Fenretinide + ABT-751 in neuroblastoma xenografts

ABT-751 is a colchicine-binding site microtubule inhibitor. Fenretinide (4-HPR) is a synthetic retinoid; both agents have shown activity against neuroblastoma in laboratory models and clinical trials. We investigated the antitumor activity of 4-HPR + the microtubule-targeting agents ABT-751, vincristine, paclitaxel, vinorelbine, or colchicine in laboratory models of recurrent neuroblastoma. Drug cytotoxicity was assessed in vitro by a fluorescence-based assay (DIMSCAN) and in subcutaneous xenografts in nu/nu mice. Reactive oxygen species levels (ROS), apoptosis, and mitochondrial depolarization were measured by flow cytometry; cytochrome c release and proapoptotic proteins by immunoblotting. 4-HPR + ABT-751 showed modest additive or synergistic cytotoxicity, mitochondrial membrane depolarization, cytochrome c release, and caspase activation compared to single agents in vitro; synergism was inhibited by antioxidants (ascorbic acid, α-tocopherol). 4-HPR + ABT-751 was highly active against four xenograft models, achieving multiple maintained complete responses. The median event-free survival (days) for xenografts from 4 patients combined were control = 28, 4-HPR = 49, ABT-751 = 77, and 4-HPR + ABT-751 > 150 (P < 0.001). Apoptosis (TUNEL) was significantly higher in 4-HPR + ABT-751-treated tumors than with single agents (P < 0.01) and was inhibited by ascorbic acid and α-tocopherol (P < 0.01), indicating that ROS from 4-HPR enhanced the activity of ABT-751. 4-HPR also enhanced the activity against neuroblastoma xenografts of vincristine or paclitaxel but the latter combinations were less active than 4-HPR + ABT-751. Our data support clinical evaluation of 4-HPR combined with ABT-751 in recurrent and refractory neuroblastoma.

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Dynamic Assessment of Value During High-Cost Cancer Treatment: A Response to American Society of Clinical Oncology and European Society of Medical Oncology [Editorial]

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Improving the Quality and Value of Cancer Care: A Work in Progress--The 2016 Joseph V. Simone Award and Lecture [Editorial]

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Association of Practice-Level Hospital Use With End-of-Life Outcomes, Readmission, and Weekend Hospitalization Among Medicare Beneficiaries With Cancer [Original Contribution]

Purpose:

To determine the relationships between hospital use of treating oncology practices and patient outcomes.

Patients and Methods:

Retrospective analysis of 397,646 Medicare beneficiaries who received anticancer therapy in 2012. Each beneficiary was associated with a practice; practices were ranked on the basis of risk-adjusted hospital use, that is, inpatient intensity. Outcomes included 30-day readmission, weekend admissions, intensive care unit stays in the last month of life, and hospice stay of ≥ 7 days. Outcomes were measured for each quartile of practice-level inpatient intensity. We fit multivariable logistic regression models to calculate adjusted odds ratios (ORs) for each outcome for each quartile of inpatient intensity.

Results:

Total 30-day readmissions were 22.8% and 31.9% (OR, 1.45; 95% CI, 1.39 to 1.50) for patients in practices with the lowest versus highest quartiles of inpatient intensity, respectively; unplanned readmissions were 19.8% and 27.1% (OR, 1.36; 95% CI, 1.31 to 1.41), respectively. The proportion of admissions that occurred on weekends was similar across quartiles. Patients of practices in the highest quartiles of inpatient intensity had higher rates of death in an ICU stay in the last month of life (25.5% versus 18.0%; OR, 1.33; 95% CI, 1.19 to 1.49) and a lower rate of hospice stay of at least 7 days (50.9% to 42.5%; OR, 0.79; 95% CI, 0.74 to 0.86).

Conclusion:

Medical oncology practices that seek to reduce hospitalizations should consider focusing initially on processes related to end-of-life care and care transitions.

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Overcoming the Implementation Gap in Multidisciplinary Oncology Care Programs [Editorial]

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CancerLinQ Update [Presentation Summary]

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What Adult Cancer Care Can Learn From Pediatrics [Editorial]

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Improving Oral Oncolytic Patient Self-Management [Quality in Action]

Purpose:

Managing patients who are taking oral oncolytics is challenging because of the changing paradigm from frequent supervision during intravenous therapy to periodic observation with oral administration of drugs. We joined the Michigan Oncology Quality Consortium (MOQC) Oral Oncolytics Collaborative in 2013 to identify opportunities for improvement in this area.

Methods:

We completed MOQC's baseline self-assessment and performed an audit of medical records for 25 patients prescribed an oral oncolytic from May 2011 to July 2013. We implemented the following MOQC resources: a tracking system for patients taking oral oncolytics, patient education with drug-specific self-care guidelines, use of a modified Edmonton Symptom Assessment Scale, and a medication adherence questionnaire to be used on scheduled follow-up calls and return visits. We modified our workflow to include a standard teaching session and consistent follow-up phone calls. We conducted a retrospective postimplementation medical records audit from August 2013 to September 2014.

Results:

Baseline self-assessment revealed lack of start date documentation and lack of consistent follow-up. A baseline medical records audit showed that 48% of patients discontinued their medication without consulting their physician, and start date documentation was available for only 52% of patients. After participating in the quality initiative, 100% of patients sampled had a documented start date, and no patients discontinued their drug on their own. Seventeen percent had a dose reduction as a result of toxicity, as directed by the physician.

Conclusion:

The introduction of new office procedures to easily identify all patients receiving oral therapy and improvement in patients' ability to manage symptoms at home with the use of self-care guidelines contributed to an improvement in managing patients who are taking oral oncolytics.

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Process Mapping With Times, Process Measures, and Labor Costs [Editorial]

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Defining High-Quality Palliative Care in Oncology Practice: An American Society of Clinical Oncology/American Academy of Hospice and Palliative Medicine Guidance Statement [Care Delivery]

Purpose:

Integrated into routine oncology care, palliative care can improve symptom burden, quality of life, and patient and caregiver satisfaction. However, not all oncology practices have access to specialist palliative medicine. This project endeavored to define what constitutes high-quality primary palliative care as delivered by medical oncology practices.

Methods:

An expert steering committee outlined 966 palliative care service items, in nine domains, each describing a candidate element of primary palliative care delivery for patients with advanced cancer or high symptom burden. Using modified Delphi methodology, 31 multidisciplinary panelists rated each service item on three constructs: importance, feasibility, and scope within medical oncology practice.

Results:

Panelists endorsed the highest proportion of palliative care service items in the domains of End-of-Life Care (81%); Communication and Shared Decision Making (79%); and Advance Care Planning (78%). The lowest proportions were in Spiritual and Cultural Assessment and Management (35%) and Psychosocial Assessment and Management (39%). In the largest domain, Symptom Assessment and Management, there was consensus that all symptoms should be assessed and managed at a basic level, with more comprehensive management for common symptoms such as nausea, vomiting, diarrhea, dyspnea, and pain. Within the Appropriate Palliative Care and Hospice Referral domain, there was consensus that oncology practices should be able to describe the difference between palliative care and hospice to patients and refer patients appropriately.

Conclusion:

This statement describes the elements comprising high-quality primary palliative care for patients with advanced cancer or high symptom burden, as delivered by oncology practices. Oncology providers wishing to enhance palliative care delivery may find this information useful to inform operational changes and quality improvement efforts.

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Four Years Running: The ASCO Quality Care Symposium [Foreword]

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Celecoxib for the Prevention of Colorectal Adenomas: Results of a Suspended Randomized Controlled Trial

Background: Cyclooxygenase (COX)-2 inhibitors such as celecoxib were designed to preserve anti-inflammatory activity without inhibiting COX-1. Downregulation of COX-2 inhibits colorectal carcinogenesis.

Methods: The Selenium and Celecoxib Trial was a randomized, placebo-controlled trial of once-daily selenium 200 µg and celecoxib 400 mg, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of adenomas. The primary outcome was development of new adenomas. Celecoxib was suspended early because of cardiovascular toxicity in other trials. Accrual to selenium or placebo continued. Before suspension, 824 participants were randomly assigned to celecoxib or placebo, of whom 712 (86.4%) were available for analysis. All statistical tests were two-sided.

Results: In the placebo and celecoxib arms of 356 participants each, adenoma detection was 47.5% and 49.7% (relative risk [RR] = 1.04, 95% confidence interval [CI] = 0.90 to 1.21, P = .58), respectively, after median periods of 13.6 and 14.2 months on intervention. Among participants colonoscoped within 12 months of discontinuing intervention (n = 244), overall adenoma recurrence (RR = 0.69, 95% CI = 0.48 to 0.98, P = .04) and recurrence with advanced adenomas (RR = 0.23, 95% CI = 0.07 to 0.80, P = .02) were reduced with celecoxib. Reduction of adenoma recurrence was greatest in participants with previous advanced adenomas. Celecoxib increased risk of hypertension in participants with pre-existing cardiovascular risk factors compared with placebo (hazard ratio = 2.19, 95% CI = 1.07 to 4.50, P = .03).

Conclusions: Limited-duration celecoxib prevents adenoma recurrence in patients with prior high-risk adenomas, in whom strategies to minimize cardiovascular toxicity might be feasible.

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Selenium Supplementation for Prevention of Colorectal Adenomas and Risk of Associated Type 2 Diabetes

Background: Selenium supplementation may help to prevent colorectal cancer; as precursors of colorectal cancer, colorectal adenomas are a surrogate for colorectal cancer. Selenium supplementation may increase risk of type 2 diabetes (T2D).

Methods: The Selenium and Celecoxib (Sel/Cel) Trial was a randomized, placebo controlled trial of selenium 200 µg daily as selenized yeast and celecoxib 400 mg once daily, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of colorectal adenomas. The primary outcome was adenoma development. Celecoxib was suspended because of cardiovascular toxicity in other trials, but accrual continued to selenium and placebo. A total of 1621 participants were randomly assigned to selenium or placebo, of whom 1374 (84.8%) were available for analysis. All statistical tests were two-sided.

Results: In the respective placebo and selenium arms of 689 and 685 participants, adenoma detection after medians of 33.6 (range = 0.0–85.1 months) and 33.0 months (range = 0.0–82.6 months) were 42.8% and 44.1% (relative risk [RR] = 1.03, 95% confidence interval [CI] = 0.91 to 1.16, P = .68). In participants with baseline advanced adenomas, adenoma recurrence was reduced by 18% with selenium (RR = 0.82, 95% CI = 0.71 to 0.96, P = .01). In participants receiving selenium, the hazard ratio for new-onset T2D was 1.25 (95% CI = 0.74 to 2.11, P = .41), with a statistically significantly increased risk of selenium-associated T2D among older participants (RR = 2.21; 95% CI = 1.04 to 4.67, P = .03).

Conclusions: Overall, selenium did not prevent colorectal adenomas and showed only modest benefit in patients with baseline advanced adenomas. With limited benefit and similar increases in T2D to other trials, selenium is not recommended for preventing colorectal adenomas in selenium-replete individuals.

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Improved Survival With Integration of Chinese Herbal Medicine Therapy in Patients With Acute Myeloid Leukemia: A Nationwide Population-Based Cohort Study

Purpose. Acute myeloid leukemia (AML) is the most deadly subtype of leukemia, and many patients with this disease seek other complementary therapies, one of which is Chinese medicine. We set out to provide reliable data regarding the benefit of Chinese herbal medicine (CHM) for AML patients, using mortality as the main outcome measure. We also characterized the herbal prescriptions of patients. Methods. Using the Taiwanese National Health Insurance Research Database, we performed a nationwide population-based cohort study among AML patients from 1997 to 2010. The Cox regression model was used to adjust for comorbidities and other variables, and the hazard ratios (HRs) of CHM users and non–CHM users were compared. Results. After 1:1 matching, 498 patients were included into the study. The HR of the CHM group was 0.41 (95% CI = 0.26-0.65; P = .0001) compared with the non-CHM group. This decrease in HR was also shown to be dose dependent (P < .001). The 3 single-herbs most commonly prescribed were Salvia miltiorrhiza (Dan Shen), Astragalus membranaceus (Huang Qi), and Spatholobus suberectus (Ji Xue Teng). The 3 mutli-herb products most commonly prescribed were Jia Wei Xiao Yao San, Gui Pi Tang, and Qi Ju Di Huang Wan. Conclusion. Prospective controlled clinical data is still needed, however, this study provides real-world data regarding the benefit AML patients may have from CHM. This study suggests that all AML patients, regardless of age or other prognostic factors, may achieve longer survival times when receiving CHM in addition to standard therapy.

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Cancer Chemopreventive Effects of Boswellia sacra Gum Resin Hydrodistillates on Invasive Urothelial Cell Carcinoma: Report of a Case

A 52-year-old Hispanic male presented with hematuria and was later diagnosed with a large invasive high-grade urothelial cell carcinoma (UCC) of the urinary bladder, but with ambiguous pT1/pT2 staging regarding musclaris propria invasion by UCC. The conventional treatment including radical cystoprostatectomy followed by neoadjuvant chemotherapy with or without radiation therapy was presented. The patient decided to delay the standard therapy until a later stage, but elected to go through transurethral resection of bladder tumor (TURBT) without Bacillus Calmette-Guérin instillation. Following TURBT, the patient started oral Boswellia sacra gum resin (aka frankincense or Ru Xiang in Chinese) hydrodistillates (BSGRH) administration at 3 mL daily with lifestyle changes, and continued this regimen in the last 25 months. Within the first year after diagnosis, the patient experienced 2 recurrences. Recurrent tumors were removed by TURBT alone and both tumors were far smaller than the original one. After the second recurrence, the patient has no detectible cancer in the bladder based on cystoscopy for 14 months and has an intact genitourinary system. His liver and kidney functions are considered to be normal based on blood chemistry tests. This index case suggests that BSGRH may have cancer chemopreventive effects on UCC. The use of Boswellia-derived products in the management of cancer has been well document in other published studies, and boswellic acids have been suggested to be the major component. However, BSGRH contains very little boswellic acids. Demonstration of cancer chemoprevention using BSGRH is one step forward in isolating the key components other than boswellic acids in frankincense. The critical question as to whether these components can simultaneously activate multiple pathways in cancer cells to execute cancer suppression/cytotoxicity or prevention effects remains to be addressed. More studies including identification of key molecules, pharmacokinetics of major compounds, as well as long-term benefits and possible adverse effects will be needed to meet the guidelines of the US Food and Drug Administration for botanical drug development.

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Acupuncture for Managing Cancer-Related Insomnia: A Systematic Review of Randomized Clinical Trials

Background. Insomnia is a prominent complaint of cancer patients that can significantly affect their quality of life and symptoms related to sleep quality. Conventional drug approaches have a low rate of success in alleviating those suffering insomnia. The aim of this systematic review was to assess the efficacy of acupuncture in the management of cancer-related insomnia. Methods. A total of 12 databases were searched from their inception through January 2016 without language restriction. Randomized controlled trials (RCTs) and quasi-RCTs were included if acupuncture was used as the sole intervention or as an adjunct to another standard treatment for any cancer-related insomnia. The data extraction and the risk of bias assessments were performed by 2 independent reviewers. Results. Of the 90 studies screened, 6 RCTs were included. The risk of bias was generally unclear or low. Three RCTs showed equivalent effects on the Pittsburgh Sleep Quality Index and 2 RCTs showed the similar effects on response rate to those of conventional drugs at the end of treatment. The other RCT showed acupuncture was better than hormone therapy in the numbers of hours slept each night and number of times woken up each night. The 3 weeks of follow-up in 2 RCTs showed superior effects of acupuncture compared with conventional drugs, and a meta-analysis showed significant effects of acupuncture. Two RCTs tested the effects of acupuncture on cancer-related insomnia compared with sham acupuncture. One RCT showed favourable effects, while the other trial failed to do so. Conclusion. There is a low level of evidence that acupuncture may be superior to sham acupuncture, drugs or hormones therapy. However, the number of studies and effect size are small for clinical significance. Further clinical trials are warranted.

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Family caregiver communication tool: A new measure for tailoring communication with cancer caregivers

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CA-125 Testing, CT Scans Still Used for Ovarian Cancer Surveillance Despite Lack of Proven Benefit

Despite evidence of no benefit from a 2009 randomized clinical trial, a new study shows that doctors appear to still routinely use the CA-125 blood test to monitor women for recurrent ovarian cancer. The findings, published July 21 in JAMA Oncology, also suggest that computed tomography (CT) scans continue to be routinely used to check for recurrences even though clinical practice guidelines discourage this practice. 

Many women who are in remission after treatment for ovarian cancer will eventually have a recurrence of the disease. One approach doctors have used to monitor patients for a recurrence and make decisions about care is regular blood testing to look for a rise in levels of CA-125, a protein that may be found in high amounts in women with ovarian cancer. However, results of a randomized, phase III clinical trial reported at a national conference in 2009 and published in 2010 showed that CA-125 testing for early detection of recurrent disease increased the use of chemotherapy and decreased patients' quality of life without improving overall survival.

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Immunosenescence: limitations of natural killer cell-based cancer immunotherapy

Abstract

Cancer is primarily considered a disease of old age. Immunosenescence refers to the age-associated changes in the immune system, and its contribution to the increased risk of cancer in old individuals has been discussed for many years. Natural killer (NK) cells are cytotoxic innate immune cells specialized in defence against tumour and virus-infected cells. NK cell cytotoxicity is the result of a fine balance between activating and inhibitory receptors. Several activating receptors have been identified that recognize different ligands frequently found over-expressed on tumour cells or virus-infected cells. The most important NK cell inhibitory receptors interact with major histocompatibility complex class I molecules expressed on almost all nucleated cells preventing NK cell-mediated lysis of healthy cells. NK cell immunosenescence is characterized by a redistribution of NK cell subsets, a diminished expression of several activating receptors and lower per-cell cytotoxicity. Altered expression of activating receptors has also been described in young and elderly cancer patients probably due to chronic exposure to ligands on tumour cells. Thus, the effect of both age and cancer may act synergistically to diminish NK cell-mediated tumour immunosurveillance. Different strategies harnessing the power of NK cells to target tumour cells have been designed including adoptive therapy with autologous or allogeneic expanded NK cells. In addition, checkpoint blockade of inhibitory receptors and the use of agonist antibodies to stimulate activating receptors are emerging areas of research. In this context, the effect of immunosenescence should be considered to improve the efficiency of cancer immunotherapy.

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Sexuality after a cancer diagnosis: A population-based study

BACKGROUND

This study explored differences in sexual activity, function, and concerns between cancer survivors and cancer-free controls in a population-based study.

METHODS

The data were from 2982 men and 3708 women who were 50 years old or older and were participating in the English Longitudinal Study of Ageing. Sexual well-being was assessed with the Sexual Relationships and Activities Questionnaire, and cancer diagnoses were self-reported.

RESULTS

There were no differences between cancer survivors and controls in levels of sexual activity (76.0% vs 78.5% for men and 58.2% vs 55.5% for women) or sexual function. Men and women with cancer diagnoses were more dissatisfied with their sex lives than controls (age-adjusted percentages: 30.9% vs 19.8% for men [P = .023] and 18.2% vs 11.8% for women [P = .034]), and women with cancer were more concerned about levels of sexual desire (10.2% vs 7.1%; P = .006). Women diagnosed < 5 years ago were more likely to report difficulty with becoming aroused (55.4% vs 31.8%; P = .016) and achieving orgasm (60.6% vs 28.3%; P < .001) and were more concerned about sexual desire (14.8% vs 7.1%; P = .007) and orgasmic experience (17.6% vs 7.1%; P = .042) than controls, but there were no differences in men.

CONCLUSIONS

Self-reports of sexual activity and functioning in older people with cancer are broadly comparable to age-matched, cancer-free controls. There is a need to identify the causes of sexual dissatisfaction among long-term cancer survivors despite apparently normal levels of sexual activity and function for their age. The development of interventions addressing low sexual desire and problems with sexual functioning in women is also important and may be particularly relevant for cancer survivors after treatment. Cancer 2016. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Indirect Calorimetry: Is it Required to Maximize Patient Outcome from Nutrition Therapy?

Abstract

Nutrition support regimens which fail to meet caloric requirements may adversely affect morbidity. This study evaluated the importance of accuracy of nutritional regimens and whether indirect calorimetry (IC) is required to optimize patient response. Patients admitted to a long-term acute care hospital, on mechanical ventilation, made nil per os NPO and placed on enteral nutrition (EN), were enrolled. At baseline and weekly for 3 weeks, two experienced critical care physicians estimated caloric needs, followed by IC. Patients were randomized to receive EN determined by physician estimates or by IC. Accuracy of physician estimates and adequacy of nutrition therapy were the primary study endpoints. Results showed that while estimates of caloric requirements appeared to be accurate, averaging 109.3 ± 26 % of actual requirements measured by IC for all subjects (n = 27), there was wide variation above and below the mean. Only 32 % of estimated values were within 10 % of measured requirements. Delivery of nutrition in both groups was suboptimal, with all patients receiving only 82.0 ± 15.4 % of goal requirements. There were no differences between groups regarding outcome (duration mechanical ventilation, healing of pressure sores). Physiologic consequences to hypocaloric feeding were seen nonetheless, with adequacy of feeding correlating significantly (p < 0.05) to mean respiratory quotient (RQ), albumin, and prealbumin. Increasing BMI was shown to correlate significantly with a reduction in accuracy of physician estimates (p < 0.001). BMI was found to be inversely correlated with prealbumin level and RQ. While caloric requirements of critically ill patients can be estimated by predictive equations, estimates decrease in accuracy as BMI increases. In this experience, use of IC failed to improve clinical outcomes. Delivery of the prescribed EN regimen continues to be a limiting factor.

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MR imaging features that distinguish spinal cavernous angioma from hemorrhagic ependymoma and serial MRI changes in cavernous angioma

Abstract

Cavernous angiomas of the spinal cord exhibit imaging characteristics that may overlap with those of hemorrhagic ependymoma. In the present study, we aimed to identify specific magnetic resonance imaging (MRI) findings that could be used to differentiate cavernous angioma from hemorrhagic ependymoma, and to evaluate serial MRI changes in cases of cavernous angioma. We retrospectively evaluated MR images of spinal cord tumors collected at our hospital from 2007 to 2015. From this cohort of images, 11 pathologically confirmed cavernous angiomas and 14 pathologically confirmed hemorrhagic ependymomas were compared with respect to the size of the tumor, longitudinal location, axial location, enhancement pattern, syrinx, edema, tumor margin, signal intensity of T2WI, signal intensity of T1WI, and longitudinal spreading of the hemorrhage. Serial MR images of seven spinal cavernous angiomas were reviewed. Small size, eccentric axial location, minimal enhancement, and absence of edema were more frequently observed on images of cavernous angioma compared to those of hemorrhagic ependymoma (p < 0.01). Serial MRI changes in cases of cavernous angioma included increased longitudinal spreading of the hemorrhage (6/7, 86 %) and emergence of high signal intensity on T1WI (1/7, 14 %). Small size, eccentric axial location, minimal enhancement, and absence of edema are significant MRI findings that may be used to distinguish Type I and Type II spinal cavernous angiomas from hemorrhagic ependymomas. Furthermore, longitudinal spreading of the hemorrhage may be observed on follow-up MRIs of cavernous angiomas.

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Clinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients

Abstract

Genomic research of high grade glioma (HGG) has revealed complex biology with potential for therapeutic impact. However, the utilization of this information and impact upon patient outcome has yet to be assessed. We performed capture-based next generation sequencing (NGS) genomic analysis assay of 236/315 cancer-associated genes, with average depth of over 1000 fold, to guide treatment in HGG patients. We reviewed clinical utility and response rates in correlation to NGS results. Forty-three patients were profiled: 34 glioblastomas, 8 anaplastic astrocytomas, and one patient with anaplastic oligodendroglioma. Twenty-five patients were profiled with the 315 gene panel. The median number of identified genomic alterations (GAs) per patient was 4.5 (range 1–23). In 41 patients (95 %) at least one therapeutically-actionable GA was detected, most commonly in EGFR [17 (40 %)]. Genotype-directed treatments were prescribed in 13 patients, representing a 30 % treatment decision impact. Treatment with targeted agents included everolimus as a single agent and in combination with erlotinib; erlotinib; afatinib; palbociclib; trametinib and BGJ398. Treatments targeted various genomic findings including EGFR alterations, mTOR activation, cell cycle targets and FGFR1 mutations. None of the patients showed response to respective biologic treatments. In this group of patients with HGG, NGS revealed a high frequency of GAs that lead to targeted treatment in 30 % of the patients. The lack of response suggests that further study of mechanisms of resistance in HGG is warranted before routine use of biologically-targeted agents based on NGS results.

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Prognostic role of microRNA-21 expression in gliomas: a meta-analysis

Abstract

MicroRNA-21 (miRNA-21) has recently been shown to be a promising prognostic tumor biomarker. However, few studies have not supported this idea and have shown inconsistent data. Thus, we conducted a meta-analysis to elucidate the predictive value of miRNA-21 in gliomas. The relevant studies were identified by performing online search in PubMed, EMBASE and Web of Science databases up to Apr 2016. This meta-analysis study included seven eligible studies, consisting of 1121 gliomas and 533 glioblastoma multiforme (GBM) patients. Heterogeneity between studies was assessed using Egger's and Begg's test. Hazard ratios (HRs) with 95 % confidence intervals (CIs) for overall survival (OS), which compared the expression levels of miRNA-21 in patients with gliomas, were extracted and estimated. Our analysis revealed that the high expression of miRNA-21 is associated with the worse OS in gliomas. Further subgroup analysis indicated that increased expression of miRNA-21 was also associated with OS in GBM patients. Moreover, we observed a correlation between miRNA-21 expression and the World Health Organization defined gliomas grading system (WHO grade). Besides, high miRNA-21 expression was significantly correlated with lowered OS both in the Asian group and non-Asian group. In the cut-off subgroup analysis, both mean cut off value and median cut off value were significantly associated with OS. The expression level of miRNA-21 was not high in low KPS (Karnofsky score) group. miRNA-21 appears to be a promising biomarker for predicting the progression of patients with gliomas or GBM. However, due to the limited sample size, further prospective or retrospective multi-center well designed studies with adequate sample size should be conducted to verify its definite prognostic value.

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It’s TIME for a biomarker-driven approach to cancer immunotherapy

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Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy

Abstract

Immune-checkpoint blocking antibodies have demonstrated objective antitumor responses in multiple tumor types including melanoma, non-small cell lung cancer (NSCLC), and renal cell cancer (RCC). In melanoma, an increase in overall survival has been demonstrated with anti-CTLA-4 and PD-1 inhibition. However, a plethora of immune-mediated adverse events has been reported with these agents. Immune-mediated cardiotoxicity induced by checkpoint inhibitors has been reported in single cases with variable presentation, including myocarditis and pericarditis.

Among six clinical cancer centers with substantial experience in the administration of immune-checkpoint blocking antibodies, eight cases of immune-related cardiotoxicity after ipilimumab and/or nivolumab/pembrolizumab were identified. Diagnostic findings, treatment and follow-up are reported. A large variety of cardiotoxic events with manifestations such as heart failure, cardiomyopathy, heart block, myocardial fibrosis and myocarditis was documented.

This is the largest case series to date describing cardiotoxicity of immune-checkpoint blocking antibodies. Awareness, monitoring of patients with pre-existing cardiac disorders and prompt evaluation by the treatment team is essential. Treatment including application of steroids is critical for patient safety.

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Circulating protein and antibody biomarker for personalized cancer immunotherapy

Abstract

Immune checkpoint blockade therapies are revolutionizing standard cancer treatments. Immune checkpoint inhibitors likely function to enhance the tumor specific antigen response in order to achieve favorable clinical outcomes. Thus, continuous efforts to identify the common tumor-specific antigens are essential for the broad clinical application of these therapies. Several immunoproteomics approaches have been used in order to screen for this specificity. In a recent article from Jhaveri and colleagues published in the February issue of Cancer Immunology Research, antibody biomarkers were screened in pancreatic cancer patients who received allogeneic, granulocyte-macrophage colony stimulating factor-secreting pancreatic cancer vaccine (GVAX) by using a serum antibody-based SILAC immunoprecipitation (SASI) approach. Using this assay, several new tumor antigens (MYPT1, PSMC5 and TRFR) were identified that were found to have significantly different expression in tumors compared with normal tissue. Moreover, patients with detectable antibodies showed improved disease-free survival after GVAX therapy. These targets need to be further validated to determine the full spectrum of tumor antigen immunogencity and their potential clinical application. In addition to antibodies, circulating protein, DNA and RNA in peripheral blood are under clinical investigation as liquid biopsies and have the potential to provide guidance for future personalized cancer immunotherapy.

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Grover’s-like drug eruption in a patient with metastatic melanoma under ipilimumab therapy

Abstract

Background

Dermatologic toxicity is an important adverse effect of immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 receptor (PD-1) or PD ligand 1 (PD-L1). Skin toxicity most commonly includes a maculopapular erythematous rash and pruritus. Rarely life threatening complications such as Steven's Johnson syndrome or toxic epidermal necrolysis may occur.

Case presentation

Here we report the uncommon event of a drug-induced transient acantholytic dermatosis (Grover's disease) in a 73-year-old Caucasian male treated with ipilimumab for metastatic melanoma. Five weeks after initiation of therapy, the patient developed a widespread polymorphic papulovesicular dermatosis on the trunk and proximal extremities with intense pruritus. Skin biopsy showed acantholytic dyskeratosis with interface dermatitis consistent with a Grover's-like drug eruption.

Conclusions

These findings should raise awareness for uncommon immune-related dermatological toxicities of immunomodulatory antibodies targeting the CTLA-4 signaling axis. We recommend biopsies of unexpected skin lesions to rapidly identify dermatological adverse events of immune checkpoint inhibitors.

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A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma

Abstract

Background

Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in almost all preclinical models, radiation is delivered in single doses or short courses of high doses (hypofractionated radiation). By contrast in most clinical settings, radiation is delivered as standard small daily fractions of 1.8-2 Gy to achieve total doses of 50–54 Gy (fractionated radiation). We do not yet know the optimal dose and scheduling of radiation for combination with chemotherapy and immunotherapy.

Methods

To address this, we analyzed the effect of neoadjuvant standard fractionated and hypofractionated chemoradiation on immune cells in patients with locally advanced and borderline resectable pancreatic adenocarcinoma.

Results

We found that standard fractionated chemoradiation resulted in a significant and extended loss of lymphocytes that was not explained by a lack of homeostatic cytokines or response to cytokines. By contrast, treatment with hypofractionated radiation therapy avoided the loss of lymphocytes associated with conventional fractionation.

Conclusion

Hypofractionated neoadjuvant chemoradiation is associated with reduced systemic loss of T cells.

Trial registration

ClinicalTrials.gov NCT01342224, April 21, 2011; NCT01903083, July 2, 2013.

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Adenosine-generating ovarian cancer cells attract myeloid cells which differentiate into adenosine-generating tumor associated macrophages – a self-amplifying, CD39- and CD73-dependent mechanism for tumor immune escape

Abstract

Background

Ovarian cancer (OvCA) tissues show abundant expression of the ectonucleotidases CD39 and CD73 which generate immunomodulatory adenosine, thereby inhibiting cytotoxic lymphocytes. Little, however, is known about the effect of adenosine on myeloid cells. Considering that tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) constitute up to 20 % of OvCA tissue, we investigated the effect of adenosine on myeloid cells and explored a possible contribution of myeloid cells to adenosine generation in vitro and ex vivo.

Methods

Monocytes were used as human blood-derived myeloid cells. After co-incubation with SK-OV-3 or OAW-42 OvCA cells, monocyte migration was determined in transwell assays. For conversion into M2-polarized "TAM-like" macrophages, monocytes were co-incubated with OAW-42 cells. Ex vivo TAMs were obtained from OvCA ascites. Macrophage phenotypes were investigated by intracellular staining for IL-10 and IL-12. CD39 and CD73 expression were assessed by FACS analysis both on in vitro-induced TAM-like macrophages and on ascites-derived ex situ-TAMs. Myeloid cells in solid tumor tissue were analyzed by immunohistochemistry. Generation of biologically active adenosine by TAM-like macrophages was measured in luciferase-based reporter assays. Functional effects of adenosine were investigated in proliferation-experiments with CD4⁺ T cells and specific inhibitors.

Results

When CD39 or CD73 activity on OvCA cells were blocked, the migration of monocytes towards OvCA cells was significantly decreased. In vivo, myeloid cells in solid ovarian cancer tissue were found to express CD39 whereas CD73 was mainly detected on stromal fibroblasts. Ex situ-TAMs and in vitro differentiated TAM-like cells, however, upregulated the expression of CD39 and CD73 compared to monocytes or M1 macrophages. Expression of ectonucleotidases also translated into increased levels of biologically active adenosine. Accordingly, co-incubation with these TAMs suppressed CD4⁺ T cell proliferation which could be rescued via blockade of CD39 or CD73.

Conclusion

Adenosine generated by OvCA cells likely contributes to the recruitment of TAMs which further amplify adenosine-dependent immunosuppression via additional ectonucleotidase activity. In solid ovarian cancer tissue, TAMs express CD39 while CD73 is found on stromal fibroblasts. Accordingly, small molecule inhibitors of CD39 or CD73 could improve immune responses in ovarian cancer.

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PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction?

Abstract

Research in cancer immunology is currently accelerating following a series of cancer immunotherapy breakthroughs during the last 5 years. Various monoclonal antibodies which block the interaction between checkpoint molecules PD-1 on immune cells and PD-L1 on cancer cells have been used to successfully treat non-small cell lung cancer (NSCLC), including some durable responses lasting years. Two drugs, nivolumab and pembrolizumab, are now FDA approved for use in certain patients who have failed or progressed on platinum-based or targeted therapies while agents targeting PD-L1, atezolizumab and durvalumab, are approaching the final stages of clinical testing. Despite impressive treatment outcomes in a subset of patients who receive these immune therapies, many patients with NSCLC fail to respond to anti-PD-1/PD-L1 and the identification of a biomarker to select these patients remains highly sought after. In this review, we discuss the recent clinical trial results of pembrolizumab, nivolumab, and atezolizumab for NSCLC, and the significance of companion diagnostic testing for tumor PD-L1 expression.

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Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF -mutated metastatic melanoma

Abstract

Background

Ipilimumab (IPI), an anti-CTLA-4 antibody, and vemurafenib (VEM), a BRAF inhibitor, have distinct mechanisms of action and shared toxicities (e.g., skin, gastrointestinal [GI] and hepatobiliary disorders) that may preclude concomitant administration. Concurrent administration of IPI and VEM previously showed significant dose-limiting hepatotoxicity in advanced melanoma. This single-arm, open-label, phase II study evaluated a sequencing strategy with these two agents in previously untreated patients with BRAF-mutated advanced melanoma.

Methods

This study was divided into two parts. During Part 1 (VEM1-IPI), patients received VEM 960 mg twice daily for 6 weeks followed by IPI 10 mg/kg every 3 weeks for 4 doses (induction), then every 12 weeks (maintenance) beginning at week 24 until disease progression or unacceptable toxicity. During Part 2 (VEM2), patients who progressed after IPI received VEM at their previously tolerated dose. The primary objective was to estimate the incidence of grade 3/4 drug-related skin adverse events (AEs) during VEM1-IPI.

Results

All patients who were initially treated with VEM (n = 46) received IPI induction therapy; 8 received IPI maintenance and 19 were treated during VEM2. During VEM1-IPI, the incidence of grade 3/4 drug-related AEs associated with the skin, GI tract, and hepatobiliary system was 32.6 %, 21.7 %, and 4.3 %, respectively. There were no drug-related deaths. At a median follow-up of 15.3 months, median overall survival was 18.5 months. Median progression-free survival was 4.5 months.

Conclusions

VEM (960 mg twice daily for 6 weeks) followed by IPI 10 mg/kg has a manageable safety profile. The benefits/risks of BRAF inhibitors followed by immunotherapy should be evaluated further in light of continuing developments in treatment options for metastatic melanoma.

Trial registration

ClinicalTrials.gov identifier: NCT01673854 (CA184-240) Registered 24 August 2012

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Systematic Review of Current Devices for 24-h Intraocular Pressure Monitoring

Abstract

Glaucoma is a common optic neuropathy that can lead to irreversible vision loss, and intraocular pressure (IOP) is the only known modifiable risk factor. The primary method of treating glaucoma involves lowering IOP using medications, laser and/or invasive surgery. Currently, we rely on in-office measurements of IOP to assess diurnal variation and to define successful management of disease. These measurements only convey a fraction of a patient's circadian IOP pattern and may frequently miss peak IOP levels. There is an unmet need for a reliable and accurate device for 24-h IOP monitoring. The 24-h IOP monitoring devices that are currently available and in development fall into three main categories: self-monitoring, temporary continuous monitoring, and permanent continuous monitoring. This article is a systematic review of current and future technologies for measuring IOP over a 24-h period.

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68 Ga-PSMA PET-CT Imaging of Metastatic Adenoid Cystic Carcinoma

Abstract

A patient with a history of adenoid cystic carcinoma of the nasal cavity presented himself with bone pain and an elevated PSA level. On suspicion of metastatic prostate cancer a ⁶⁸Ga-PSMA PET-CT was performed. The PET-CT showed numerous lung and non-sclerotic bone metastasis. Biopsy of a bone metastasis was performed and pathology showed adenoid cystic carcinoma instead of prostate cancer. Immunohistochemical PSMA staining of the primary tumour showed intense PSMA expression in adenoid cystic carcinoma tumour cells. Because of the high PSMA expression of adenoid cystic carcinoma, ⁶⁸Ga-PSMA PET-CT might be a promising imaging modality for this malignancy.

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Impact of primary para-aortic lymphadenectomy on distant failure in locally advanced cervical cancer patients treated in the era of image-guided adaptive brachytherapy

Abstract

To investigate the impact of a primary para-aortic lymphadenectomy (PAL) in locally advanced cervical cancer patients receiving definitive chemoradiation, we reviewed the clinical records of consecutive patients treated in our Institution and receiving an external beam irradiation followed with an image-guided adaptive brachytherapy for a locally advanced cervical cancer. We examined the impact of performing a primary PAL as part of primary staging for guiding irradiation fields in patients without extra-pelvic PET uptake. The outcome of patients presenting para-aortic lymph node uptake (PALNU) was also examined. 186 patients were identified. Median follow-up was 44.4 months. Patients receiving a primary PAL (PAL group) and those who received upfront pelvic chemoradiation (no-PAL group) did not significantly differ for loco-regional failures. Survival without distant failure (DFFS), including para-aortic relapses, was at 3 years 87 % (95 % CI 84–90 %) in PAL group, 67 % (95 % CI 59–85 %) in the no-PAL group and 44 % (95 % CI 32–66 %) in the PALNU group (p = 0.04 for comparison between PAL and no-PAL groups). In a multivariate model including para-aortic lymphadenectomy, pelvic nodal uptake and high-risk clinical target volume as adjustment variables, a para-aortic lymphadenectomy was significant for DFS (HR = 0.47, 95 % CI 0.26–0.84, p = 0.01). Although confounding factors could account for these retrospective results, a primary PAL with tailored irradiation fields based on para-aortic histological findings seems to be associated with a better control for distant metastases. A randomized trial is testing the benefit of this strategy.

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Age- and gender-related characteristics of the pubic symphysis and triradiate cartilage in pediatric computed tomography

Abstract

Background

There is little information on the pubic symphysis' normal CT appearance in children.

Objective

We sought to generate age-, gender- and maturity-related symphyseal width appearances in CT scans.

Materials and methods

Pelvic CT scans performed for any reason during a 6-year period in patients younger than 18 years were retrospectively analyzed. The symphysis width was measured in the axial plane and the triradiate cartilage was classified as open or closed.

Results

Four hundred twenty-seven CT scans were evaluated and 350 remained for analysis. Age- and gender-related measurements of the symphysis width are illustrated on various centile graphs. When grouping children by age in years 0–6, 7–11, 12–15 and 16–17, mean (standard deviation) symphysis width was 5.4 mm (0.9), 5.3 mm (1.1), 4.1 mm (1.1) and 3.5 mm (1.0), respectively, in girls and 5.9 mm (1.3), 5.4 mm (1.2), 5.2 mm (1.1) and 4.0 mm (1.0), respectively, in boys. Boys and girls were significantly different in the age groups 12–15 years (P<0.001) and 16-17 years (P=0.04). In the mature pelvis, the symphyseal gap is significantly (P<0.001) shorter in both genders, and in girls compared to boys (P=0.04).

Conclusion

The pubic symphysis width in children differs according to age, gender and maturity. The reference values published herein may help detect symphyseal injury.

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Effect of the forward-projected model-based iterative reconstruction solution algorithm on image quality and radiation dose in pediatric cardiac computed tomography

Abstract

Background

Some iterative reconstruction algorithms are useful for reducing the radiation dose in pediatric cardiac CT. A new iterative reconstruction algorithm (forward-projected model-based iterative reconstruction solution) has been developed, but its usefulness for radiation dose reduction in pediatric cardiac CT is unknown.

Objective

To investigate the effect of the new algorithm on CT image quality and on radiation dose in pediatric cardiac CT.

Materials and methods

We obtained phantom data at six dose levels, as well as pediatric cardiac CT data, and reconstructed CT images using filtered back projection, adaptive iterative dose reduction 3-D (AIDR 3-D) and the new algorithm. We evaluated phantom image quality using physical assessment. Four radiologists performed visual evaluation of cardiac CT image quality.

Results

In the phantom study, the new algorithm effectively suppressed noise in the low-dose range and moderately generated modulation transfer function, yielding a higher signal-to-noise ratio compared with filtered back projection or AIDR 3-D. When clinical cardiac CT was performed, images obtained by the new method had less perceived image noise and better tissue contrast at similar resolution compared with AIDR 3-D images.

Conclusion

The new algorithm reduced image noise at moderate resolution in low-dose CT scans and improved the perceived quality of cardiac CT images to some extent. This new algorithm might be superior to AIDR 3-D for radiation dose reduction in pediatric cardiac CT.

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Patterns of Loss to Follow-Up Care Among Childhood Cancer Survivors

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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A Review of the Oncology Patient's Challenges for Utilizing Fertility Preservation Services

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Algorithmic approach to neuroendocrine tumors in targeted biopsies: Practical applications of immunohistochemical markers

Neuroendocrine tumors (NETs) constitute a heterogeneous group of neoplasms with distinct biological behaviors, depending on the site of origin and the degree of tumor proliferation. Although advances in biochemical and radiological modalities have enhanced the ability to detect NETs, tissue diagnosis remains the gold standard to assess tumor characteristics for treatment decision making. In an era with growing demands for precision diagnostics based on smaller tissue samples, immunohistochemistry has become an indispensable tool in the pathologist's repertoire. In conjunction with clinical findings and cytomorphology, complementary use of 1) markers of neuroendocrine differentiation, 2) markers confirming epithelial nature, 3) markers of cellular proliferation, 4) transcription factors and hormonal markers, as well as 5) predictive and prognostic markers may be necessary to guide patient management in NETs. The current review summarizes common applications of these immunohistochemical markers when confronted with a potential neuroendocrine neoplasm, and proposes a stepwise algorithmic approach to avoid diagnostic errors in targeted biopsies. Cancer Cytopathol 2016. © 2016 American Cancer Society.

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Endothelin-1 (ET-1) induces resistance to bortezomib in human multiple myeloma cells via a pathway involving the ETB receptor and upregulation of proteasomal activity

Abstract

Purpose

Bortezomib (BTZ) is used for the treatment of multiple myeloma (MM). However, a significant proportion of patients may be refractory to the drug. This study aimed to investigate whether the endothelin (ET-1) axis may act as an escape mechanism to treatment with bortezomib in MM cells.

Methods

NCI-H929 and RPMI-8226 (human MM cell lines) were cultured with or without ET-1, BTZ, and inhibitors of the endothelin receptors. ET-1 levels were determined by ELISA, while the protein levels of its receptors and of the PI3K and MAPK pathways' components by western blot. Effects of ET-1 on cell proliferation were studied by MTT and on the ubiquitin proteasome pathway by assessing the chymotryptic activity of the 20S proteasome in cell lysates.

Results

Endothelin receptors A and B (ET_AR and ET_BR, respectively) were found to be expressed in both cell lines, with the RPMI-8226 cells that are considered resistant to BTZ, expressing higher levels of ET_BR and in addition secreting ET-1. Treatment of the NCI-H929 cells with ET-1 increased proliferation, while co-incubation of these cells with ET-1 and BTZ decreased BTZ efficacy with concomitant upregulation of 20S proteasomal activity. Si-RNA silencing or chemical blockade of ET_BR abrogated the protective effects of ET-1. Finally, data suggest that the predominant signaling pathway involved in ET-1/ET_BR-induced BTZ resistance in MM cells may be the MAPK pathway.

Conclusion

Our data suggest a possible role of the ET-1/ET_BR axis in regulating the sensitivity of MM cells to BTZ. Thus, combining bortezomib with strategies to target the ET-1 axis could prove to be a novel promising therapeutic approach in MM.

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Voltage-gated sodium channel Nav1.7 promotes gastric cancer progression through MACC1-mediated upregulation of NHE1

Abstract

Voltage-gated sodium channels (VGSCs), which are aberrantly expressed in several human cancers, affect cancer cell behavior; however, their role in gastric cancer (GC) and the link between these channels and tumorigenic signaling remains unclear. The aims of this study were to determine the clinicopathological significance and role of the VGSC Na_v1.7 in GC progression and to investigate the associated mechanisms. Here, we report that the SCN9A gene encoding Na_v1.7 was the most abundantly expressed VGSC subtype in GC tissue samples and two GC cell lines (BGC-823 and MKN-28 cells). SCN9A expression levels were also frequently found to be elevated in GC samples compared to nonmalignant tissues by real-time PCR. In the 319 GC specimens evaluated by immunohistochemistry, Na_v1.7 expression was correlated with prognosis, and transporter Na⁺/H⁺ exchanger-1 (NHE1) and oncoprotein metastasis-associated in colon cancer-1 (MACC1) expression. Na_v1.7 suppression resulted in reduced voltage-gated sodium currents, decreased NHE1 expression, increased extracellular pH and decreased intracellular pH, and ultimately, reduced invasion and proliferation rates of GC cells and growth of GC xenografts in nude mice. Na_v1.7 inhibition led to reduced MACC1 expression, while MACC1 inhibition resulted in reduced NHE1 expression in vitro and in vivo. Mechanistically, the suppression of Na_v1.7 decreased NF-κB p65 nuclear translocation via p38 activation, thus reducing MACC1 expression. Downregulation of MACC1 decreased c-Jun phosphorylation and subsequently reduced NHE1 expression, whereas the addition of hepatocyte growth factor (HGF), a c-Met physiological ligand, reversed the effect. These results indicate that Na_v1.7 promotes GC progression through MACC1-mediated upregulation of NHE1. Therefore, Na_v1.7 is a potential prognostic marker and/or therapeutic target for GC. This article is protected by copyright. All rights reserved.

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Changes in cytogenetics and molecular genetics in acute myeloid leukemia from childhood to adult age groups

BACKGROUND

To obtain better insight into the biology of acute myeloid leukemia (AML) in various age groups, this study focused on the genetic changes occurring during a lifetime.

METHODS

This study analyzed the relation between age and genetics from birth to 100 years in 5564 patients with de novo AML diagnosed from 1998 to 2012 (1192 patients from nationwide pediatric studies [AML Berlin-Frankfurt-Münster studies 98 and 2004] and 4372 adults registered with the Munich Leukemia Laboratory).

RESULTS

The frequencies of cytogenetic subgroups were age-dependent. Favorable subtypes (t(8;21), inv(16)/t(16;16), and t(15;17)) decreased in general from the pediatric age group (2 to < 18 years; 33%) to the oldest groups (<5% for > 70 years; P < .0001). Unfavorable cytogenetics (–7/del(7), –5/del(5q) or 5p, inv(3)/t(3;3), t(6;9), complex karyotype, 12p, 17p, and 11q23/mixed-lineage leukemia aberrations, excluding t(9;11)) were frequent (42%) in infants (<2 years), had a low frequency in children and young adults (<22%), and increased in frequency up to 36% in patients older than 85 years (P = .01). This was even more significant for complex karyotypes (P ≤ .0001), which also showed a strong increase in the absolute age-specific incidence with age. Interestingly, the frequency of 11q23 abnormalities decreased from infants to older patients. The proportion of clinically relevant molecular aberrations of CCAAT/enhancer binding protein α, nucleophosmin (NPM1), and NPM1/fms-related tyrosine kinase 3–internal tandem duplication increased with age.

CONCLUSIONS

Altogether, with the exclusion of infants, a significant decrease in the proportion of favorable cytogenetic subtypes and an increase in unfavorable cytogenetics were observed with increasing age. These findings indicate different mechanisms for the pathogenesis of AML; these different mechanisms also suggest directions for etiological research and contribute to the more unfavorable prognosis with increasing age. Cancer 2016. © 2016 American Cancer Society.

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A novel prognostic model for osteosarcoma using circulating CXCL10 and FLT3LG

BACKGROUND

Osteosarcoma (OS) is the most common malignant pediatric bone tumor. The identification of novel biomarkers for early prognostication will facilitate risk-based stratification and therapy. This study investigated the significance of circulating cytokines/chemokines for predicting the prognosis at the initial diagnosis.

METHODS

Luminex assays were used to measure cytokine/chemokine concentrations in blood samples from a discovery cohort of OS patients from Texas Children's Hospital (n = 37) and an independent validation cohort obtained from the Children's Oncology Group (n = 233). After the validation of the biomarkers, a multivariate model was constructed to stratify the patients into risk groups.

RESULTS

The circulating concentrations of C-X-C motif chemokine ligand 10 (CXCL10), Fms-related tyrosine kinase 3 ligand (FLT3LG), interferon γ (IFNG), and C-C motif chemokine ligand 4 (CCL4) were significantly associated with overall survival in both cohorts. Among these candidates, CXCL10 and FLT3LG were independent of the existing prognostic factor, metastasis at diagnosis, and CCL4 further discriminated cancer cases from controls. CXCL10, FLT3LG, and the metastatic status at diagnosis were combined to develop a multivariate model that significantly stratified the patients into 4 distinct risk groups (P = 1.6 × 10⁻⁸). The survival analysis showed that the 5-year overall survival rates for the low-, intermediate-, high-, and very high–risk groups were 77%, 54%, 47%, and 10%, respectively, whereas the 5-year event-free survival rates were 64%, 47%, 27%, and 0%, respectively. Neither CXCL10 nor FLT3LG tumor expression was significantly associated with survival.

CONCLUSIONS

High circulating levels of CXCL10 and FLT3LG predicted worse survival for patients with OS. Because both CXCL10 and FL3LG axes are potentially targetable, further study may lead to novel risk-based stratification and therapy for OS. Cancer 2016. © 2016 American Cancer Society.

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Family-based exome-wide assessment of maternal genetic effects on susceptibility to childhood B-cell acute lymphoblastic leukemia in hispanics

BACKGROUND

Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) compared with other ethnic groups, but to the authors' knowledge, the genetic basis for these racial disparities remain incompletely understood. Genome-wide association studies of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of the maternal genotype on phenotype development in the offspring) also may play a role in ALL susceptibility.

METHODS

The authors conducted a family-based exome-wide association study of maternal genetic effects among Hispanics with childhood B-cell ALL using the Illumina Infinium HumanExome BeadChip. A discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families were used.

RESULTS

Three maternal single-nucleotide polymorphisms (SNPs) approached the study threshold for significance after correction for multiple testing (P<1.0 × 10⁻⁶): MTL5 rs12365708 (testis expressed metallothionein-like protein [tesmin]) (relative risk [RR], 2.62; 95% confidence interval [95% CI], 1.61-4.27 [P = 1.8 × 10⁻⁵]); ALKBH1 rs6494 (AlkB homolog 1, histone H2A dioxygenase) (RR, 3.77; 95% CI, 1.84-7.74 [P = 3.7 × 10⁻⁵]); and NEUROG3 rs4536103 (neurogenin 3) (RR, 1.75; 95% CI, 1.30-2.37 [P = 1.2 × 10⁻⁴]). Although effect sizes were similar, these SNPs were not nominally significant in the replication cohort in the current study. In a meta-analysis comprised of the discovery cohort and the replication cohort, these SNPs were still not found to be statistically significant after correction for multiple comparisons (rs12365708: pooled RR, 2.27 [95% CI, 1.48-3.50], P = 1.99 × 10⁻⁴; rs6494: pooled RR, 2.31 [95% CI, 1.38-3.85], P = .001; and rs4536103: pooled RR, 1.67 [95% CI, 1.29-2.16] P = 9.23 × 10⁻⁵).

CONCLUSIONS

In what to the authors' knowledge is the first family-based based exome-wide association study to investigate maternal genotype effects associated with childhood ALL, the results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, 3 maternal SNPs were identified that may play a modest role in susceptibility. Cancer 2016. © 2016 American Cancer Society.

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Frailty as determined by a comprehensive geriatric assessment-derived deficit-accumulation index in older patients with cancer who receive chemotherapy

BACKGROUND

Frailty has been suggested as a construct for oncologists to consider in treating older cancer patients. Therefore, the authors assessed the potential of creating a deficit-accumulation frailty index (DAFI) from a largely self-administered comprehensive geriatric assessment (CGA).

METHODS

Five hundred patients aged ≥65 years underwent a CGA before receiving chemotherapy. A DAFI was constructed, resulting in a 51-item scale, and cutoff values were examined for patients in the robust/nonfrail (cutoff value, 0.0 < 0.2), prefrail (cutoff value, 0.2 < 0.35), and frail (cutoff value, ≥ 0.35) groups.

RESULTS

Two hundred and fifty patients (50%) were nonfrail, 197 (39%) were prefrail, and 52 (11%) were frail. Older patients (aged ≥ 80 years) and those who had lower education, were living alone, and had higher stage disease were associated with prefrail/frail status. Prefrail/frail patients were more likely to have grade ≥3 toxicity but not to have a dose delay or reduction, and they were more likely to discontinue drug and be hospitalized. The association with grade ≥3 toxicity was attenuated by controlling for a toxicity risk calculator, but the other outcomes were not.

CONCLUSIONS

A deficit-accumulation frailty index can be constructed from a CGA in older patients with cancer and can indicate the frailty status of the population. The frailty status so determined is associated both with outcomes likely because of chemotherapy toxicity and with those likely because of age-related physiologic and functional deficits and thus can be useful in the overall assessment of the patient. Cancer 2016. © 2016 American Cancer Society.

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Robotic assisted placement of hepatic artery infusion pump is a safe and feasible approach

Background

Hepatic artery infusion (HAI) chemotherapy can be combined with systemic chemotherapy for the treatment of isolated unresectable colorectal liver metastases (IU-CRLM) and intrahepatic cholangiocarcinoma (U-ICC). However, HAI pump placement requires a major laparotomy that may be associated with morbidity. We hypothesized that the computer-assisted robotic platform would be well suited for this procedure and report the first single institutional case series of robotic assisted HAI pump placement for primary and secondary malignancies of the liver.

Methods

A retrospective review of patients who underwent robotic assisted HAI pump placement from January 2008 to January 2016. Peri-operative outcomes were evaluated.

Results

A total of 24 consecutive patients underwent robotic assisted HAI pump placement. Median age was 61 years and 50% were females. Main indications were colorectal cancer = 17 (71%) and intrahepatic cholangiocarcinoma = 4 (17%). The majority (87.5%) of patients had bilobar disease with a median of 6 liver lesions. Concurrent procedures including ablation +/− resection and colectomies were performed in 58% of the patients. Median operative time was 282 min, with median blood loss of 100 ml and length of stay 6 days. Conversion to open was required in one (4%) case. Grade 3 or higher complications were seen in 13% of cases and pump related complications were seen in 21% of patients. All except one HAI pumps could be used for pump chemotherapy. CUSUM analysis of operative time indicated a learning curve of eight cases.

Conclusion

Robotic assisted placement of HAI pump placement is safe, feasible, and obviates the need for major laparotomy. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Use of implicit persuasion in decision making about adjuvant cancer treatment: A potential barrier to shared decision making

Publication date: October 2016
Source:European Journal of Cancer, Volume 66
Author(s): Ellen G. Engelhardt, Arwen H. Pieterse, Anja van der Hout, Hanneke J.C.J.M. de Haes, Judith R. Kroep, Patricia Quarles van Ufford-Mannesse, Johanneke E.A. Portielje, Ellen M.A. Smets, Anne M. Stiggelbout
BackgroundShared decision making (SDM) is widely advocated, especially for preference-sensitive decisions like those on adjuvant treatment for early-stage cancer. Here, decision making involves a subjective trade-off between benefits and side-effects, and therefore, patients' informed preferences should be taken into account. If clinicians consciously or unconsciously steer patients towards the option they think is in their patients' best interest (i.e. implicit persuasion), they may be unwittingly subverting their own efforts to implement SDM. We assessed the frequency of use of implicit persuasion during consultations and whether the use of implicit persuasion was associated with expected treatment benefit and/or decision making.MethodsObservational study design in which consecutive consultations about adjuvant systemic therapy with stage I–II breast cancer patients treated at oncology outpatient clinics of general teaching hospitals and university medical centres were audiotaped, transcribed and coded by two researchers independently.ResultsIn total, 105 patients (median age = 59; range: 35–87 years) were included. A median of five (range: 2–10) implicitly persuasive behaviours were employed per consultation. The number of behaviours used did not differ by disease stage (P = 0.07), but did differ by treatment option presented (P = 0.002) and nodal status (P = 0.01). About 50% of patients with stage I or node-negative disease were steered towards undergoing chemotherapy, whereas 96% of patients were steered towards undergoing endocrine therapy, irrespective of expected treatment benefit. Decisions were less often postponed if more implicit persuasion was used (P = 0.03).InterpretationOncologists frequently use implicit persuasion, steering patients towards the treatment option that they think is in their patients' best interest. Expected treatment benefit does not always seem to be the driving force behind implicit persuasion. Awareness of one's use of these steering behaviours during decision making is a first step to help overcome the performance gap between advocating and implementing SDM.



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Physical activity and survival in breast cancer

Publication date: October 2016
Source:European Journal of Cancer, Volume 66
Author(s): Gunn Ammitzbøll, Karen Søgaard, Randi V. Karlsen, Anne Tjønneland, Christoffer Johansen, Kirsten Frederiksen, Pernille Bidstrup
PurposeKnowledge about lifestyle factors possibly influencing survival after breast cancer (BC) is paramount. We examined associations between two types of postdiagnosis physical activity (PA) and overall survival after BC.Patients and methodsWe used prospective data on 959 BC survivors from the Diet, Cancer, and Health cohort, all enrolled before diagnosis. Self-reported PA was measured as time per activity, and estimated metabolic equivalent task (MET)–hours per week were summed for each activity. We constructed measures for household, exercise, and total PA. The association between postdiagnosis PA and all-cause mortality was estimated as hazard ratio (HRs) based on Cox proportional hazards model, with time since diagnosis as the underlying time scale. Prediagnosis PA, body mass index (BMI), and receptor status were examined as potential effect modifiers.ResultsWe identified 144 deaths from all causes during the study period. In adjusted analyses, exercise PA above eight MET h/week compared to lower levels of activity was significantly associated with improved overall survival (HR, 0.68; confidence interval [CI]: 0.47–0.99). When comparing participation in exercise to non-participation, we found a 44% risk reduction in overall survival (HR, 0.56; CI: 0.33–0.95). Neither between household nor total PA and overall survival did, we find significant associations. Prediagnosis PA, BMI, and receptor status did not modify the effect significantly.ConclusionExercise PA corresponding to 2.5 h or more of brisk weekly walking after BC diagnosis may reduce mortality by up to 32% compared to low-level exercise. Participation in exercise PA may reduce mortality by 44% compared to non-participation.



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The impact of lymph node dissection and adjuvant chemotherapy on survival: A nationwide cohort study of patients with clinical early-stage ovarian cancer

Publication date: October 2016
Source:European Journal of Cancer, Volume 66
Author(s): Marjolein Kleppe, Maaike A. van der Aa, Toon Van Gorp, Brigitte F.M. Slangen, Roy F.P.M. Kruitwagen
IntroductionTo establish the impact of lymph node dissection and chemotherapy on survival in patients with early-stage epithelial ovarian cancer (EOC).MethodsAll Dutch patients with International Federation of Gynaecology and Obstetrics (FIGO) stage I–IIA and IIIA1 EOC between 2000 and 2012 were included. Data concerning age, stage, tumour grade, histological subtype, hospital type, lymph node dissection, adjuvant chemotherapy and survival were extracted from the Netherlands Cancer Registry.ResultsOf 3658 patients included, 1813 (49.6%) had lymph nodes removed. Relative survival of patients with lymph node dissection (including those with lymph node metastases) was significantly better than that of patients without, also after correcting for stage, tumour grade, histology and age (89% and 82%, respectively; relative excess risk [RER], 0.64; 95% confidence interval [CI]: 0.52–0.78). There was a positive correlation between the number of removed lymph nodes and overall survival (after excluding patients with lymph node metastases). Of patients with stage I–IIA EOC who had ≥10 lymph nodes removed, there was no difference in relative survival between those who received chemotherapy and those who did not (RER, 0.51; 95% CI: 0.15–1.64). This was also true for a subgroup of patients with high-risk features (stage IC and IIA and/or tumour grade 3 and/or clear cell histology [RER, 0.90; 95% CI: 0.46–1.99]).ConclusionAdequate dissection of at least 10 but preferably ≥20 lymph nodes should be standard procedure for the staging of early-stage EOC. Adjuvant chemotherapy after an adequate lymph node dissection does not seem to contribute to a better relative survival.



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Acute neurovascular events in cancer patients receiving anti-vascular endothelial growth factor agents: Clinical experience in Paris University Hospitals

Publication date: October 2016
Source:European Journal of Cancer, Volume 66
Author(s): Camille Tlemsani, Olivier Mir, Dimitri Psimaras, Yann-Alexandre Vano, Michel Ducreux, Bernard Escudier, Benoit Rousseau, Delphine Loirat, Bernard Ceccaldi, Thierry André, François Goldwasser, Damien Ricard
BackgroundDespite the increasing and broadening use of agents targeting the vascular endothelial growth factor (VEGF) pathway, little is known on their acute neurovascular toxicities.MethodsThis retrospective, multi-centre study examined the characteristics of patients with solid tumours who experienced an ischaemic or haemorrhagic stroke, a transient ischaemic accident (TIA) or a posterior reversible encephalopathy syndrome (PRES) while under anti-VEGF and until 8 weeks after termination of treatment and evaluated their management in our institutions from 2004 to 2014. Patients with newly diagnosed or progressive cerebral metastases at the time of the acute neurovascular event were excluded.ResultsThirty-four patients (55.9% men) were identified, and experienced either ischaemic stroke (n = 18), PRES (n = 9), TIA (n = 6) or haemorrhagic stroke (n = 1). At initiation of anti-VEGF agents, 64.7% of patients had previous cardiovascular risk factors, and 52.9% had hypertension. Eight patients (23.5%) had received cerebral radiotherapy, five of which concomitantly to anti-VEGF treatment. Six (17%) patients died in the 8 weeks following the acute neurovascular event, and only 55.9% recovered their initial neurological status. Overall, 1-year and 2-year survival rates after the acute neurovascular event were 67.9% and 50%, respectively. When anti-VEGF agents were reintroduced (n = 6), severe vascular toxicity recurred in two patients.ConclusionsNeurovascular events under VEGF treatments are potentially severe, and the management of comorbid conditions has to be improved. A prospective collection of data and standardised management of such events is therefore being structured in our institutions.



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Nurse-led group consultation intervention reduces depressive symptoms in men with localised prostate cancer: a cluster randomised controlled trial

Abstract

Background

Radiotherapy for localised prostate cancer has many known and distressing side effects. The efficacy of group interventions for reducing psychological morbidity is lacking. This study investigated the relative benefits of a group nurse-led intervention on psychological morbidity, unmet needs, treatment-related concerns and prostate cancer-specific quality of life in men receiving curative intent radiotherapy for prostate cancer.

Methods

This phase III, two-arm cluster randomised controlled trial included 331 men (consent rate: 72 %; attrition: 5 %) randomised to the intervention (n = 166) or usual care (n = 165). The intervention comprised four group and one individual consultation all delivered by specialist uro-oncology nurses. Primary outcomes were anxious and depressive symptoms as assessed by the Hospital Anxiety and Depression Scale. Unmet needs were assessed with the Supportive Care Needs Survey-SF34 Revised, treatment-related concerns with the Cancer Treatment Scale and quality of life with the Expanded Prostate Cancer Index −26. Assessments occurred before, at the end of and 6 months post-radiotherapy. Primary outcome analysis was by intention-to-treat and performed by fitting a linear mixed model to each outcome separately using all observed data.

Results

Mixed models analysis indicated that group consultations had a significant beneficial effect on one of two primary endpoints, depressive symptoms (p = 0.009), and one of twelve secondary endpoints, procedural concerns related to cancer treatment (p = 0.049). Group consultations did not have a significant beneficial effect on generalised anxiety, unmet needs and prostate cancer-specific quality of life.

Conclusions

Compared with individual consultations offered as part of usual care, the intervention provides a means of delivering patient education and is associated with modest reductions in depressive symptoms and procedural concerns. Future work should seek to confirm the clinical feasibility and cost-effectiveness of group interventions.

Trial registration

Australian and New Zealand Clinical Trials Registry ANZCTRN012606000184572. 1 March 2006.

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Antipsychotic-induced Akathisia in cancer settings

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Speaking the same language: a feasibility trial for a novel visual communication tool for oncologist-patient treatment discussions

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Functional and clinical significance of the integrin alpha chain CD49d expression in chronic lymphocytic leukemia.

Related Articles

Functional and clinical significance of the integrin alpha chain CD49d expression in chronic lymphocytic leukemia.

Curr Cancer Drug Targets. 2016 Aug 9;

Authors: Bo MD, Tissino E, Benedetti D, Caldana C, Bomben R, Del Poeta G, Gaidano G, Rossi FM, Bulian P, Zucchetto A, Gattei V

Abstract
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of neoplastic cells with the morphological appearance of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. CD49d, the α chain of the α4β1 integrin heterodimer, is one of the main interactors between CLL cells and accessory cells in the microenvironmental sites and one of the main predictors of overall survival. In particular, CD49d is known to play a pivotal role in mediating both cell-cell and cell-matrix interactions in CLL-involved tissues eventually delivering prosurvival signals and protecting CLL cells from drug-induced damages. Treatment strategies targeting the α4β1 integrin could represent an interesting option in CLL. In this context, the recombinant anti-CD49d antibody natalizumab demonstrated the potential to overcome stromal cell-induced resistance of B cell lymphoma cells against cytotoxic drugs and rituximab in-vitro. Moreover, a specific interest for the CD49d molecule raises from the clinical activity of the recently proposed inhibitors of kinases downstream the BCR that has been recently related with the inside-out activation of the α4β1 integrin. In the review, we addressed in detail the role of CD49d in CLL cells, including clinical impact, relationship with specific cytogenetic features, and CD49d-dependent interactions in lymph node and bone marrow microenvironment responsible for growth- and survival- supporting signals, eventually influencing CLL prognosis and therapeutic options.

PMID: 27514846 [PubMed - as supplied by publisher]

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Treatment registry for outcomes in patients with castration-resistant prostate cancer (TRUMPET): a methodology for real-world evidence and research

Future Oncology Ahead of Print.


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PET imaging of recurrent and metastatic prostate cancer with novel tracers

Future Oncology Ahead of Print.


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Researcher Interview: Aviv Regev

For this Researcher Interview, CCG Communications Manager Amy E. Blum, M.A. spoke to Aviv Regev, Ph.D. Dr. Regev is a Core Member at the Broad Institute, Associate Professor of Biology at MIT, and an Early Career Scientist at the Howard Hughes Medical Institute. 

Amy E. Blum: Your research focuses on molecular circuitry. For starters, what are molecular circuits?

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The Cancer Council Australia Medical Student Essay Competition

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Developing and Evaluating Multimedia Patient Education Tools to Better Prepare Prostate-Cancer Patients for Radiotherapy Treatment (Randomized Study)

Abstract

The purpose of this study is to determine the effectiveness of multimedia educational tools to improve CT planning preparation for intensity modulated radiotherapy (IMRT) for prostate cancer. Many patients are not prepared when given verbal preparation instructions to have a full bladder and empty rectum for their IMRT and require being rescanned, which results in additional costs for the patient and the hospital. A pamphlet and video outlining the proper preparation for prostate IMRT was created to decrease additional scans and the associated costs, while increasing patient satisfaction. A controlled, randomized experimental group study was conducted to examine the effectiveness of the multimedia tools (the video and the pamphlet), as compared to the pamphlet only, in preparing patients for their planning CT appointment. We found no statistical difference between the multimedia group and the pamphlet group in patients' preparedness for their appointments and the rescanning rate. However, patients in the multimedia group indicated that they felt more prepared about their treatment after watching the video and stated that they would recommend the video to other patients with prostate cancer. Furthermore, patients who had to wait longer for their planning CT appointment felt less prepared by the materials than those with a shorter wait time. We recommend reducing wait times between appointments as much as possible to increase patients' preparedness for the planning CT. We conclude that providing multimedia treatment information and minimizing wait times increases patients' feelings of preparedness leading to a more positive treatment experience and reducing costly rescans.

Trial registration: ClinicalTrials.gov NCT02410291

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