulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in CRC patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of CRC activated by the Wnt/β-catenin and PI3K signaling pathways. Conclusion: These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways and thus could be proposed as a novel CRC prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of CRC patients carrying APC and PI3KCA mutations.

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A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma

Purpose: Anti-GD2 monoclonal antibodies (mAb), acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines and haploidentical natural killer (NK) cells. Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40mg/m2/dose, days 2-5), GMCSF and IL-2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4) and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally-derived NK cells were administered with courses 2, 4 and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL-2 receptor alpha (sIL-2Ra) levels and human anti-human antibodies (HAHA) were obtained. Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK cell infusions. The response rate was 61.5% (4 CR, 1 VGPR, 3 PR) and 5 had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived one year. Hu14.18K322A pharmacokinetics were not affected by chemotherapy or HAHA. All patients had increased sIL-2Ra levels, indicating immune activation. Conclusions: Chemotherapy plus hu14.18K322A, cytokines and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly-diagnosed neuroblastoma.

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Integrated analysis reveals tubal and ovarian originated serous ovarian cancer and predicts differential therapeutic responses

Purpose: The relative importance of fallopian tube (FT) compared to ovarian surface epithelium (OSE) in the genesis of serous type of ovarian cancer (SOC) is still unsettled. Here, we followed an integrated approach to study the tissue origin of SOC, as well as its association with clinical outcome and response to therapeutic drugs. Experimental Design: A collection of transcriptome data of 80 FTs, 89 OSEs and 2,668 SOCs was systematically analyzed to determine the characteristic of FT-like and OSE-like tumors. A molecular signature was developed for identifying tissue origin of SOC and then was used to re-evaluate the prognostic genes and therapeutic biomarkers of SOC of different tissue origins. IHC staining of tissue array and functional experiments on a panel of ovarian cancer cell lines were used to further validate the key findings. Results: The expression patterns of tissue specific genes, prognostic genes and molecular markers all support a dualistic tissue origin of SOC, from either FT or OSE. A molecular signature was established to identify the tissue identity of SOCs. Surprisingly, the signature showed a strong association with overall survival [OSE-like versus FT-like, HR = 4.16, 95%CI, 2.67-6.48, p<10-9]. The phamacogenomic approach revealed AXL to be a therapeutic target of the aggressive OSE-derived SOC. Conclusions: SOC has two subtypes originated from either FT or OSE, which show different clinical and pathological features.

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Immunomodulation by entinostat in renal cell carcinoma patients receiving high dose interleukin 2: a multicenter, single-arm, phase 1/2 trial (NCI-CTEP#7870)

Purpose: Based on preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high dose interleukin 2 (IL-2) in a renal cell carcinoma model by down-regulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high dose IL-2 in patients with metastatic clear cell renal cell carcinoma (ccRCC). Experimental Design: Clear cell histology, no prior treatments, and being sufficiently fit to receive high dose IL-2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, PO every14 days) and a fixed standard dose of IL-2 (600,000 units/kg IV). Each course was 85 days. The primary end point was objective response rate and toxicity. Secondary end points included progression-free survival and overall survival. Results: 47 patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% (95% CI 22%-53%), the median progression-free survival was 13.8 months (95% CI 6.0-18.8), and the median overall survival was 65.3 months (95% CI 52.6.-65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Treg were observed following treatment with entinostat, and lower numbers were associated with response (p=0.03). Conclusions: This trial suggests a promising clinical activity for entinostat in combination with high dose Il-2 in ccRCC patients, and provides the first example of an epigenetic agent being rationally combined with immunotherapy.

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Amplification of 1q32.1 refines the molecular classification of endometrial carcinoma

Purpose: Molecular classification of endometrial cancer (EC) identified distinct molecular subgroups. However, the largest subset of ECs remains poorly characterized and is referred to as the 'non-specific molecular profile' (NSMP) subgroup. Here, we aimed at refining the classification of this subgroup by profiling somatic copy number aberrations (SCNAs). Experimental Design: SCNAs were analyzed in 141 ECs using whole-genome SNP arrays and pooled with 361 ECs from The Cancer Genome Atlas. Genomic Identification of Significant Targets In Cancer (GISTIC) identified statistically-enriched SCNAs and penalized Cox regression assessed survival effects. The prognostic significance of relevant SCNAs was validated using multiplex ligation-dependent probe amplification in 840 ECs from the PORTEC-1/2 trials. Copy number status of genes was correlated with gene expression to identify potential cancer drivers. One plausible oncogene was validated in vitro using antisense oligonucleotide-based strategy. Results: SCNAs affecting chromosome 1q32.1 significantly correlated with worse relapse-free survival (RFS) in the NSMP subgroup (HR=2.12; 95%CI, 1.26-3.59; P=0.005). This effect was replicated in NSMP ECs from PORTEC-1/2 (HR=2.34; 95%CI, 1.17-4.70; P=0.017). A new molecular classification including the 1q32.1 amplification improved risk prediction of recurrence. MDM4 gene expression strongly correlated with 1q32.1 amplification. Silencing MDM4 inhibited cell growth in cell lines carrying 1q32.1 amplification, but not in non-amplified cell lines. Vice versa, increasing MDM4 expression in non-amplified cell lines stimulated cell proliferation. Conclusions: 1q32.1 amplification was identified as a prognostic marker for poorly-characterized NSMP ECs, refining the molecular classification of this subgroup. We functionally validated MDM4 as a potential oncogenic driver in the 1q32.1 region.

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