American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Nutrition Screening and Therapy Within a Surgical Enhanced Recovery Pathway

Perioperative malnutrition has proven to be challenging to define, diagnose, and treat. Despite these challenges, it is well known that suboptimal nutritional status is a strong independent predictor of poor postoperative outcomes. Although perioperative caregivers consistently express recognition of the importance of nutrition screening and optimization in the perioperative period, implementation of evidence-based perioperative nutrition guidelines and pathways in the United States has been quite limited and needs to be addressed in surgery-focused recommendations. The second Perioperative Quality Initiative brought together a group of international experts with the objective of providing consensus recommendations on this important topic with the goal of (1) developing guidelines for screening of nutritional status to identify patients at risk for adverse outcomes due to malnutrition; (2) address optimal methods of providing nutritional support and optimizing nutrition status preoperatively; and (3) identifying when and how to optimize nutrition delivery in the postoperative period. Discussion led to strong recommendations for implementation of routine preoperative nutrition screening to identify patients in need of preoperative nutrition optimization. Postoperatively, nutrition delivery should be restarted immediately after surgery. The key role of oral nutrition supplements, enteral nutrition, and parenteral nutrition (implemented in that order) in most perioperative patients was advocated for with protein delivery being more important than total calorie delivery. Finally, the role of often-inadequate nutrition intake in the posthospital setting was discussed, and the role of postdischarge oral nutrition supplements was emphasized. Accepted for publication October 27, 2017. Funding: The Perioperative Quality Initiative (POQI) meeting received financial assistance from the American Society for Enhanced Recovery (ASER). Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). For the Perioperative Quality Initiative (POQI) 2 Workgroup, see Supplemental Digital Content, Appendix 1, http://ift.tt/2n5LfOn. Reprints will not be available from the authors. Address correspondence to Timothy E. Miller, MB, ChB, FRCA, Division of General, Vascular and Transplant Anesthesia, Duke University Medical Center, Box 3094, Durham, NC 27710. Address e-mail to timothy.miller2@duke.edu. © 2018 International Anesthesia Research Society

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Age Does Not Affect Metoprolol’s Effect on Perioperative Outcomes (From the POISE Database)

BACKGROUND: Perioperative β-blockade reduces the incidence of myocardial infarction but increases that of death, stroke, and hypotension. The elderly may experience few benefits but more harms associated with β-blockade due to a normal effect of aging, that of a reduced resting heart rate. The tested hypothesis was that the effect of perioperative β-blockade is more significant with increasing age. METHODS: To determine whether the effect of perioperative β-blockade on the primary composite event, clinically significant hypotension, myocardial infarction, stroke, and death varies with age, we interrogated data from the perioperative ischemia evaluation (POISE) study. The POISE study randomly assigned 8351 patients, aged ≥45 years, in 23 countries, undergoing major noncardiac surgery to either 200 mg metoprolol CR daily or placebo for 30 days. Odds ratios or hazard ratios for time to events, when available, for each of the adverse effects were measured according to decile of age, and interaction term between age and treatment was calculated. No adjustment was made for multiple outcomes. RESULTS: Age was associated with higher incidences of the major outcomes of clinically significant hypotension, myocardial infarction, and death. Age was associated with a minimal reduction in resting heart rate from 84.2 (standard error, 0.63; ages 45–54 years) to 80.9 (standard error, 0.70; ages >85 years; P

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Using the Ventrain With a Small-Bore Catheter: Ventilation or Just Oxygenation?

No abstract available

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The Effects of Agrin Isoforms on Diabetic Neuropathic Pain in a Rat Streptozotocin Model

BACKGROUND: Diabetes mellitus affects 9.3% of the US population and increases risks of surgery and complications. Diabetic neuropathic pain (DNP), one of the main consequences of diabetes mellitus, is extremely difficult to treat. Current medications yield limited benefits and/or have severe adverse effects. Therefore, new, effective treatment is needed. METHODS: Streptozotocin at 55 mg/kg was injected intraperitoneally in rats to induce diabetes mellitus. Diabetic rats exhibiting neuropathic pain underwent intrathecal injection of purified agrin proteins at various doses and were then tested for tactile allodynia to evaluate whether DNP was inhibited. The agrin effects were also analyzed with patch-clamp recording on spinal cord slices. RESULTS: Fifty–kilo Dalton agrin (Agr50) at 0.2 and 2 ng suppressed DNP when given intrathecally, while 25- and 75-kDa agrin (Agr25, Agr75) had little effect. The suppressive effect of Agr50 lasted 4 hours after a single bolus injection. The difference in effects of Agr50 on mean withdrawal threshold (4.6 ± 2.2 g before treatment to 26 ± 0 g after treatment) compared with that of Agr25 (4.9 ± 2.0 g to 4.9 ± 2.0 g) and Agr75 (5.3 ± 2.3 g to 9.2 ± 2.5 g) was highly significant (P

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Electroencephalography and Brain Oxygenation Monitoring in the Perioperative Period

Maintaining brain function and integrity is a pivotal part of anesthesiological practice. The present overview aims to describe the current role of the 2 most frequently used monitoring methods for evaluation brain function in the perioperative period, ie, electroencephalography (EEG) and brain oxygenation monitoring. Available evidence suggests that EEG-derived parameters give additional information about depth of anesthesia for optimizing anesthetic titration. The effects on reduction of drug consumption or recovery time are heterogeneous, but most studies show a reduction of recovery times if anesthesia is titrated along processed EEG. It has been hypothesized that future EEG-derived indices will allow a better understanding of the neurophysiological principles of anesthetic-induced alteration of consciousness instead of the probabilistic approach most often used nowadays. Brain oxygenation can be either measured directly in brain parenchyma via a surgical burr hole, estimated from the venous outflow of the brain via a catheter in the jugular bulb, or assessed noninvasively by near-infrared spectroscopy. The latter method has increasingly been accepted clinically due to its ease of use and increasing evidence that near-infrared spectroscopy–derived cerebral oxygen saturation levels are associated with neurological and/or general perioperative complications and increased mortality. Furthermore, a goal-directed strategy aiming to avoid cerebral desaturations might help to reduce these complications. Recent evidence points out that this technology may additionally be used to assess autoregulation of cerebral blood flow and thereby help to titrate arterial blood pressure to the individual needs and for bedside diagnosis of disturbed autoregulation. Accepted for publication December 8, 2017. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Thomas W. L. Scheeren, MD, PhD, Department of Anaesthesiology, University Medical Center Groningen, PO Box 30 001, 9700 RB Groningen, the Netherlands. Address e-mail to t.w.l.scheeren@umcg.nl. © 2018 International Anesthesia Research Society

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In Response

No abstract available

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Comparison of Intranasal Dexmedetomidine and Oral Pentobarbital Sedation for Transthoracic Echocardiography in Infants and Toddlers: A Prospective, Randomized, Double-Blind Trial

BACKGROUND: Acquisition of transthoracic echocardiographic (TTEcho) images in children often requires sedation. The optimal sedative for TTEcho has not been determined. Children with congenital heart disease are repeatedly exposed to sedatives and anesthetics that may affect brain development. Dexmedetomidine, which in animals alters brain structure to a lesser degree, may offer advantages in this vulnerable population. METHODS: A prospective, randomized, double-blind trial enrolled 280 children 3–24 months of age undergoing outpatient TTEcho, comparing 2.5 µg·kg−1 intranasal dexmedetomidine to 5 mg·kg−1 oral pentobarbital. Rescue sedation, for both groups, was intranasal dexmedetomidine 1 µg·kg−1. The primary outcome was adequate sedation within 30 minutes without rescue sedation, assessed by blinded personnel. Secondary outcomes included number of sonographer pauses, image quality in relation to motion artifacts, and parental satisfaction. RESULTS: Success rates with a single dose were not different between sedation techniques; 85% in the pentobarbital group and 84% in the dexmedetomidine group (P = .8697). Median onset of adequate sedation was marginally faster with pentobarbital (16.5 [interquartile range, 13–21] vs 18 [16–23] minutes for dexmedetomidine [P = .0095]). Time from drug administration to discharge was not different (P = .8238) at 70.5 (64–83) minutes with pentobarbital and 70 (63–82) minutes with dexmedetomidine. Ninety-five percent of sedation failures with pentobarbital and 100% of dexmedetomidine failures had successful rescue sedation with intranasal dexmedetomidine. CONCLUSIONS: Intranasal dexmedetomidine was comparable to oral pentobarbital sedation for TTEcho sedation in infants and did not increase the risk of clinically important adverse events. Intranasal dexmedetomidine appears to be an effective "rescue" sedative for both failed pentobarbital and dexmedetomidine sedation. Dexmedetomidine could be a safer option for repeated sedation in children, but further studies are needed to assess long-term consequence of repeated sedation in this high-risk population. Accepted for publication December 1, 2017. Funding: This research was funded by a grant from the Children's Heart Association of Cincinnati and departmental support. The authors declare no conflicts of interest. Clinical trial registration: NCT02250820. LMA is a registered trademark of Teleflex Incorporated or its affiliates. Reprints will not be available from the authors. Address correspondence to Jeffrey W. Miller, MD, Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 2001, Cincinnati, OH. Address e-mail to Jeff.Miller@cchmc.org. © 2018 International Anesthesia Research Society

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Free flaps for head and neck cancer in paediatric and neonatal patients

Purpose of review To review recent literature on the subject of free tissue transfer options in paediatric head and neck surgery, with a particular emphasis on highlighting the advantages and disadvantages of different reconstructions in the paediatric patient. Recent findings Free tissue transfer in paediatric patients is predictable and applicable for a wide range of congenital and acquired defects in the head and neck. The free fibula flap is a mainstay of mandibular reconstruction and allows excellent implant-supported prosthodontic rehabilitation and growth potential at the recipient site with little or no donor site morbidity. Other less commonly explored options include the deep circumflex iliac artery flap, scapula flap and medial femoral condyle flap. The gracilis mucle remains the mainstay for facial reanimation with other options including pectoralis minor, rectus abdominis, extensor digitorum brevis and latissimus dorsi. There are compelling arguments for centralization of services and creative strategies in postoperative rehabilitation (e.g. play therapy). Summary Free flaps in paediatric patients are a viable option and may even have advantages relative to adults because of the absence of atherosclerosis, purported lower risk of vasospasm and proportionally larger vessel size. Transfer earlier in life maximizes functional potential and 'normalizes' treatment. Correspondence to Ross Elledge, Specialty Registrar (ST6) in Oral and Maxillofacial Surgery, Department of Oral and Maxillofacial Surgery, Queen Elizabeth Hospital, Birmingham B15 2TH, West Midlands, UK. Tel: +44(0)78 758 28359;. E-mail: rosselledge@doctors.net.uk Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Evidence establishing a link between prenatal and early-life stress and asthma development

Purpose of review The objective of this review is to provide an update on our evolving understanding of the effects of stress in pregnancy and during early development on the onset of asthma-related phenotypes across childhood, adolescence, and into early adulthood. Recent findings Accumulating evidence over the past 2 decades has established that prenatal and early-life psychological stress and stress correlates (e.g., maternal anxiety or depression) increase the risk for childhood respiratory disorders. Recent systematic reviews and meta-analyses including numerous prospective epidemiological and case–control studies substantiate a significant effect of prenatal stress and stress in early childhood on the development of wheeze, asthma, and other atopic-related disorders (eczema and allergic rhinitis), with many studies showing an exposure–response relationship. Offspring of both sexes are susceptible to perinatal stress, but effects differ. The impact of stress on child wheeze/asthma can also be modified by exposure timing. Moreover, coexposure to prenatal stress can enhance the effect of chemical stressors, such as prenatal traffic-related air pollution, on childhood respiratory disease risk. Understanding complex interactions among exposure dose, timing, child sex, and concurrent environmental exposures promises to more fully characterize stress effects and identify susceptible subgroups. Although the link between perinatal stress and childhood asthma-related phenotypes is now well established, pathways by which stress predisposes children to chronic respiratory disorders are not as well delineated. Mechanisms central to the pathophysiology of wheeze/asthma and lung growth and development overlap and involve a cascade of events that include disrupted immune, neuroendocrine, and autonomic function as well as oxidative stress. Altered homeostatic functioning of these integrated systems during development can enhance vulnerability to asthma and altered lung development. Summary Mechanistic studies that more comprehensively assess biomarkers reflecting alterations across interrelated stress response systems and associated regulatory processes, in both pregnant women and young children, could be highly informative. Leveraging high-throughput systems-wide technologies to include epigenomics (e.g., DNA methylation, microRNAs), transcriptomics, and microbiomics as well as integrated multiomics are needed to advance this field of science. Understanding stress-induced physiological changes occurring during vulnerable life periods that contribute to chronic respiratory disease risk could lead to the development of preventive strategies and novel therapeutic interventions. Correspondence to Rosalind J. Wright, MD, MPH, Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1198, New York, NY 10029, USA. Tel: +1 212 241 5287; fax: +1 212 289 8569; e-mail: rosalind.wright@mssm.edu Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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NKX6.1 hypermethylation predicts the outcome of stage II colorectal cancer patients undergoing chemotherapy

Abstract

Colorectal cancer (CRC) is a common malignancy worldwide. CRC patients in the same stage often present with dramatically different clinical scenarios. Thus, robust prognostic biomarkers are urgently needed to guide therapies and improve treatment outcomes. The NKX6.1 gene has been identified as a hypermethylation marker in cervical cancer, functioning as a metastasis suppressor by regulating epithelial–mesenchymal transition. Here, we investigated whether hypermethylation of NKX6.1 might be a prognostic biomarker for CRC. By analyzing the methylation and expression of NKX6.1 in CRC tissues and CRC cell lines. We quantitatively examined the NKX6.1 methylation levels in 151 pairs of CRC tissues by using methylation-specific polymerase chain reaction analysis and found that NKX6.1 was hypermethylated in 35 of 151 CRC tissues (23%). NKX6.1 gene expression was inversely correlated with the DNA methylation level in CRC cell lines in vitro. Then, we analyzed the association of NKX6.1 methylation with clinical characteristics of these CRC patients. Our data demonstrated that patients with NKX6.1 methylation presented poorer 5-year overall survival (P=0.0167) and disease-free survival (P=0.0083) than patients without NKX6.1 methylation after receiving adjuvant chemotherapy. Most importantly, these data revealed that stage II CRC patients with NKX6.1 methylation had poorer 5-year disease-free survival (P=0.0322) than patients without NKX6.1 methylation after adjuvant chemotherapy. Our results demonstrate that methylation of NKX6.1 is a novel prognostic biomarker in CRC and that it may be used as a predictor of the response to chemotherapy. This article is protected by copyright. All rights reserved.

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Wiring taste receptor cells to the central gustatory system

Abstract

Taste receptor cells in the tongue are epithelial in nature and turnover frequently. Taste receptor cell-associated neurons carrying bitter, sweet or sour signals never turnover and are hardwired to specific gustatory centers in the brain. How can ever-changing bitter or sweet receptors find never-changing neurons that must match the specificity of the signal? This article reviews a recent paper published in Nature (Lee et al., 2017, 548:330-333) that identified two molecules belonging to the semaphorin axon guidance family of molecules (SEMA3A and SEMA7A) that help maintain the "labelled line principle" between peripheral bitter or sweet receptors and their respective central projection area in the gustatory center.

This article is protected by copyright. All rights reserved.

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Evidence establishing a link between prenatal and early-life stress and asthma development

Purpose of review The objective of this review is to provide an update on our evolving understanding of the effects of stress in pregnancy and during early development on the onset of asthma-related phenotypes across childhood, adolescence, and into early adulthood. Recent findings Accumulating evidence over the past 2 decades has established that prenatal and early-life psychological stress and stress correlates (e.g., maternal anxiety or depression) increase the risk for childhood respiratory disorders. Recent systematic reviews and meta-analyses including numerous prospective epidemiological and case–control studies substantiate a significant effect of prenatal stress and stress in early childhood on the development of wheeze, asthma, and other atopic-related disorders (eczema and allergic rhinitis), with many studies showing an exposure–response relationship. Offspring of both sexes are susceptible to perinatal stress, but effects differ. The impact of stress on child wheeze/asthma can also be modified by exposure timing. Moreover, coexposure to prenatal stress can enhance the effect of chemical stressors, such as prenatal traffic-related air pollution, on childhood respiratory disease risk. Understanding complex interactions among exposure dose, timing, child sex, and concurrent environmental exposures promises to more fully characterize stress effects and identify susceptible subgroups. Although the link between perinatal stress and childhood asthma-related phenotypes is now well established, pathways by which stress predisposes children to chronic respiratory disorders are not as well delineated. Mechanisms central to the pathophysiology of wheeze/asthma and lung growth and development overlap and involve a cascade of events that include disrupted immune, neuroendocrine, and autonomic function as well as oxidative stress. Altered homeostatic functioning of these integrated systems during development can enhance vulnerability to asthma and altered lung development. Summary Mechanistic studies that more comprehensively assess biomarkers reflecting alterations across interrelated stress response systems and associated regulatory processes, in both pregnant women and young children, could be highly informative. Leveraging high-throughput systems-wide technologies to include epigenomics (e.g., DNA methylation, microRNAs), transcriptomics, and microbiomics as well as integrated multiomics are needed to advance this field of science. Understanding stress-induced physiological changes occurring during vulnerable life periods that contribute to chronic respiratory disease risk could lead to the development of preventive strategies and novel therapeutic interventions. Correspondence to Rosalind J. Wright, MD, MPH, Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1198, New York, NY 10029, USA. Tel: +1 212 241 5287; fax: +1 212 289 8569; e-mail: rosalind.wright@mssm.edu Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Clinicopathological and 123I-FP-CIT SPECT correlations in patients with dementia

Abstract

The relationship between clinicopathologic diagnosis and ¹²³I-FP-CIT SPECT in 18 patients with dementia (12 with Lewy body disease) from one center in the United States was assessed. The sensitivity and specificity of abnormal ¹²³I-FP-CIT SPECT with reduced striatal uptake on visual inspection for predicting Lewy body disease were 91.7% and 83.3%, respectively. The mean calculated putamen to occipital ratio (mPOR) based on regions of interest was significantly reduced in Lewy body disease compared to non-Lewy body disease cases (P = 0.002). In this study, abnormal ¹²³I-FP-CIT SPECT was strongly associated with underlying Lewy body disease pathology, supporting the utility of ¹²³I-FP-CIT SPECT in the clinical diagnosis of dementia with Lewy bodies.

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Hydration prevents chronic hyperglycaemic patients from neurological deterioration post-ischaemic stroke

Objectives

To determine whether chronic hyperglycaemia predisposes patients to dehydration, which may promote neurological deterioration, and to investigate whether dehydration control improves functional outcome.

Patients and Methods

This study included 355 patients hospitalized with acute ischaemic stroke and diabetes mellitus who fulfilled the glycaemic gap ≤0. We used the following cut-offs: (i) no chronic hyperglycaemia (glycated haemoglobin A1c [HbA1c] < 7%) and (ii) chronic hyperglycaemia (HbA1c ≥ 7%). The chronic hyperglycaemic patients were randomly divided into the control group and the hydration group. Hydration therapy was only initiated in the hydration group. The blood urea nitrogen (BUN)/creatinine (Cr) ratio was used as an indicator of dehydration. Stroke severity on admission and discharge was assessed by means of National Institutes of Health Stroke Scale (NIHSS).

Results

The mean baseline BUN/Cr ratios were higher in the control group and hydration group than in the no chronic hyperglycaemia group. The mean BUN/Cr ratio decreased from 91.22 ± 29.95 on the first day to 77.03 ± 18.23 on the third day (P < .001) in the hydration group. On the third day after admission, there was no significant difference in the BUN/Cr ratio between the hydration group and the no chronic hyperglycaemia group (P = .831). Moreover, neurological deterioration was highest in the control group (33.6%, 36/107), followed by the hydration group (10.5%, 11/105) and the no chronic hyperglycaemia group (5.6%, 8/143).

Conclusions

Chronic hyperglycaemia was associated with the admission NIHSS score and neurological deterioration after excluding the effect of stress hyperglycaemia. Furthermore, hydration therapy may help prevent neurological deterioration.

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Electroclinical findings and long-term outcomes in epileptic patients with inv dup (15)

Objective

To define the electroclinical phenotype and long-term outcomes in a cohort of patients with inv dup (15) syndrome.

Material and Methods

The electroclinical data of 45 patients (25 males) affected by inv dup (15) and seizures were retrospectively analysed, and long-term follow-up of epilepsy was evaluated.

Results

Epilepsy onset was marked by generalized seizures in 53% of patients, epileptic spasms in 51%, focal seizures in 26%, atypical absences in 11% and epileptic falls in 9%. The epileptic syndromes defined were: generalized epilepsy (26.7%), focal epilepsy (22.3%), epileptic encephalopathy with epileptic spasms as the only seizure type (17.7%) and Lennox-Gastaut syndrome (33.3%). Drug-resistant epilepsy was detected in 55.5% of patients. There was a significant higher prevalence of seizure-free patients in those with seizure onset after the age of 5 years and with focal epilepsy, with respect to those with earlier epilepsy onset because most of these later developed an epileptic encephalopathy (69.2% vs 34.4%; P = .03), usually Lennox-Gastaut Syndrome in type. In fact, among patients with early-onset epilepsy, those presenting with epileptic spasms as the only seizure type associated with classical hypsarrhythmia achieved seizure freedom (P < .001) compared to patients with spasms and other seizure types associated with modified hypsarrhythmia.

Conclusions

Epilepsy in inv dup (15) leads to a more severe burden of disease. Frequently, these patients show drug resistance, in particular when epilepsy onset is before the age of five and features epileptic encephalopathy.

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A review discussing fluciclovine (18F) PET/CT imaging in the detection of recurrent prostate cancer

Future Oncology, Ahead of Print.


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The prognostic analysis of different metastatic patterns in extensive-stage small-cell lung cancer patients: a large population-based study

Future Oncology, Ahead of Print.


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Nutritional and Environmental Influences on Athlete Health and Performance

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Upper Respiratory Symptoms, Gut Health and Mucosal Immunity in Athletes

Abstract

Upper respiratory symptoms remain the most common illness in athletes. Upper respiratory symptoms during heavy training and competition may impair performance. Preventing illness is the primary reason for the use of supplements, such as probiotics and prebiotics, for maintaining or promoting gut health and immune function. While exercise-induced perturbations in the immune system may increase susceptibility to illness and infection, growing evidence indicates that upper respiratory symptoms are related to a breakdown in the homeostatic regulation of the mucosal immune system of the airways. Balancing protection of the respiratory tract with normal physiological functioning requires dynamic orchestration between a wide array of immune parameters. The intestinal microbiota regulates extra-intestinal immunity via the common mucosal immune system and new evidence implicates the microbiota of the nose, mouth and respiratory tract in upper respiratory symptoms. Omics' approaches now facilitate comprehensive profiling at the molecular and proteomic levels to reveal new pathways and molecules of immune regulation. New targets may provide for personalised nutritional and training interventions to maintain athlete health.

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Cover Image

The cover image, by P. Aïdan et al., is based on the Technical Note Bilateral vagal automatic periodic stimulation in single-incision transaxillary robotic total thyroidectomy, DOI 10.1111/coa.12698.

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Author Guidelines

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Issue Information

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Endoscopic ultrasonography (EUS)-guided laser ablation (LA) of adrenal metastasis from pancreatic adenocarcinoma

Abstract

Endoscopic ultrasonography (EUS)-guided laser ablation (LA) is potentially applicable to tumours in the left lobe of the liver and pancreas. This report seeks to introduce the novel use of EUS-guided LA for left adrenal metastases from pancreatic adenocarcinoma. A 70-year-old female was referred to our hospital for dull abdominal pain and tiredness for 1 month. Computed tomography (CT) discovered a 1.0 × 1.7 cm mass in the area of the left adrenal gland. The lesion was highly suspicious for metastasis due to her history of pancreatic adenocarcinoma 1 year ago, which was removed through radical surgery. Intraoperative frozen-section pathology revealed a tumour invading the left adrenal gland. The left adrenal mass was clearly visualised on EUS and exhibited irregular hyper-enhancement during contrast. The tumour was successfully treated by four sessions of EUS-guided LA. After the procedure, symptomatic relief was achieved and remained. At the 4-month follow-up, contrast-enhanced CT revealed that the volume of the target was significantly decreased. Here, we introduced a new method for left adrenal metastasis using thermal ablation through EUS. As a potential alternative access to the percutaneous approach, EUS-guided LA may provide a minimally invasive treatment to relieve the tumour burdens and symptoms when applied accurately.

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Congratulations to Abby Wade, CA Speech-Language-Hearing Association Outstanding Student Awardee!

Abby Wade

Congratulations to Abby Wade who was awarded the District 9 Outstanding Student award from the California Speech-Language-Hearing Association.  This award is given to a student who has demonstrated excellent academic work and a commitment to their discipline.

Abby is in her second year of the Speech-Language Pathology Program and besides being an excellent student and clinician, she demonstrates a strong commitment to professional service and to furthering the relationship between research and clinical practice.  Abby has been instrumental in developing a graduate student chapter of the National Student Speech-Language-Hearing Association at SDSU. Under her leadership as President, the chapter has developed a mentoring program across undergraduate and graduate students and graduate students and alumni, sent 20 students to attend the ASHA convention, and organized several service and fundraising events.

Abby and her peers will enjoy a productive spring semester where they will host an inaugural pre-professional training program and our annual Speech-Language Awareness and Information Day (SAID), send students to CSHA, and continue service and fundraising events. Further, Abby does all of this while also serving as coordinator of the Integrative Preschool Project in Dr. Pruitt-Lord's research lab and presenting research at various conferences. Abby is a rising leader in the profession!

The award will be presented to Abby Wade at the CSHA state meeting in Sacramento, March 2018.

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Developmental patterns and variation among early theropods

Abstract

Understanding ontogenetic patterns is important in vertebrate paleontology because the assessed skeletal maturity of an individual often has implications for paleobiogeography, species synonymy, paleobiology, and body size evolution of major clades. Further, for many groups the only means of confidently determining ontogenetic status of an organism is through the destructive process of histological sampling. Although the ontogenetic patterns of Late Jurassic and Cretaceous dinosaurs are better understood, knowledge of the ontogeny of the earliest dinosaurs is relatively poor because most species-level growth series known from these groups are small (usually, maximum of n ~ 5) and incomplete. To investigate the morphological changes that occur during ontogeny in early dinosaurs, I used ontogenetic sequence analysis (OSA) to reconstruct developmental sequences of morphological changes in the postcranial ontogeny of the early theropods Coelophysis bauri and Megapnosaurus rhodesiensis, both of which are known from large sample sizes (n = 174 and 182, respectively). I found a large amount of sequence polymorphism (i.e. intraspecific variation in developmental patterns) in both taxa, and especially in C. bauri, which possesses this variation in every element analyzed. Megapnosaurus rhodesiensis is similar, but it possesses no variation in the sequence of development of ontogenetic characters in the tibia and tarsus. Despite the large amount of variation in development, many characters occur consistently earlier or later in ontogeny and could therefore be important morphological features for assessing the relative maturity of other early theropods. Additionally, there is a phylogenetic signal to the order in which homologous characters appear in ontogeny, with homologous characters appearing earlier or later in developmental sequences of early theropods and the close relatives of dinosaurs, silesaurids. Many of these morphological features are important characters for the reconstruction of archosaurian phylogeny (e.g. trochanteric shelf). Because these features vary in presence or appearance with ontogeny, these characters should be used with caution when undertaking phylogenetic analyses in these groups, since a specimen may possess certain character states owing to ontogenetic stage, not evolutionary relationships.

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Differentiation and classification of thoracolumbar transitional vertebrae

Abstract

The literature states that transitional vertebrae at any junction are characterized by features retained from two adjacent regions in the vertebral column. Currently, there is no published literature available that describes the prevalence or morphology of thoracolumbar transitional vertebrae (TLTV). The aim of this study was to identify the qualitative characteristics of transitional vertebrae at the thoracolumbar junction and establish a technique to differentiate the various subtypes that may be found. A selection of vertebral columns from skeletal remains (n = 35) were evaluated in this study. Vertebrae were taken based on features that are atypical for vertebrae in each relative region. The transitional vertebrae were qualitatively identified based on overlapping thoracic and lumbar features of vertebrae at the thoracolumbar junction. The following general overlapping characteristics were observed: aplasia or hypoplasia of the transverse process, irregular orientation on the superior articular process and atypical mammillary bodies. The results show that the most frequent location of the transitional vertebrae was in the thoracic region (f = 23). The second most frequent location was in the lumbar region (f = 10). In two specimens of the selection (f = 2), an additional 13th thoracic vertebra was present which functioned as a transitional vertebra. This study concluded that one can accurately identify the characteristics of transitional vertebrae at the thoracolumbar junction. In addition, the various subtypes can be differentiated according to the region in the vertebral column the vertebra is located in and the relative number of vertebral segments in the adjacent regions of the vertebral column. This provides a qualitative tool for researchers to differentiate the transitional vertebrae from distinctly different typical thoracic or lumbar vertebrae at the thoracolumbar junction.

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Changes in biodistribution on 68 Ga-DOTA-Octreotate PET/CT after long acting somatostatin analogue therapy in neuroendocrine tumour patients may result in pseudoprogression

Abstract

Background

To evaluate the effects of long-acting somatostatin analogue (SSA) therapy on ⁶⁸Ga-DOTA-octreotate (GaTate) uptake at physiological and metastatic sites in neuroendocrine tumour (NET) patients.

Methods

Twenty-one patients who underwent GaTate PET/CT before and after commencement of SSA therapy were reviewed. Maximum standardized uptake values (SUVmax) were measured in normal organs. Changes in uptake of 49 metastatic lesions in 12 patients with stable disease were also compared. Serum chromogranin-A (CgA) levels were available for correlation between scans in 17/21 patients.

Results

Mean thyroid, spleen and liver SUVmax decreased significantly following SSA therapy from a baseline of 5.9 to 3.5, 30.3 to 23.1 and 10.3 to 8.0, respectively (p = < 0.0001 for all). Pituitary SUVmax increased from 10.2 to 11.0 (p = 0.004) whereas adrenal and salivary gland SUVmax did not change. Tumour SUVmax increased in 7 of 12 patients with stable disease; CgA was stable or decreasing in 5 of these patients. 30/49 (61%) metastatic lesions had an increase in SUVmax and lesion-to-liver uptake ratio increased in 40/49 (82%) following SSA therapy.

Conclusion

Long-acting SSA therapy decreases GaTate uptake in the thyroid, spleen and liver but in most cases increases intensity of uptake within metastases. This has significant implications for interpretation of GaTate PET/CT following commencement of therapy as increased intensity alone may not represent true progression. Our findings also suggest pre-dosing with SSA prior to PRRT may enable higher doses to be delivered to tumour whilst decreasing dose to normal tissues.

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Neuromyelitis optica spectrum disorder secondary to treatment with anti-PD-1 antibody nivolumab: the first report

Abstract

Background

Immune checkpoint blockade is developed as standard treatment for non-small cell lung cancer. However immune-related adverse events (irAE) have still unknown complications. Here, we report a patient with lung squamous cell carcinoma who developed neuromyelitis optica spectrum disorder with nivolumab.

Case presentation

A 75-year-old Japanese man with lung squamous cell carcinoma was administered nivolumab as second-line treatment. Two months after treatment with nivolumab, he presented acute paralysis in the bilateral lower limbs, sensory loss. Spinal magnetic resonance imaging showed T2 hyperintense lesions between C5-6 and Th12-L1. He was diagnosed with neuromyelitis optica spectrum disorder (NMOSD) by anti-aquaporin-4 antibody-positive in the serum and other examinations. After treatment, steroid reactivity was poor.

Conclusion

This is the first patient who developed anti-AQP4 antibody-positive NMOSD as a nivolumab-induced irAE. Clinicians should be aware of this kind of potential neurological complication by using immune check point inhibitor and start the treatment of this irAE as soon as possible.

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Shifting breast cancer surveillance from current hospital setting to a community based setting: a cost-effectiveness study

Abstract

Background

This study explores the effectiveness and cost-effectiveness of surveillance after breast cancer treatment provided in a hospital-setting versus surveillance embedded in the community-based National Breast Cancer Screening Program (NBCSP).

Methods

Using a decision tree, strategies were compared on effectiveness and costs from a healthcare perspective over a 5-year time horizon. Women aged 50–75 without distant metastases that underwent breast conserving surgery in 2003–2006 were selected from the Netherlands Cancer Registry (n = 14,093). Key input parameters were mammography sensitivity and specificity, risk of loco regional recurrence (LRR), and direct healthcare costs. Primary outcome measure was the proportion true test results (TTR), expressed as the positive and negative predictive value (PPV, NPV). The incremental cost-effectiveness ratio (ICER) is defined as incremental costs per TTR forgone.

Results

For the NBCSP-strategy, 13,534 TTR (8 positive; 13,526 negative), and 12,923 TTR (387 positive; 12,536 negative) were found for low and high risks respectively. For the hospital-based strategy, 26,663 TTR (13 positive; 26,650 negative) and 24,883 TTR (440 positive; 24,443 negative) were found for low and high risks respectively. For low risks, the PPV and NPV for the NBCSP-based strategy were 3.31% and 99.88%, and 2.74% and 99.95% for the hospital strategy respectively. For high risks, the PPV and NPV for the NBCSP-based strategy were 64.10% and 98.87%, and 50.98% and 99.71% for the hospital-based strategy respectively. Total expected costs of the NBCSP-based strategy were lower than for the hospital-based strategy (low risk: €1,271,666 NBCSP vs €2,698,302 hospital; high risk: €6,939,813 NBCSP vs €7,450,150 hospital), rendering ICERs that indicate cost savings of €109 (95%CI €95–€127) (low risk) and €43 (95%CI €39–€56) (high risk) per TTR forgone.

Conclusion

Despite expected cost-savings of over 50% in the NBCSP-based strategy, it is nearly 50% lower accurate than the hospital-based strategy, compromising the goal of early detection of LRR to an extent that is unlikely to be acceptable.

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Direct augmented reality computed tomographic angiography technique (ARC): an innovation in preoperative imaging

Abstract

Background

Since the advent of free tissue transfer approximately 40 years ago, constant improvement particularly in the preoperative planning phase has led to flap success rate reaching 99% and improved patient outcomes. The use of imaging, such as computed tomographic angiography (CTA) or magnetic resonance angiography (MRA), for preoperative planning is now routine. However, current image modalities are restricted by being represented in two dimensions (2D) and have led to clinicians seeking novel methods of utilising the scan data, such as augmented (AR) or virtual reality (VR) and holograms. These mixed-reality devices facilitate a natural mode of visual perception and have the capacity to introduce tactile feedback. However, most AR devices are currently expensive, bulky and complicated and require tedious image registration processes. We illustrate our projector-based direct AR technique using CTA, or ARC, for preoperative planning.

Methods

Our bespoke ARC method consists of compact, affordable hardware (MacBook, Philips pocket projector and a 15-cm ruler) and free, open-source software (OsiriX). We have utilised this technique in six cases of perforator flaps of the thigh and abdomen (anterolateral thigh (ALT), transverse upper gracilis (TUG) and deep inferior epigastric artery perforator (DIEP) flaps.

Results

In all cases, 3D-reconstructed images of perforators from CTA were accurately projected onto the donor site. System calibration was rapid and convenient to use.

Conclusions

We illustrate a novel technique of projector-based AR CTA (or ARC) for preoperative planning in perforator flaps. The technique is affordable and readily reproducible.

Level of Evidence: Level IV, diagnostic study.

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Fc-mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models

A critical benchmark in the development of antibody-based therapeutics is demonstration of efficacy in preclinical mouse models of human disease, many of which rely on immunodeficient mice. However, relatively little is known about how the biology of various immunodeficient strains impacts the in vivo fate of these drugs. Here we used immunoPET radiotracers prepared from humanized, chimeric and murine monoclonal antibodies against four therapeutic oncologic targets to interrogate their biodistribution in four different strains of immunodeficient mice bearing lung, prostate, and ovarian cancer xenografts. The immunodeficiency status of the mouse host as well as both the biological origin and glycosylation of the antibody contributed significantly to the anomalous biodistribution of therapeutic monoclonal antibodies in an Fc receptor-dependent manner. These findings may have important implications for the preclinical evaluation of Fc-containing therapeutics and highlight a clear need for biodistribution studies in the early stages of antibody drug development.

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Keratin 19 expression in hepatocellular carcinoma is regulated by fibroblast-derived HGF via a MET-ERK1/2-AP1 and SP1 axis

Keratin (KRT) 19 is a poor prognostic marker for hepatocellular carcinoma (HCC), however regulatory mechanisms underlying its expression remain unclear. We have previously reported the presence of fibrous tumor stroma in KRT19-positive HCC, suggesting that crosstalk between cancer-associated fibroblasts (CAF) and tumor epithelial cells could regulate KRT19 expression. This was investigated in this study using an in vitro model of paracrine interaction between HCC cell lines (HepG2, SNU423) and hepatic stellate cells (HSC), a major source of hepatic myofibroblasts. HSCs upregulated transcription and translation of KRT19 in HCC cells via paracrine interactions. Mechanistically, hepatocyte growth factor (HGF) from HSCs activated c-MET and the MEK-ERK1/2 pathway which upregulated KRT19 expression in HCC cells. Further, AP1 (JUN/FOSL1) and SP1, downstream transcriptional activators of ERK1/2, activated KRT19 expression in HCC cells. In clinical specimens of human HCC (n=339), HGF and KRT19 protein expression correlated with CAF levels. In addition, HGF or MET protein expression was associated with FOSL1 and KRT19 expression and was found to be a poor prognostic factor. Analysis of data from The Cancer Genome Atlas also revealed KRT19 expression was closely associated with CAF and MET-mediated signaling activities. These results provide insights into the molecular background of KRT19-positive HCC that display an aggressive phenotype.

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Myeloma Cells are Activated in Bone Marrow Microenvironment by the CD180/MD-1 Complex which Senses Lipopolysaccharide

Multiple myeloma (MM) cells acquire dormancy and drug resistance via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment. Elucidating the mechanisms underlying the regrowth of dormant clones may contribute to further improvement of the prognosis of MM patients. In this study, we find that the CD180/MD-1 complex, a non-canonical LPS receptor, is expressed on MM cells but not on normal counterparts, and its abundance is markedly upregulated under adherent and hypoxic conditions. Bacterial LPS and anti-CD180 antibody, but not other TLR ligands, enhanced the growth of MM cells via activation of MAP kinases ERK and JNK in positive correlation with expression levels of CD180. Administration of LPS significantly increased the number of CD180/CD138 double-positive cells in a murine xenograft model when MM cells were inoculated with direct attachment to BMSC. Knockdown of CD180 canceled the LPS response in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the CD180 gene. Both cell adhesion and hypoxia activated transcription of the CD180 gene by increasing Ikaros expression and its binding to the promoter region. Pharmacological targeting of Ikaros by the immunomodulatry drug lenalidomide ameliorated the response of MM cells to LPS in a CD180-dependent manner in vitro and in vivo. Thus, the CD180/MD-1 pathway may represent a novel mechanism of growth regulation of MM cells in a BM milieu and may be a therapeutic target of preventing the regrowth of dormant MM cells.

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Downregulation of membrane trafficking proteins and lactate conditioning determine loss of dendritic cell function in lung cancer

Restoring antigen presentation for efficient and durable activation of tumor-specific CD8+ T cell responses is pivotal to immunotherapy, yet the mechanisms that cause subversion of dendritic cells (DC) functions are not entirely understood, limiting the development of targeted approaches. In this study, we show that bone fide DC resident in lung tumor tissues or DC exposed to factors derived from whole lung tumors become refractory to endosomal and cytosolic sensor stimulation and fail to secrete IL-12 and IFN-I. Tumor conditioned DC exhibited downregulation of the SNARE VAMP3, a regulator of endosomes trafficking we found to be required for cross-presentation of tumor antigens and DC-mediated tumor rejection. Dissection of cell-extrinsic suppressive pathways identified lactic acid in the tumor microenvironment as sufficient to inhibit type-I interferon downstream of TLR3 and STING. DC conditioning by lactate also impacted adaptive function, accelerating antigen degradation and impairing cross-presentation. Importantly, DC conditioned by lactate failed to prime anti-tumor responses in vivo. These findings provide a new mechanistic viewpoint to the concept of DC suppression and hold potential for future therapeutic approaches.

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Tumor-stroma IL-1{beta}-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer

Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of interleukin-1 receptor associated kinase 4 (IRAK4) suppresses NF-κB activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NF-κB. IRAK4 expression in CAF promoted NF-κB activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL-1β as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL-1β rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL-1β expression associated strongly with poor overall survival. Together, our studies establish a tumor-stroma IL-1β-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC.

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Anti-estrogen therapy increases plasticity and cancer stemness of prolactin-induced ER{alpha}+ mammary carcinomas

Although anti-estrogen therapies are successful in many patients with estrogen receptor alpha-positive (ERα+) breast cancer, 25-40% fail to respond. Although multiple mechanisms underlie evasion of these treatments, including tumor heterogeneity and drug-resistant cancer stem cells (CSCs), further investigations have been limited by the paucity of preclinical ERα+ tumor models. Here we examined a mouse model of prolactin-induced aggressive ERα+ breast cancer, which mimics the epidemiologic link between prolactin exposure and increased risk for metastatic ERα+ tumors. Like a subset of ERα+ patient cancers, the prolactin-induced adenocarcinomas contained two major tumor subpopulations that expressed markers of normal luminal and basal epithelial cells. CSC activity was distributed equally across these two tumor subpopulations. Treatment with the selective estrogen receptor downregulator (SERD), ICI 182,780 (ICI), did not slow tumor growth, but induced adaptive responses in CSC activity, increased markers of plasticity including target gene reporters of Wnt/Notch signaling and epithelial-mesenchymal transition, and increased double positive (K8/K5) cells. In primary tumorsphere cultures, ICI stimulated CSC self-renewal, and was able to overcome the dependence of self-renewal upon Wnt or Notch signaling individually, but not together. Our findings demonstrate that treatment of aggressive mixed lineage ERα+ breast cancers with a SERD does not inhibit growth, but rather evokes tumor cell plasticity and regenerative CSC activity, predicting likely negative impacts on patient tumors with these characteristics.

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Opium Consumption and the Incidence of Cancer: Does Opium Account as an Emerging Risk Factor for Gastrointestinal Cancer?

Abstract

Purpose

Some epidemiological studies have shown an association between opium consumption and the incidence of gastrointestinal (GI) cancer. The present study was designed to investigate the effects of opium on the initiation of GI cancer in rats.

Methods

Forty-five rats were randomly divided into three groups; each received different treatment for 40 weeks. The rats in group 1 received purified water, while animals in group 2 were treated with 5 mg/kg diethylnitrosamine (DEN) orally for 8 weeks and continued with purified water by the end of the experiment. The third experimental group received 300 mg/kg opium for 16 weeks and then continued with 50 mg/kg phenobarbital by the end of the 40th week. The growth of tumors in the treated groups was assessed by histological changes and the up/down expression of p53, cdkn1, cdk2, e-cdh, and n-cdh genes in different parts of GI tract.

Results

Histological examinations revealed that DEN was able to induce the growth of tumor in GI tract as shown by active mitotic figure in different regions of GI system and hyperplasia of hepatocytes associated with infiltration of inflammatory cells, intestinal villous hypertrophy, and colorectal adenoma. There was also significant (p < 0.05) overexpression of p53, cdk2, and n-Cdh genes in different parts of digestive system in DEN-treated group. However, these pathological changes and the degradation of gene expression were not observed in the opium-treated group.

Conclusion

The results of this study suggest that the opium does not promote the initiation of cancer in GI tract.

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Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced cancers of the gastrointestinal tract or anus

Purpose: Genomic profiling of tumor biopsies from advanced gastrointestinal (GI) and anal cancers is increasingly used to inform treatment. In some cases, tissue biopsy can be prohibitive, and we sought to investigate whether analysis of blood-derived circulating tumor DNA (ctDNA) may provide a minimally invasive alternative. Experimental Design: Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 417 patients with GI carcinomas to assess the presence of genomic alterations (GA) and compare with matched tissue samples. Results: Evidence of ctDNA was detected in 344/417 (82%) samples, and of these ≥1 one reportable GA was detected in 89% (306/344) of samples. Frequently altered genes were TP53 (72%), KRAS (35%), PIK3CA (14%), BRAF (8%), and EGFR (7%). In temporally matched ctDNA and tissue samples available from 25 patients, 86% of alterations detected in tissue were also detected in ctDNA, including 95% of short variants, but only 50% of amplifications. Conversely, 63% of alterations detected in ctDNA were also detected in matched tissue. Examples demonstrating clinical utility are presented. Conclusions: Genomic profiling of ctDNA detected potentially clinically relevant GAs in a significant subset of patients with GI carcinomas. In these tumor types, most alterations detected in matched tissue were also detected in ctDNA, and, with the exception of amplifications, ctDNA sequencing routinely detected additional alterations not found in matched tissue, consistent with tumor heterogeneity. These results suggest feasibility and utility of ctDNA testing in advanced GI cancers as a complementary approach to tissue testing, and further investigation is warranted.

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Nitric Oxide Production by Myeloid Derived Suppressor Cells Plays a Role in Impairing Fc Receptor-Mediated Natural Killer Cell Function.

Purpose: Monoclonal antibodies (mAb) are used to treat solid and hematological malignancies, and work in part through Fc receptors (FcR) on natural killer cells (NK). However, FcR mediated functions of NK cells from cancer patients are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy.  Experimental Design: Co-cultures of autologous NK cells and MDSC from cancer patients were used to study the effect of MDSC on NK cell FcR mediated functions including antibody dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro. Mouse breast cancer models were utilized to study the effect of MDSC on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and a MDSC targeting agent.  Results: Cancer patient MDSC were found to significantly inhibit NK cell FcR mediated functions including ADCC, cytokine production, and signal transduction in a contact independent manner. In addition, adoptive transfer of MDSC abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK cell functions and signal transduction. Finally, non-specific elimination of MDSC or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer. Conclusions: MDSC antagonize NK cell FcR mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSC or inhibition of nitric oxide production offers a strategy to improve mAb therapy.

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Acquired resistance of ER- positive breast cancer to endocrine treatment confers an adaptive sensitivity to TRAIL through post-translational downregulation of c-FLIP

Purpose: One-third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need.  Here we identify a specific post-translational modification that occurs during endocrine resistance and which results in tumour susceptibility to the apoptosis inducer TNF-Related Apoptosis-Inducing Ligand (TRAIL). This potentially offers a novel stratified approach to targeting endocrine resistant breast cancer. Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL.  Tumour viability, cancer stem cell (CSC) viability (tumourspheres), tumour growth kinetics and metastatic burden were assessed.  Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed.  Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumours. Results: Breast cancer cell lines with acquired resistance to tamoxifen-(TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls.  Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo. In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve tumours, while systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumour growth, CSC-like activity and metastases. Acquired TRAIL sensitivity correlated with a reduction in intra-cellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP. Conclusions:These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine resistant breast cancers, which has both therapeutic and prognostic potential.

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What is it about a cancer diagnosis that would worry people? A population-based survey of adults in England

Abstract

Background

Surveys indicate quite high prevalence of cancer worry in the general population, but little is known about what it is about cancer that worries people. A better understanding of the origins of cancer worry may help elucidate previously found inconsistencies in its behavioural effect on cancer prevention, screening uptake, and help-seeking for symptoms. In this study, we explore the prevalence and population distribution of general cancer worry and worries about specific aspects of cancer previously identified.

Methods

A population-based survey of 2048 English adults (18–70 years, April–May 2016), using face-to-face interviews to assess demographic characteristics, general cancer worry and twelve sources of cancer worry (adapted from an existing scale), including the emotional, physical, and social consequences of a diagnosis.

Results

In general, a third of respondents (37%) never worried about cancer, 57% worried occasionally/sometimes, and 6% often/very often. In terms of specific worries, two thirds would be 'quite a bit' or 'extremely' worried about the threat to life and emotional upset a diagnosis would cause. Half would worry about surgery, radiotherapy, chemotherapy, and loss of control over life. Worries about the social consequences were less commonly anticipated: just under half would worry about financial problems or their social roles, and a quarter would be worried about effects on identity, important relationships, gender role, and sexuality. Women and younger people reported more frequent worry about getting cancer, and would be more worried about the emotional, physical, and social consequences of a cancer diagnosis (p < .001). Those from ethnic minority backgrounds reported less frequent worry about getting cancer than their white counterparts, but would be equally worried about the emotional and physical impact of a cancer diagnosis, and worried more about the social consequences of a cancer diagnosis (p < .05).

Conclusions

The majority of English adults worry at least occasionally about getting cancer, and would be most worried about the emotional and physical impact of a cancer diagnosis. Distinguishing between the various worries that cancer can evoke may help inform efforts to allay undue worries in those who are deterred by them from engaging with cancer prevention and early detection.

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Loss in working years after a breast cancer diagnosis

Loss in working years after a breast cancer diagnosis

Loss in working years after a breast cancer diagnosis, Published online: 23 January 2018; doi:10.1038/bjc.2017.456

Loss in working years after a breast cancer diagnosis

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A novel Epstein–Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy

A novel Epstein–Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy

A novel Epstein–Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy, Published online: 23 January 2018; doi:10.1038/bjc.2017.475

A novel Epstein–Barr virus-latent membrane protein-1-specific T-cell receptor for TCR gene therapy

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Back from the dead: TIL apoptosis in cancer immune evasion

Back from the dead: TIL apoptosis in cancer immune evasion

Back from the dead: TIL apoptosis in cancer immune evasion, Published online: 23 January 2018; doi:10.1038/bjc.2017.483

Back from the dead: TIL apoptosis in cancer immune evasion

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A core matrisome gene signature predicts cancer outcome

A core matrisome gene signature predicts cancer outcome

A core matrisome gene signature predicts cancer outcome, Published online: 23 January 2018; doi:10.1038/bjc.2017.458

A core matrisome gene signature predicts cancer outcome

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Comment on ‘Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer’

Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer'

Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer', Published online: 23 January 2018; doi:10.1038/bjc.2017.416

Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer'

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Development and validation of a plasma-based melanoma biomarker suitable for clinical use

Development and validation of a plasma-based melanoma biomarker suitable for clinical use

Development and validation of a plasma-based melanoma biomarker suitable for clinical use, Published online: 23 January 2018; doi:10.1038/bjc.2017.477

Development and validation of a plasma-based melanoma biomarker suitable for clinical use

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Reply to ‘Comment on ‘Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer”

Reply to 'Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer"

Reply to 'Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer", Published online: 23 January 2018; doi:10.1038/bjc.2017.464

Reply to 'Comment on 'Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer"

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Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota

Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota

Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota, Published online: 23 January 2018; doi:10.1038/bjc.2017.435

Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota

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Clinical Trial Shows Significant Hearing Improvement from ASNHL Treatment

Swiss biopharmaceutical company Auris Medical is developing AM-111, a treatment for acute inner ear (sensorineural) hearing loss (ASNHL). Phase 2 and Phase 3 clinical trials of AM-111 resulted in clinically significant hearing improvement among a population of test subjects.

AM-111, which has both European Medicines Agency and US Food & Drug Administration (FDA) orphan drug treatment designation for ASNHL including hearing loss from acoustic trauma, ISSNHL or idiopathic sudden sensorineural hearing loss, and surgery-induced acoustic trauma, is formulated in biodegradable, biocompatible gel that contains an intracellular transporter, and D-JNKI-1 (brimapitide), which is an inhibitor of the JNK stress kinase. AM-111 treatment is delivered in a single dose locally administered into the middle ear by an ENT physician/otolaryngologist.

JNK or c-Jun N-terminal kinase, which is also referred to stress-activated protein kinase (SAPK), is a group of multifunctional-signaling molecules that become active in response to various cellular stresses and to inflammatory mediators. AM-111's 2015 clinical development plan explains that JNK is a signal transmitting enzyme that regulates a number of important cellular activities including apoptosis or death of cells. Here's is a separate research on JNK.

AM-111 prevents/reduces chronic hearing loss and supports recovery processes by entering into cells and attaching to JNK to deter apoptosis reaction and inflammatory response, which may lead to permanent loss of hair cells and cochlear neurons.

At the end of AM-111's Phase 2 clinical trial, which was administered to 210 sufferers of either ASNHL following acute noise trauma or ISSNHL, results show evident improvement in hearing and speech discrimination in patients with severe to profound cases of hearing loss. Results of HEALOS Phase 3 trial, which was conducted in several countries in Europe and Asia double-blind, randomized, and was a placebo-controlled study administered to 256 ASNHL sufferers from severe to profound sudden deafness within 72 hours from onset, provide clinical evidence that AM-111 significantly improved hearing in the subpopulation of patients with profound hearing loss. This study information sheet shows the brief methodology and results released this month.

Following the promising new data from HEALOS trial, Professor Hinrich Staecker, MD, PhD, of the Department of Otolaryngology-Head and Neck Surgery at University of Kansas Medical Center, said in a press release that "Profound sudden deafness can have a major impact on patients' cognitive and auditory function as well as quality of life. It has a poor prognosis, frequently with little or no hearing recovery, and there are no effective treatments. If approved, AM-111 has the potential to address the unmet need for novel therapeutics which can improve hearing during the acute stage of profound sudden deafness and reduce the substantial risk of severe life-long hearing impairment."

Auris Medical plans to discuss the regulatory pathway based on the clinical trials' results.

Published: 1/23/2018 3:43:00 PM

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Seltene Differenzialdiagnose therapierefraktärer cervikaler Lymphadenitis und Fieber bei einem Kind

Laryngo-Rhino-Otol
DOI: 10.1055/s-0044-100258

© Georg Thieme Verlag KG Stuttgart · New York

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HPV bei Oropharynxkarzinomen in der 8. Ausgabe der TNM-Klassifikation

Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-123028

Die 8. Ausgabe der TNM-Klassifikation ist seit dem 01.01.2017 gültig und beinhaltet Veränderungen dieser Klassifikation für verschiedene Malignome. Solche Änderungen zeigen sich im Kopf-Hals-Bereich für Plattenepithelkarzinome des Oropharynx (OPC): es wird zwischen HPV-positiven und HPV-negativen Karzinomen unterschieden, um durch die daran adaptierte neue Stadieneinteilung die Prognose der Patienten mit OPC insgesamt besser abschätzen zu können. Die Anwendung der neuen TNM-Klassifikation beim HPV-positiven OPC führt in vielen Fällen zu einem signifikanten Downstaging von lokal fortgeschrittener (UICC III/IV) hin zu lokal begrenzter (UICC I/II) Erkrankung. Letzterem zugrundliegende Daten mit einem signifikanten Überlebensvorteil der Patienten mit HPV-positiven OPC entstammen bisher ausschließlich retrospektiven Analysen, die nicht dafür ausgelegt sind zu testen, ob deeskalierte Therapieregime den Überlebensvorteil dieser Patienten erhalten können. Dieser CME-Beitrag versucht Antworten auf offene Fragen hinsichtlich Pathologie, Tumorcharakteristik und Lebensstil-Faktoren zu geben, die für die Prognose dieser Patientenpopulation eine Rolle spielen. Nur die genaue Kenntnis aller Parameter, die die Überlebenszeiten von Patienten mit OPC beeinflussen und die präzise Interpretation vorliegender und noch zu erhebender Daten wird es ermöglichen, den Patienten entsprechend ihrem Risikoprofil die bestmögliche Therapie anzubieten und so das bestmögliche Behandlungsergebnis zu erzielen.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Expanded Endoscopic Endonasal Resection of Retrochiasmatic Craniopharyngioma

J Neurol Surg B
DOI: 10.1055/s-0038-1623524

This video abstract demonstrates the use of the expanded endoscopic endonasal approach for the resection of a retrochiasmatic craniopharyngioma. These tumors are notoriously difficult to treat, and many approaches have been tried to facilitate safe and effective resection. The endoscopic endonasal approach has been increasingly utilized for selected sellar/suprasellar pathology. We present the case of a 39-year-old man who was found to have a cystic, partially calcified suprasellar mass consistent with a craniopharyngioma. To facilitate robust skull base repair, a vascularized nasoseptal flap was harvested. A wide sphenoidotomy was performed and the sella and tuberculum were exposed. After the dural opening and arachnoid dissection, the stalk was identified, merging seamlessly with the tumor capsule. The lesion was then internally debulked with the use of an ultrasonic aspirator. The capsule was then dissected off of the optic chiasm, thalamus, and hypothalamus. The cavity was inspected with an angled endoscope to ensure complete resection. A multilayered reconstruction was performed using autologous fascia lata, the previously harvested nasoseptal flap, and dural sealant. Postoperatively, the patient did have expected panhypopituitarism but remained neurologically intact and had improvement in his vision. In conclusion, this video demonstrates how an expanded endonasal approach can be used to safely resect a craniopharyngioma, even when in close proximity to delicate structures such as the optic chiasm.The link to the video can be found at: https://youtu.be/tahjHmrXhc4.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Whole Versus Partial Bladder Radiation: Use of an Image-guided Hypofractionated IMRT Bladder-preservation Protocol

Objectives: To report our institutional experience using definitive chemoradiation via whole bladder (WB) and partial bladder (PB) treatment in muscle-invasive bladder cancer. Combining intensity-modulated radiation therapy with image-guidance can improve the therapeutic ratio. Materials and Methods: Retrospective analysis of 26 patients with clinical stage T2-4 N0-2 M0 urothelial cancer treated in 2009 to 2012; 16 received WB radiation and 10 received PB radiation. PB/tumor boost volume included visibly thickened bladder wall or tumor localized on cystoscopy. WB radiation delivered 45 to 50.4 Gy to bladder/lymph nodes, then sequential 19.8 to 21.6 Gy tumor boost (1.8 Gy/fx). PB radiation was 45 to 50 Gy to lymph nodes (1.8 to 2 Gy/fx) and simultaneous integrated boost to 55 to 62.5 Gy to tumor only (2.2 to 2.5 Gy/fx). The primary endpoint was local control, defined as no muscle-invasive recurrence. Secondary endpoints were overall survival, toxicity, and cost. Results: Mean age was 77 and median follow-up was 20 months. Freedom from local recurrence was 86% at 2 years (PB 100%, WB 77%). Overall survival was 80% at 1 year (PB 88%, WB 75%), and 55% at 2 years (PB 70%, WB 48%, P=0.38). Failure was predominantly distant. Toxicities were minimal (3 late grade 3 ureteral, 1 acute grade 4 renal), and all resolved. No cystectomies were performed for toxicity. Hypofractionation reduces treatment time and costs by one third. Conclusions: Image-guided hypofractionated PB radiation provides local control with similar survival to WB therapy, with minimal toxicity. Hypofractionation also offers time and cost advantages. Our results need to be validated in a larger, multi-institutional cohort.

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Hypofractionated Versus Standard Fractionated Proton-beam Therapy for Low-risk Prostate Cancer: Interim Results of a Randomized Trial PCG GU 002

Objective: To identify differences in terms of quality of life, the American Urological Association Symptom Index (AUA), or adverse events (AEs) among patients with prostate cancer treated with either standard fractionation or hypofractionation proton-beam therapy. Materials and Methods: Patients were prospectively randomized to receive 38 Gy relative biological effectiveness (RBE) in 5 treatments (n=49) or 79.2 Gy RBE in 44 treatments (n=33). All patients had low-risk prostate cancer and were treated with proton therapy using fiducial markers and daily image guidance. Results: Median follow-up for both groups was 18 months; 33 patients had follow-up of 2 years or longer. Baseline median (range) AUA was 4.7 (0 to 13) for the 38 Gy RBE arm and 4.8 (0 to 17) for the 79.2 Gy RBE arm. We observed no difference between the groups regarding the Expanded Prostate Index Composite urinary, bowel, or sexual function scores at 3, 6, 12, 18, or 24 months after treatment. The only significant difference was the AUA score at 12 months (8 for the 38 Gy RBE arm vs. 5 for the 79.2 Gy RBE arm; P=0.04); AUA scores otherwise were similar between groups. No grade 3 or higher AEs occurred in either arm. Conclusions: Patients treated with proton therapy in this randomized trial tolerated treatment well, with excellent quality-of-life scores, persistent low AUA, and no grade 3 or higher AEs on either arm. We showed no apparent clinical difference in outcomes with hypofractionated proton-beam therapy compared with standard fractionation on the basis of this interim analysis.

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The Birth of the Illegitimate Linear No-Threshold Model: An Invalid Paradigm for Estimating Risk Following Low-dose Radiation Exposure

This paper examines the birthing process of the linear no-threshold model with respect to genetic effects and carcinogenesis. This model was conceived >70 years ago but still remains a foundational element within much of the scientific thought regarding exposure to low-dose ionizing radiation. This model is used today to provide risk estimates for cancer resulting from any exposure to ionizing radiation down to zero dose, risk estimates that are only theoretical and, as yet, have never been conclusively demonstrated by empirical evidence. We are literally bathed every second of every day in low-dose radiation exposure due to natural background radiation, exposures that vary annually from a few mGy to 260 mGy, depending upon where one lives on the planet. Irrespective of the level of background exposure to a given population, no associated health effects have been documented to date anywhere in the world. In fact, people in the United States are living longer today than ever before, likely due to always improving levels of medical care, including even more radiation exposure from diagnostic medical radiation (eg, x-ray and computed tomography imaging examinations) which are well within the background dose range across the globe. Yet, the persistent use of the linear no-threshold model for risk assessment by regulators and advisory bodies continues to drive an unfounded fear of any low-dose radiation exposure, as well as excessive expenditures on putative but unneeded and wasteful safety measures.

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Total Lifetime and Cancer-related Costs for Elderly Patients Diagnosed With Anal Cancer in the United States

Objective: To determine the lifetime and phase-specific cost of anal cancer management and the economic burden of anal cancer care in elderly (66 y and older) patients in the United States. Patients and Methods: For this study, we used Surveillance Epidemiology and End Results-Medicare linked database (1992 to 2009). We matched newly diagnosed anal cancer patients (by age and sex) to noncancer controls. We estimated survival time from the date of diagnosis until death. Lifetime and average annual cost by stage and age at diagnosis were estimated by combining survival data with Medicare claims. The average lifetime cost, proportion of patients who were elderly, and the number of incident cases were used to estimate the economic burden. Results: The average lifetime cost for patients with anal cancer was US$50,150 (N=2227) (2014 US dollars). The average annual cost in men and women was US$8025 and US$5124, respectively. The overall survival after the diagnosis of cancer was 8.42 years. As the age and stage at diagnosis increased, so did the cost of cancer-related care. The anal cancer–related lifetime economic burden in Medicare patients in the United States was US$112 million. Conclusions: Although the prevalence of anal cancer among the elderly in the United States is small, its economic burden is considerable.

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To What Extent Does Radiotherapy Improve the Quality of Life of Patients With Bone Metastasis?: A Prospective, Single-Institutional Study

Purpose/Objectives: Radiation therapy (RT) is an effective method of palliating painful bone metastases and improves the quality of life (QoL) of these patients. The purpose of this trial is 2-fold: to quantify the impact of RT in the QoL of patients with bone metastasis and to compare the QoL results between the most used schemes of RT at our Centre. Materials and Methods: A consecutive sample of patients with bone metastasis treated with RT in the Complejo Hospitalario de Navarra, Spain, was addressed between January 2011 and November 2012. The QoL was measured with the Quality of Life Questionnaire-C15-Palliative questionnaire, a short version of the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire-C30 for palliative care. Two assessments were proposed for each patient: one on the first day of the treatment and the other one a month after the end of the radiotherapy sessions. One hundred and sixteen patients completed the first questionnaire and 75 completed the second one (65%). Results: Significant differences appeared in 9 domains, with better QoL in the second assessment. Five areas (physical functioning, global, fatigue, nausea, dyspnea, and constipation) showed little change (between 5 and 9 points), 3 (emotional functioning, insomnia, and appetite loss) showed moderate change (10 to 20 points), and 1 (pain) showed a very positive change (>30 points). When we compare the QoL scores between the 2 most used schemes of RT (30 Gy/10 fractions vs. 20 Gy/4 to 5 fractions), there are no significant differences in any QoL areas (and in 2 areas P was near 0.05). Conclusions: Palliative RT is a very active treatment for patients with bone metastasis regardless of age, location, primary tumor, or RT scheme. RT significantly improves the QoL, fundamentally by controlling pain and reducing analgesic use. Shorter schemes of RT produce at least—if not better—the same effect on QL than longer schemes (30 Gy).

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A Phase II Study of Biweekly Cisplatin, Fixed-Dose-Rate Gemcitabine and Infusional 5-Fluorouracil in Patients With Metastatic Pancreatic and Biliary Cancers

Objectives: Combinations of gemcitabine, 5-fluorouracil (5-FU), and platinum have demonstrated improved outcomes compared with singlet chemotherapy in pancreatic and biliary cancers. This phase II study examined efficacy and safety of a novel schedule of cisplatin, fixed-dose-rate gemcitabine and infusional 5-FU. Materials and Methods: Patients with metastatic adenocarcinoma of the pancreas or biliary tract, previously untreated or having received 1 cytotoxic regimen for advanced disease, were treated with gemcitabine 1000 mg/m2 intravenously (IV) over 100 minutes, cisplatin 35 mg/m2 IV over 30 minutes, and 5-FU 2400 mg/m2 IV over 48 hours on day 1 of a 14-day cycle. Patients were treated until disease progression or for 12 cycles. After 12 cycles, patients with stable or responding disease could continue gemcitabine and 5-FU. The primary endpoint was objective response. Results: Thirty-nine patients were treated: 8 with biliary cancer (all untreated) and 31 with pancreatic cancer (17 untreated, 14 previously treated). Best response in 25 untreated patients was partial response in 40%, stable disease in 40%, and progressive disease in 20%. In 14 previously treated pancreatic patients, best response was partial response in 7%, stable disease in 50%, and progressive disease in 43%. Median overall survival in untreated patients was 10.3 versus 4.9 months in previously treated patients. Adverse events were primarily uncomplicated hematologic toxicity, ≥grade 3 neutropenia (54%), anemia (21%), and thrombocytopenia (13%). Conclusion: Biweekly cisplatin, fixed-dose-rate gemcitabine, and infusional 5-FU demonstrated a high response rate and were well tolerated, encouraging further investigation of this regimen in metastatic pancreatic and biliary cancers.

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The Evolving Role of Tumor Treating Fields in Managing Glioblastoma: Guide for Oncologists

Glioblastoma (GBM) is a devastating brain tumor with poor prognosis despite advances in surgery, radiation, and chemotherapy. Survival of patients with glioblastoma remains poor, with only 1 in 4 patients alive at 2 years, and a 5-year survival rate of about 5%. Recurrence is nearly universal and, after recurrence, prognosis is poor with very short progression-free survival and overall survival (OS). Various salvage chemotherapy strategies have been applied with limited success. Tumor Treating Fields (TTFields) are a novel treatment modality approved for treatment of either newly diagnosed or recurrent GBM. TTFields therapy involves a medical device and transducer arrays to provide targeted delivery of low intensity, intermediate frequency, alternating electric fields to produce antimitotic effects selective for rapidly dividing tumor cells with limited toxicity. In the phase 3 EF-14 trial, TTFields plus temozolomide provided significantly longer progression-free survival and OS compared with temozolomide alone in patients with newly diagnosed GBM after initial chemoradiotherapy. The addition of TTFields to standard therapy improved median OS from 15.6 to 20.5 months (P=0.04). In the phase 3 EF-11 trial, for recurrent GBM, TTFields provided comparable efficacy as investigator's choice systemic therapy, with improved patient-reported quality of life and a lower incidence of serious adverse events. Primary toxicity associated with TTFields is skin irritation generally managed with array relocation and topical treatments including antibiotics and steroids. TTFields therapy has demonstrated proven efficacy in management of GBM, including improvement in OS for patients with newly diagnosed GBM, and is under current investigation in other brain and extracranial tumors.

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Clinical Outcomes of Patients With Gastrointestinal Malignancies Participating in Phase I Clinical Trials

Objectives: Early-phase clinical trials play a pivotal role in drug development. However, limited data are available on outcomes of gastrointestinal (GI) cancer patients enrolled in phase I clinical trials. Here, we evaluated the characteristics associated with survival in GI cancer patients participating in phase I clinical trials and attempted to validate previously established prognostic models. Materials and Methods: All consecutive patients with advanced GI tumors who participated in phase I clinical trials at our institution from January 2007 to December 2013 and received at least 1 dose of the study drug were included. Cox regression models were used to estimate multivariable-adjusted hazard ratio (HR) and 95% confidence interval. Results: In 243 study patients (median age, 62 y [range, 26 to 82 y]; 55% male), treatment included chemotherapy only (14%), targeted therapy (41%), chemotherapy+targeted therapy (42%), and others (2%) for the following disease types: pancreatic (42%), colorectal (34%), gastroesophageal (10%), hepatobiliary (13%), and others (2%). Response rate was 4%, with 38% achieving stable disease and 42% having progressive disease. Median survival was 5.8 months (range, 0.2 to 52.4 mo). Our multivariable Cox regression analyses included the following as predictors of survival: Eastern Cooperative Oncology Group performance score ≥1 (HR=1.76), prior systemic therapies ≥2 (HR=1.63), lactate dehydrogenase >618 IU/L (HR=1.85), sodium >135 mmol/L (HR=0.46), and white blood count >6×109/L (HR=1.5). Our data set was consistent with previous prognostic scores. Conclusions: This is the largest study to assess clinical outcomes in this patient population. Phase I trials provide clinical benefit to patients with advanced GI malignancies and should be recommended as a treatment option in appropriate patients.

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PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study BrUOG 244

Purpose: Efficacy signals but substantial myelosuppression were demonstrated in a single arm phase II study of paclitaxel poliglumex (PPX) in combination with temozolomide (TMZ) and radiation therapy (RT) for first-line treatment of glioblastoma. The objective of this randomized phase II trial was to assess the efficacy and safety of single-agent PPX with RT (PPX/RT) versus TMZ with RT (TMZ/RT) for glioblastoma without O6-methylguanine-DNA methyltransferase (MGMT) methylation. Materials and Methods: Patients with glioblastoma with unmethylated MGMT without prior chemotherapy or RT were eligible. Patients were randomly assigned 2:1 to PPX, 50 mg/m2/wk for 6 weeks, or standard TMZ, with concurrent 60.0 Gy RT. One month after completion of chemoradiation all patients received standard maintenance TMZ. The primary endpoint was progression-free survival (PFS). Results: Of the 164 patients enrolled, 86 were MGMT unmethylated. Of these, 63 patients were randomized (42 to PPX/RT and 21 to TMZ/RT). Fifty-nine patients could be analyzed. The median PFS was 9 months in the PPX/RT group and 9.5 months in the TMZ/RT group (hazard ratio in the PPX/RT group, 1.10; 95% confidence interval, 0.79-2.08; P=0.75). Median overall survival was 16 versus 14.8 months for PPX/RT and TMZ/RT groups, respectively (hazard ratio, 1.44; 95% confidence interval, 0.75-2.77; P=0.27). In the PPX and TMZ groups 44% versus 22% of patients, respectively, experienced one or more grade 3 or higher toxicities during chemoradiation. Conclusions: PPX/RT did not improve PFS or overall survival. This study provides an effective trial design for screening RT sensitizers in glioblastoma.

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Does Delaying Surgical Resection After Neoadjuvant Chemoradiation Impact Clinical Outcomes in Locally Advanced Rectal Adenocarcinoma?: A Single-Institution Experience

Objectives: Surgical resection for locally advanced rectal adenocarcinoma commonly occurs 6 to 10 weeks after completion of neoadjuvant chemoradiation (nCRT). We sought to determine the optimal timing of surgery related to the pathologic complete response rate and survival endpoints. Methods: The study is a retrospective analysis of 92 patients treated with nCRT followed by surgery from 2004 to 2011 at our institution. Univariate and multivariate analyses were performed to assess the impact of timing of surgery on locoregional control, distant failure (DF), disease-free survival, and overall survival (OS). Results: Time-to-surgery was ≤8 weeks (group A) in 72% (median 6.1 wk) and >8 weeks (group B) in 28% (median 8.9 wk) of patients. No significant differences in patient characteristics, locoregional control, or pathologic complete response rates were noted between the groups. Univariate analysis revealed that group B had significantly shorter time to DF (group B, median 33 mo; group A, median not reached, P=0.047) and shorter OS compared with group A (group B, median 52 mo; group A, median not reached, P=0.03). Multivariate analysis revealed that increased time-to-surgery showed a significant increase in DF (HR=2.96, P=0.02) and trends toward worse OS (HR=2.81, P=0.108) and disease-free survival (HR=2.08, P=0.098). Conclusions: We found that delaying surgical resection longer than 8 weeks after nCRT was associated with an increased risk of DF. This study, in combination with a recent larger study, questions the recent trend in promoting surgical delay beyond the traditional 6 to 10 weeks. Larger, prospective databases or randomized studies may better clarify surgical timing following nCRT in rectal adenocarcinoma.

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