Transfusion practices in traumatic brain injury

Purpose of review The aim of this review is to summarize the recent studies looking at the effects of anemia and red blood cell transfusion in critically-ill patients with traumatic brain injury (TBI), describe the transfusion practice variations observed worldwide, and outline the ongoing trials evaluating restrictive versus liberal transfusion strategies for TBI. Recent findings Anemia is common among critically-ill patients with TBI, it is also thought to exacerbate secondary brain injury, and is associated with an increased risk of poor outcome. Conversely, allogenic red blood cell transfusion carries its own risks and complications, and has been associated with worse outcomes. Globally, there are large reported differences in the hemoglobin threshold used for transfusion after TBI. Observational studies have shown differential results for improvements in cerebral oxygenation and metabolism after red blood cell transfusion in TBI. Summary Currently, there is insufficient evidence to make strong recommendations regarding which hemoglobin threshold to use as a transfusion trigger in critically-ill patients with TBI. There is also uncertainty whether the restrictive transfusion strategy used in general critical care can be extrapolated to acutely brain injured patients. Ultimately, the consequences of anemia-induced cerebral injury need to be weighed up against the risks and complications associated with red blood cell transfusion. Correspondence to Victoria A. McCredie, MBChB, PhD, Department of Critical Care Medicine, 2nd Floor McLaughlin Rm 411-J, Toronto Western Hospital, University Health Network, 399 Bathurst St, Toronto, Canada M5T 2S8. Tel: +1 416 302 1959; e-mail: Victoria.McCredie@uhn.ca Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Staff and family response to end-of-life care in the ICU

Purpose of review End-of-life (EOL) care can be stressful for clinicians as well as patients and their relatives. Decisions to withhold or withdraw life-sustaining therapy vary widely depending on culture, beliefs and organizational norms. The following review will describe the current understanding of the problem and give an overview over interventional studies. Recent findings EOL care is a risk factor for clinician burnout; poor work conditions contribute to emotional exhaustion and intent to leave. The impact of EOL care on families is part of the acute Family Intensive Care Unit Syndrome (FICUS) and the Post Intensive Care Syndrome–Family (PICS-F). Family-centered care (FCC) acknowledges the importance of relatives in the ICU. Several interventions have been evaluated, but evidence for their effectiveness is at best moderate. Some interventions even increased family stress. Interventional studies, which address clinician burnout are rare. Summary EOL care is associated with negative outcomes for ICU clinicians and relatives, but strength of evidence for interventions is weak because we lack understanding of associated factors like work conditions, organizational issues or individual attitudes. In order to develop complex interventions that can successfully mitigate stress related to EOL care, more research is necessary, which takes into account all potential determinants. Correspondence to Dr Konrad Reinhart, ML, Senior Professor, Jena University Hospital, Chairman Global Sepsis Alliance, Paul-Schneider-Street 2, 07747 Jena, Germany. E-mail: konrad.reinhart@med.uni-jena.de Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Pediatric trauma transfusion and cognitive aids

Purpose of review Trauma is the most common cause of pediatric mortality. Much of the research that led to life-saving interventions in adults, however, has not been replicated in the pediatric population. Children have important physiologic and anatomic differences from adults, which impact hemostasis and transfusion. Hemorrhage is a leading cause of death in trauma, and children have important differences in their coagulation profiles. Transfusion strategies, including the massive transfusion protocol and use of antifibrinolytics, are still controversial. In addition to the blood that is lost from the injury itself, trauma leads to inflammation and to a dysfunction in hemostasis, causing coagulopathy. Recent findings In one study in which children suffered from mainly blast and penetrating injuries in a combat setting (PEDTRAX trial), the early administration of tranexamic acid was associated with decreased mortality. Some authors suggest that this result may not apply to blunt trauma, which is much more common in children in noncombat settings. Using thromboelastography to guide the administration of recombinant Factor VIIa has been done in selected cases and may represent a future avenue of research. Summary This article explores new research from the past year in pediatric trauma, starting with the physiologic differences in pediatric red blood cells and coagulation profiles. We also looked at the dramatic change in thinking over the past decade in the tolerable level of anemia in critically ill pediatric patients, as well as scales for determining the need for massive transfusion and exploring if the concepts of damage control resuscitation apply to children. Other strategies, such as avoiding hypothermia, and the selective administration of antifibriniolytics, are important in pediatric trauma as well. Future research that is pediatric focused is needed for the optimal care of our youngest patients. Correspondence: Anna Clebone, MD, Assistant Professor, Department of Anesthesia and Critical Care, University of Chicago, 5841 S. Maryland Ave. MC-4028, Chicago, IL 60637, USA. Tel: +773 702 6700; e-mail: aclebone@dacc.uchicago.edu Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Spirituality at the end of life

Purpose of review There is increasing emphasis on medical care of the whole patient. This holistic approach encompasses supporting the spiritual or religious needs of the patient. Particularly at the end of life, spiritual concerns may come to the fore as patients recognize and accept their impending death. Physicians may also recognize this spiritual distress but may not be clear on how to provide spiritual support. Recent findings Tools to screen for spiritual concerns are available for physicians to use. Some physicians wish to go further, supporting patients at the end of life in their spiritual quest. Other physicians express concern about causing more distress to patients in a time of significant need. Descriptions of educational tools, as well as the difference between spiritual generalists and spiritual specialists have emerged. Integration of chaplains into the medical team caring for patients at the end of life will also enhance care of the whole patient. Summary The increasing emphasis on whole patient care is leading to increasing focus on spiritual concerns of patients. Although not every patient has an interest in spiritual conversation, most do and medical teams will need to become more educated about appropriate spiritual engagement. Correspondence to Cynthiane J. Morgenweck, MD, MA, Center for Bioethics and Medical Humanities, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Tel: +1 414 955 8498; e-mail: cmorg@mcw.edu Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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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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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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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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Celiac disease associated with aplastic anemia in a 6-year-old girl: a case report and review of the literature

Celiac disease may present with hematological abnormalities including long-standing anemia. Both aplastic anemia and celiac disease have a similar underlying autoimmune process but an association between the t...

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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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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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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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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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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.

http://ift.tt/2G9H4cp

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.

http://ift.tt/2rEe35F

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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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.

http://ift.tt/2E2uYRN

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.

http://ift.tt/2DwgBE2

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.

http://ift.tt/2E2jaPk

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.

http://ift.tt/2Dty3Jn

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.

http://ift.tt/2E2uYkL

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.

http://ift.tt/2DyaEGE

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.

http://ift.tt/2E4XfHl

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.

http://ift.tt/2DAFlzp

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.

http://ift.tt/2n7oclt

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.

http://ift.tt/2DyMnoi

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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via IFTTT

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.

from Cancer via ola Kala on Inoreader http://ift.tt/2n7oclt
via IFTTT

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.

http://ift.tt/2n6REcb

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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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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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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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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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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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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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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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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Patterns of Care and Outcomes of Hypofractionated Chemoradiation Versus Conventionally Fractionated Chemoradiation for Glioblastoma in the Elderly Population

Purpose: This study evaluated practice patterns, outcomes, and predictors of survival for elderly patients with glioblastoma (GBM) receiving definitive chemoradiotherapy (CRT) with either hypofractionated radiotherapy or conventionally fractionated radiotherapy. Materials and Methods: The National Cancer Data Base was queried for patients age 65 years and above diagnosed with GBM between 2006 and 2012 that received definitive CRT with either hypofractionated radiotherapy (hCRT) or conventionally fractionated radiotherapy (cCRT). Patient, tumor, and treatment parameters were extracted. Statistics included Kaplan-Meier analysis to evaluate overall survival (OS) as well as Cox proportional hazards modeling to determine variables associated with OS. Propensity score matching was performed in order to assess groups in a balanced manner while reducing indication biases. Results: Altogether, 5126 patients met inclusion criteria; 126 (2.5%) underwent hCRT, while 5000 (97.5%) received cCRT. Temporal trends revealed that the use of hCRT is rising, especially in more recent years. Patients undergoing hCRT were older, with worse performance status, treated with biopsy only, and more likely to receive treatment at an academic facility. cCRT was associated with improved median OS (10.7 vs. 6.2 mo, P

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A Review of Treatment for Breast Cancer-Related Lymphedema: Paradigms for Clinical Practice

Objectives: Breast cancer–related lymphedema (BCRL) represents a major complication of breast cancer treatment, impacting the quality of life for breast cancer survivors that develop it. The purpose of this review is to evaluate the literature surrounding BCRL treatment modalities to guide clinicians regarding risk-stratified treatment options. Methods: A review of studies over a 10-year period (January 2006 to February 2016) was performed. Noninvasive strategies evaluated included compression therapy, manual lymphatic drainage, and complex decongestive therapy (CDT). Invasive modalities evaluated included liposuction and lymphatic bypass/lymph node transfer (LNT). Our search yielded 149 initial results with 45 studies included. Results: A number of prospective studies have found that CDT is associated with volume reduction in the affected limb as well as improved quality of life, particularly in patients with early stage BCRL. With regards to invasive treatment options, data support that lymphatic bypass and LNT are associated with symptomatic and physiologic improvements, particularly in patients with more advanced BCRL. In addition, a small number of studies suggest that liposuction may be an efficacious and safe treatment for moderate to severe BCRL. Conclusions: CDT is an effective treatment modality for early stage BCRL. For more advanced BCRL, LNT has demonstrated efficacy. Further study is required with respect to comparing BCRL treatment modalities.

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