MLN8237 plus eribulin eradicates metastases via autophagy

Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubule targeting drug eribulin on different stages of metastasis in triple negative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer. Eribulin application induces accumulation of active AURKA in TNBC cells providing foundation for the combination therapy. Mechanistically, AURKA inhibition induced cytotoxic autophagy via activation of the LC3B/p62 axis and inhibition of pAKT, leading to eradication of metastases, but has no effect on growth of mammary tumor. Combination of MLN8237 with eribulin leads to a synergistic increase in apoptosis in mammary tumors, as well as cytotoxic autophagy in metastases. This preclinical data provides a new understanding of the mechanisms by which MLN8237 mediates its anti-metastatic effects and advocates for its combination with eribulin in future clinical trials for metastatic breast cancer and early stage solid tumors.

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De Novo vs Nevus-Associated Melanomas: Differences in Associations With Prognostic Indicators and Survival

Background: Although 20% to 30% of melanomas are histopathologically 'nevus associated,' the majority of melanomas arise de novo, ie, in clinically normal skin with no associated nevus. We examined whether these forms of melanoma differed in their associations with clinical and histopathologic features and patient survival.

Methods: We analyzed two prospective cohorts from our institution with protocol-driven follow-up information (NYU1, n = 1024; NYU2, n = 1125). We used univariate and multivariable analyses to examine associations between de novo vs nevus-associated melanoma classification and age, anatomic site, tumor thickness, tumor ulceration, mitotic index, histological subtype, clinical stage, and survival. We tested the associations identified in NYU1 using NYU2 as a replication cohort. All tests of statistical significance were two-sided.

Results: In NYU1, de novo melanomas were associated with tumor thickness greater than 1.0 mm (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.43 to 2.70, P < .001), ulceration (OR = 1.65, 95% CI = 1.10 to 2.54, P = .02), nodular subtype (OR = 3.26, 95% CI = 1.70 to 7.11, P = .001), greater than stage I (OR = 2.35, 95% CI = 1.65 to 3.40, P < .001), older age (OR = 1.64, 95% CI = 1.18 to 2.30, P = .004), and shorter overall survival (HR = 1.63, 95% CI = 1.22 to 2.18, P < .001). In NYU2, de novo melanoma was again statistically significantly associated with thickness greater than 1.0 mm (OR = 2.24, 95% CI = 1.72 to 2.93, P < .001), ulceration (OR = 2.88, 95% CI = 1.95 to 4.37, P < .001), nodular subtype (OR = 2.41, 95% CI = 1.75 to 3.37, P < .001), greater than stage I (OR = 2.42, 95% CI = 1.80 to 3.29, P < .001), older age (OR = 1.68, 95% CI = 1.31 to 2.17, P < .001), and shorter overall survival (HR = 2.52, 95% CI = 1.78 to 3.56, P < .001). In multivariable analysis, de novo classification was an independent, poor prognostic indicator in NYU2 (HR = 1.70, 95% CI = 1.19 to 2.44, P = .004). Male patients had a statistically significantly worse survival than female patients if their melanoma was de novo (NYU1, P < .001; NYU2, P < .001); unexpectedly, there was no sex difference in survival among patients with nevus-associated tumors.

Conclusions: These data suggest that de novo melanomas are more aggressive than nevus-associated melanomas. This classification scheme may also provide a useful framework for investigations into sex differences in melanoma outcomes.

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CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial)

CEA response may be a surrogate for response and long term outcome in (K)RAS wild-type mCRC receiving first-line targeted therapy. In the FIRE-3 trial, FOLFIRI and cetuximab induced a faster and greater CEA response than FOLFIRI and bevacizumab. CEA response correlated with longer PFS and OS. Hypothesizing that CEA reflects tumor burden greater CEA response may indicate greater antitumor efficacy.

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The Time To Progression Ratio: a new individualized volumetric parameter for early detection of clinical benefit of targeted therapies

Detecting signs of efficacy in early phase clinical trials is essential for efficient drug development. The TTP ratio is a novel endpoint that incorporates volumetrics and an intra-patients control to determine treatment efficacy. Response according to TTP ratio was correlated to Overall Survival and identified patients within the RECIST Stable Disease group who had a longer Overall Survival.

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The role of oral hygiene in head and neck cancer: Results from International Head and Neck Cancer Epidemiology (INHANCE) Consortium

This pooled analysis describes the largest and most comprehensive assessment of the association between oral hygiene indicators and HNCs to date, including oral cavity, laryngeal, hypopharyngeal, and oropharyngeal cancers. We found good oral hygiene is associated with higher lower risk of HNC. Improvements in oral hygiene by increasing oral hygiene literacy, particularly for annual dentist visits and daily tooth brushing, may be protective against HNC.

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Key concepts in MR spectroscopy and practical approaches to gaining biochemical information in children

Abstract

Magnetic resonance spectroscopy (MRS) provides independent biochemical information and has become an invaluable adjunct to MRI and other imaging modalities. This review introduces key concepts and presents basic methodological steps regarding the acquisition and the interpretation of proton MRS. We review major brain metabolites and discuss MRS dependence on age, location, echo time and field strength.

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The radiology report: a guide to thoughtful communication for radiologists and other medical professionals, by Curtis P. Langlotz

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Hermes

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MR spectroscopy in children: protocols and pitfalls in non-tumorous brain pathology

Abstract

Proton nuclear magnetic resonance spectroscopy (MRS) delivers information about cell content and metabolism in a noninvasive manner. The diagnostic strength of MRS lies in its evaluation of pathologies in combination with conventional magnetic resonance imaging (MRI). MRS in children has been most widely used to evaluate brain conditions like tumors, infections, metabolic diseases or learning disabilities and especially in neonates with hypoxic-ischemic encephalopathy. This article reviews some basic theoretical considerations, routine procedures, protocols and pitfalls and will illustrate the range of spectrum alterations occurring in some non-tumorous pediatric brain pathologies.

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Sonography of pediatric blunt scrotal trauma: what the pediatric urologist wants to know

Abstract

Pediatric blunt scrotal trauma is most often the consequence of sports injury and presents a diagnostic challenge because swelling and pain make a scrotal physical exam difficult. US with color flow and duplex Doppler is the first-line imaging modality with the goal of accurate and timely diagnosis of injury requiring surgery to preserve fertility and hormonal function. US imaging findings following blunt scrotal trauma include hydrocele, hematocele, testicular hematoma, testicular fracture, testicular rupture, compromised perfusion/testicular torsion and testicular dislocation. Importantly, several of these findings may coexist. Our goal is to present the pertinent intrascrotal anatomy, US imaging findings for each testicular injury, and contemporary management for each, with emphasis on what our pediatric urology colleagues need to know for optimal patient care.

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Pediatric Radiology Continuing Medical Education Activity

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Automated radiogrammetry is a feasible method for measuring bone quality and bone maturation in severely disabled children

Abstract

Background

Children with severe neurological impairment and intellectual disability are prone to low bone quality and fractures.

Objective

We studied the feasibility of automated radiogrammetry in assessing bone quality in this specific group of children. We measured outcome of bone quality and, because these children tend to have altered skeletal maturation, we also studied bone age.

Materials and methods

We used hand radiographs obtained in 95 children (mean age 11.4 years) presenting at outpatient paediatric clinics. We used BoneXpert software to determine bone quality, expressed as paediatric bone index and bone age.

Results

Regarding feasibility, we successfully obtained a paediatric bone index in 60 children (63.2%). The results on bone quality showed a mean paediatric bone index standard deviation score of −1.85, significantly lower than that of healthy peers (P < 0.0001). Almost 50% of the children had severely diminished bone quality. In 64% of the children bone age diverged more than 1 year from chronological age. This mostly concerned delayed bone maturation.

Conclusion

Automated radiogrammetry is feasible for evaluating bone quality in children who have disabilities but not severe contractures. Bone quality in these children is severely diminished. Because bone maturation frequently deviated from chronological age, we recommend comparison to bone-age-related reference values.

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Proton MRS imaging in pediatric brain tumors

Abstract

Magnetic resonance (MR) techniques offer a noninvasive, non-irradiating yet sensitive approach to diagnosing and monitoring pediatric brain tumors. Proton MR spectroscopy (MRS), as an adjunct to MRI, is being more widely applied to monitor the metabolic aspects of brain cancer. In vivo MRS biomarkers represent a promising advance and may influence treatment choice at both initial diagnosis and follow-up, given the inherent difficulties of sequential biopsies to monitor therapeutic response. When combined with anatomical or other types of imaging, MRS provides unique information regarding biochemistry in inoperable brain tumors and can complement neuropathological data, guide biopsies and enhance insight into therapeutic options. The combination of noninvasively acquired prognostic information and the high-resolution anatomical imaging provided by conventional MRI is expected to surpass molecular analysis and DNA microarray gene profiling, both of which, although promising, depend on invasive biopsy. This review focuses on recent data in the field of MRS in children with brain tumors.

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Case 4: an adolescent girl with left lower quadrant pain

Abstract

The imaging management of an adolescent girl with pelvic pain and ovarian pathology is discussed through the details of a specific case.

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Comments on “Use of metformin and risk of kidney cancer in patients with type 2 diabetes”, Chin-Hsiao Tseng, Eur J Cancer, 2016, No. 52, pp. 19–25

Publication date: July 2016
Source:European Journal of Cancer, Volume 61
Author(s): Roy G.P.J. de Jong, Johannes T.H. Nielen, Ad A.M. Masclee, Maryska L.G. Janssen-Heijnen, Frank de Vries




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Response to Letter to the Editor on comments on Use of metformin and risk of kidney cancer in patients with type 2 diabetes Chin-Hsiao Tseng, Eur J Cancer, 2016, No. 52, pp. 19–25

Publication date: July 2016
Source:European Journal of Cancer, Volume 61
Author(s): Chin-Hsiao Tseng




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Human papillomavirus not detected in esophageal adenocarcinoma tumor specimens-Reply

Publication date: Available online 27 May 2016
Source:Cancer Epidemiology
Author(s): Annika Antonsson, Lani Knight, David C. Whiteman




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Physical Activity, Self-Efficacy and Self-Esteem in Breast Cancer Survivors: A Panel Model

Abstract

Purpose

Physical activity (PA) has been consistently associated with improved self-esteem in breast cancer survivors. However, this relationship is poorly understood. The purpose of this study was to examine whether changes in PA and self-efficacy influenced changes in self-esteem in breast cancer survivors across six-months. Increases in PA were hypothesized to result in increases in self-efficacy which were hypothesized to influence increases in physical self-worth and global self-esteem.

Methods

Breast cancer survivors (n = 370; M_age = 56.04) wore accelerometers to measure PA and completed measures of self-efficacy (e.g., exercise and barriers self-efficacy), physical self-worth, and global self-esteem at baseline and 6 months.

Results

The hypothesized model provided a good fit to the data (χ² = 67.56, df = 26, p < .001; CFI = .98; SRMR = .05). Women with higher activity at baseline reported significantly higher levels of barrier (β = .29) and exercise (β = .23) self-efficacy. In turn, more efficacious women reported significantly higher physical self-worth (β = .26, .16). Finally, higher physical self-worth was significantly associated with greater global self-esteem (β = .47). Relationships were similar among changes in model constructs over 6 months. After controlling for covariates, the hypothesized model provided an excellent fit to the data (χ² = 59.93, df = 33, p = .003; CFI = .99; SRMR = .03).

Conclusion

Our findings provide support for the role played by PA and self-efficacy in positive self-esteem, a key component of well-being. Highlighting successful PA mastery experiences is likely to enhance self-efficacy and improve self-esteem in this population.

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Interest in Initiating an Early Phase Clinical Trial: Results of a Longitudinal Study of Advanced Cancer Patients

Abstract

Objective

Enhanced recruitment of patients with advanced cancer (ACP) to early phase (EP) trials is needed. However, selective recruitment may affect the kinds of patients who are recruited. To address whether ACP who initiate EP trial enrollment differ from those who do not, we prospectively surveyed ACP well in advance of potential trial recruitment and followed them over time to identify those who initiated the recruitment process.

Methods

EP trial initiation was defined as a patient being referred for screening to an active EP trial. Depression and anxiety were assessed with the Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder Scale (GAD-7), respectively. Demographic and disease characteristics, functional status, and patient preferences regarding decision making were examined as possible predictors of EP trial initiation.

Results

Of the 78 advanced cancer patients in the cohort studied, 21 (27%) initiated EP trial participation, while 57 (73%) did not. Of those who initiated this process, 14 (67%) went on to enroll in an EP study. Level of depression severity was associated with EP trial initiation, with rates of initiation nearly three times higher (35% vs. 12%, p = 0.054) among patients with minimal to mild levels of depression compared to those with moderate or higher levels of depression. EP trial initiation was not associated with demographic or socioeconomic variables, cancer type, functional status, quality of life, or decision-making variables.

Conclusions

The presence of elevated depressive symptoms may be associated with the EP trial recruitment and enrollment processes. This possible relationship warrants further study.

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Hospitalization and other risk factors for depressive and anxious symptoms in oncological and non-oncological patients

Abstract

Objective

Depression and anxiety are common in hospitalized patients. In particular, oncological patients might be vulnerable to depression and anxiety. The aim of this study is to assess and compare different variables and the prevalence of anxiety and depression symptoms between oncological and medically ill inpatients and to identify variables that can influence depressive and anxious symptoms during hospitalization of patients.

Methods

A total of 360 consecutive hospitalized patients completed the following questionnaires: Hospital Anxiety and Depression Scale (HADS), Patients Health Questionnaire-9, General Health Questionnaire (GHQ-12), 12-Item Short-Form Survey: physical component summary (PCS), and mental component summary (MCS). Patients were divided into oncological patients and non-oncological patients: groups 1 and 2.

Results

Only two significant differences were evident between the groups: the PCS of 12-item Short-form Survey was higher in non-oncological patient (p < 0.000), and the GHQ total score was higher in oncological patients. Variables significantly associated with HADS-D ≥ 8 were lower MCS, higher GHQ-12 score, lower PCS, more numerous previous hospitalizations, longer duration of hospitalization, and positive psychiatric family history. Variables significantly associated with HADS-A ≥ 8 were lower MCS, higher GHQ-12 score, positive psychiatric family history, longer duration of hospitalization, and younger age.

Conclusions

Anxiety and depression symptoms in concurrent general medical conditions were associated with a specific sociodemographic profile, and this association has implications for clinical care. Copyright © 2016 John Wiley & Sons, Ltd.

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A miRNAs panel promotes the proliferation and invasion of colorectal cancer cells by targeting GABBR1

Abstract

MicroRNAs (miRNAs) have been implicated in the regulation of colorectal cancer. Despite the expression of miR-17-92 cluster in cancer has been gradually revealed, the role of each individual miRNAs in colorectal cancer still remains unclear. We studied the impact of miR-106a/b, miR-20a/b, and miR-17 of miR-17-92 cluster on colorectal cancer cells. Real-time quantitative polymerase chain reactions (RT-PCR) were used to test these five miRNAs expression in colorectal cancer cell line HCT116. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays, Bromodeoxyuridine (BrdU), and Transwell invasion assays were used to explore the effects of these five miRNAs in colorectal cancer cells. Luciferase reporter assay, RT-PCR, and western blotting were performed to validate the interaction of these five miRNAs with the gamma-amino-butyric acid type B receptor 1(GABBR1). We found that these five miRNAs were significantly upregulated in colorectal cancer samples compared with normal tissues. Forced expression of these five miRNAs significantly promoted HCT116 and HT-29 cells proliferation and invasion. We further found that these five miRNAs function as oncogenes in colorectal cancer by specifically binding to the 3-untranslated regions (3′UTR) of GABBR1.Furthermore, inhibition of GABBR1 could mimic the function of miRNAs in HCT116 cells, while overexpression of GABBR1 blocked the function of miRNAs-promoted proliferation and invasion. In conclusion, miR-106a/b, miR-20a/b, and miR-17 contribute to the proliferation and invasion of colorectal cancer by targeting their common target gene, GABBR1, and played a critical role in the proliferation and invasion of colorectal cancer.

We studied the impact of miR-106a/b, miR-20a/b, and miR-17 of miR-17-92 cluster on colorectal cancer cells. miR-106a/b, miR-20a/b, and miR-17 contribute to the proliferation and invasion of colorectal cancer by targeting their common target gene, GABBR1, and played a critical role in the proliferation and invasion of colorectal cancer.

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Epithelial–mesenchymal transition, proliferation, and angiogenesis in locally advanced cervical cancer treated with chemoradiotherapy

Abstract

We evaluated the association between epithelial–mesenchymal transition (EMT)-derived markers and expression of proteins associated with cell proliferation and tumor growth, as well as their prognostic roles, in 61 patients (mean age 52 ± 10 years) with locally advanced cervical cancer, all of whom were treated with chemoradiation and intracavitary brachytherapy. We used immunohistochemical analysis to assess the expression of proteins targeted in our investigation. Various statistical analyses were then conducted to assess protein marker associations with survival outcomes. Forty-six percent of the patients were positive for human papilloma virus. Median progression-free survival (PFS) was 6.6 months (95% confidence interval [CI]: 4.0–9.1, whereas overall survival (OS) was 30.0 months (95% CI: 11–48). Multivariate analysis demonstrated that vascular endothelial growth factor (VEGF) (P = 0.002), epidermal growth factor receptor (EGFR) (P = 0.001), and TWIST2 (P = 0.001) expression levels, as well as a tumor size <6 cm (P = 0.02), influenced OS. Changes in TWIST2 levels and loss of E-cadherin expression were correlated with VEGF and EGFR levels; furthermore, patients with high TWIST2 expression had shorter OS (P = 0.0001), as those with loss of E-cadherin (P = 0.02). OS was even shorter when positive EGFR or VEGF expression was related with EMT markers (positive EGFR + negative E-cadherin: median 14 months, 95% CI: 3–24; negative EGFR + positive E-cadherin: median 31 months, 95% CI: 14–NA; P = 0.02.). The presence of EMT markers was associated with proliferative and pro-angiogenic protein expression and influenced the prognosis of locally advanced cervical cancer.

Epithelial–mesenchymal transition markers are associated with proliferative and pro-angiogenic protein expression and may influence the prognosis of locally advanced cervical cancer.

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Beyond sentinel node algorithm. Toward a more tailored surgery for cervical cancer patients

Abstract

Nowadays cervical cancer is frequently diagnosed at early stage. For these patients lymph node metastasis (LNM) is considered the most important prognostic factor. During the last decade many efforts have been made to reduce rate of complications associated with lymphadenectomy (LND). A great interest has arisen in sentinel lymph node (SLN) biopsy as a technique able to decrease number of LND performed and, at the same time, to assess lymph nodal status. High diagnostic performances have been reached thanks to SLN surgical algorithm. However, despite the efforts, about 25% of these patients undergo at least unilateral LND to meet NCCN recommendations. Data of women with International Federation of Gynecology and Obstetrics stage IA1-IB1/IIA1 cervical carcinoma were retrospectively collected by six Italian institutions. All patients underwent complete preoperative staging workup and were primarily treated by radical hysterectomy and pelvic bilateral LND. A total of 368 patients with early-stage cervical cancer were identified. Among them 333 (90.5%) showed no suspicious enlarged nodes at the preoperative magnetic resonance imaging (MRI). In this subset, tumor diameter ≥20 mm was the only independent predictor of LN status (P = 0.003). None of the 106 patients with negative MRI nodal assessment, with squamous and adenosquamous histotype and a tumor diameter less than 2 cm had LNM. Based on these results we propose a new modified SLN surgical algorithm that could safely reduce LND performed in patients with very low-risk early-stage cervical cancer.

There is a subgroup of patients at very low risk of lymph node metastasis. In these women, complete lymphadenectomy could be avoided without risk.

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Local control with 21-Gy radiotherapy for high-risk neuroblastoma

Publication date: Available online 27 May 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Dana L. Casey, Brian H. Kushner, Nai-Kong V. Cheung, Shakeel Modak, Michael P. LaQuaglia, Suzanne L. Wolden
PurposeThe optimal dose of radiation in high-risk neuroblastoma is unknown. We sought to evaluate local control following 21-Gy radiotherapy (RT) to the primary site in patients with high-risk neuroblastoma.Patients and MethodsAfter receiving dose-intensive chemotherapy and gross total resection (GTR), 246 patients (ages 1.2-17.9, median 4.0 years) with high-risk neuroblastoma underwent RT to the primary site at xxx from 2000-2014. RT consisted of 21 Gy in twice-daily fractions of 1.5 Gy each. Local failure (LF) was correlated with biologic prognostic factors and clinical findings at the time of diagnosis and start of RT.ResultsMedian follow-up of surviving patients was 6.4 years. Cumulative incidence of LF was 7.1% at 2 years post-RT and 9.8% at 5 years post-RT. The isolated LF rate was 3.0%. Eighty-six percent of all local failures were within the RT field. Local control was worse in patients who required more than one surgical resection to achieve GTR (22.4% vs 8.3%, p=0.01). There was also a trend towards inferior local control with MYCN-amplified tumors or serum LDH ≥1500 U/L (p=0.09 and p=0.06 respectively).ConclusionAfter intensive chemotherapy and maximal surgical debulking, hyperfractionated RT with 21 Gy in high-risk neuroblastoma results in excellent local control. Given the young patient age, concern for late effects, and local control >90%, dose-reduction may be appropriate for patients without MYCN amplification who achieve GTR.



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Patterns and Timing of Failure for Diffuse Large B-Cell Lymphoma After Initial Therapy in a Cohort Who Underwent Autologous Bone Marrow Transplantation for Relapse

Publication date: Available online 27 May 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sughosh Dhakal, James E. Bates, Carla Casulo, Jonathan W. Friedberg, Michael W. Becker, Jane L. Liesveld, Louis S. Constine
PurposeDespite the remarkable advances resulting from R-CHOP-based chemotherapy, a significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) will relapse or have refractory disease. For newly diagnosed patients, the role of adjuvant radiotherapy (RT) following R-CHOP remains ill-defined. We evaluated the location and timing of initial recurrence in patients with DLBCL who subsequently underwent high-dose chemotherapy with autologous stem cell transplant (HDC/ASCT) in order to direct approaches for disease surveillance, inform us about the patterns of failure of contemporary treatment strategies, and guide adjuvant treatment decisions.Materials/MethodsWe analyzed consecutive patients with DLBCL who underwent HDC/ASCT between May 1992 and March 2014 at our institution. Of the 187 evaluable patients, 8 had incomplete data, and 79 underwent HDC/ASCT as a component of initial treatment for de novo or refractory DLBCL and were excluded from further analysis.ResultsThe median age was 50.8 years; the median time to relapse was 1.3 years. Patients were segregated according to the initial stage at diagnosis with early-stage (ES) defined as stage I/II and advanced-stage (AS) defined as stage III/IV. In total, 40.4% of the ES and 75.5% of the AS patients relapsed in sites of initial disease; 68.4% of those with ES disease and 75.0% of those with AS disease relapsed in sites of initial disease only. Extranodal relapses were common (44.7% in ES and 35.9% in AS), and occurred in a variety of organs, though GI tract/liver (n = 12) was most frequent.ConclusionsMost patients with DLBCL who relapse and subsequently undergo HDC/ASCT initially recur in the previously involved disease site(s). Time to recurrence is brief suggesting that frequency of screening is most justifiably greatest in the early post-therapy years.

Teaser

A significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) will relapse or have refractory disease to initial chemotherapy. We analyze the patterns of initial disease and patterns of relapse among patients with DLBCL who subsequently underwent high-dose chemotherapy with autologous stem cell transplant (HDC/ASCT) at our institution and showed a substantial majority of patients relapse in sites of initial disease.


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Association between travel distance and choice of treatment for prostate cancer: does geography reduce patient choice?

Publication date: Available online 27 May 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Vinayak Muralidhar, Brent S. Rose, Yu-Wei Chen, Michelle D. Nezolosky, Paul L. Nguyen
ObjectiveThe choice of local therapy for patients with prostate cancer depends partially on patient preferences. We sought to determine whether the distance between a patient's home and treatment facility was related to the choice of treatment received among those opting for surgery or radiation.Materials/MethodsWe identified 222,804 patients diagnosed with NCCN low, intermediate, or high-risk N0M0 prostate cancer and treated with local therapy (surgery or radiation alone, with or without hormone therapy) using the National Cancer Database (NCDB). We used multivariable logistic regression to determine the rate of radiation therapy versus radical prostatectomy versus distance among patients living in rural and urban areas. Analyses were adjusted for geographic location within the US, age, race, Charlson/Deyo co-morbidity score, year of diagnosis, income quartile, education quartile, Gleason score, PSA, and T stage.ResultsPatients living in urban or rural areas were less likely to receive radiation compared to surgery if they lived farther from the treatment facility. Among urban patients living ≤5 miles of the treatment facility, 53.3% received radiation, compared to 47.0%, 43.6%, and 33.8% of those living 5-10, 10-15, or >15 miles away (p<0.001 in all cases). Similarly, rural patients were less likely to receive radiation the farther they lived from the treatment facility (≤25 miles: 62.3%; 25-50 miles: 55.5%; 50-75 miles: 38.4%; >75 miles: 23.8%; p<0.05 in all cases). These trends were also present when each risk group was analyzed separately.ConclusionPatients with prostate cancer in both urban and rural settings were less likely to receive radiation therapy rather than surgery the farther away they lived from a treatment center. These findings raise the possibility that the geographic availability of radiation treatment centers may be an important determinant of whether patients are able to choose radiation rather than surgery for localized prostate cancer.

Teaser

Patients with localized prostate cancer, which can be treated with either radiation or surgery, are less likely to receive radiation the farther away they live from a treatment facility. Distance to radiation treatment centers, which must be traveled daily by patients for several weeks, may be an important determinant of whether patients choose radiation therapy for prostate cancer.


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Acute lymphoblastic leukemia in a patient with MonoMAC syndrome/GATA2 haploinsufficiency

Abstract

Patients with GATA2 haploinsufficiency have a significant predisposition to developing cytopenias, unique infectious manifestations, and myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). We report a unique case of a patient who presented with B-cell acute lymphoblastic leukemia (B-ALL) and was subsequently diagnosed with monocytopenia and mycobacterium avium complex (MonoMAC) syndrome/GATA2 haploinsufficiency. The development of MDS/AML in patients with GATA2 haploinsufficiency is well described, however, the development of ALL has not been reported in the literature. ALL may be associated with GATA2 haploinsufficiency. Clinicians should be attuned to the features of the MonoMAC syndrome in patients with ALL that would prompt additional testing and alter treatment.

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Safety and efficacy of recombinant factor VIIa by pediatric age cohort: reassessment of compassionate use and trial data supporting US label

Abstract

Background

The relative safety and efficacy of recombinant activated coagulation factor VII (rFVIIa, NovoSeven® RT) across pediatric age cohorts is poorly defined. The objective of this analysis was to assess the safety and efficacy of rFVIIa in pediatric patients with congenital hemophilia with inhibitors (CHwI) in the clinical studies supporting the U.S. labeling.

Procedure

Pediatric data were derived from seven studies (five acute and two perioperative treatments) and pooled. All data were stratified by age (<2, 2 to <6, 6 to <12, and 12–16 years) and study category (acute treatment of bleeding episodes or surgery).

Results

The pediatric dataset included 172 patients; 144 received rFVIIa for the treatment of bleeding episodes and 28 for the control of bleeding perioperatively. Recombinant FVIIa was effective for 95.4% (1,026/1,076) of the evaluable bleeding episodes and had similar treatment effectiveness across pediatric age groups (range, 94.1–97.2%). The majority received doses of 90 mcg/kg. rFVIIa was effective in achieving perioperative hemostasis across pediatric age groups (range, 91–100%), with greater efficacy observed with the recommended (90 mcg/kg) versus lower dose (35 mcg/kg). A total of 88 pediatric patients experienced a total of 285 adverse drug reactions, similar in type to those reported among adult patients. A total of seven thrombotic events were recorded in seven pediatric patients; only one was confirmed related to rFVIIa upon individual case review.

Conclusions

rFVIIa is safe and effective in the treatment of bleeding episodes and prevention of periprocedure bleeding in CHwI with no apparent differences observed among pediatric age groups.

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The promise of intensity modulated radiation therapy

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Primary Cutaneous Lymphomas in Children and Adolescents

Primary cutaneous lymphomas are rare in children and mostly represented by mycosis fungoides and CD30⁺ lymphoproliferative disorders. Most pediatric cutaneous lymphomas have similar clinical/pathological features as their adult counterparts, particularly the T-cell subtypes. With regard to outcome, adult cutaneous mature T-cell lymphomas have a tendency to progression, while this appears to be relatively infrequent in children. The outcome of cutaneous B-cell lymphomas depends on subtype, with the B-lymphoblastic entity being associated with similar outcomes to precursor B acute lymphoblastic leukemia, while there are insufficient data on other entities. The diagnosis and treatment of these patients require a close collaboration between experienced pediatric pathologists, dermatologists, and oncologists. Prospective collection of longitudinal clinical and biological data from children with these rare lymphomas is needed to better understand their biological and clinical behavior and to ultimately discover the best therapeutic strategies.

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Is Nephron Sparing Surgery Justified in Wilms Tumor With Beckwith–Wiedemann Syndrome or Isolated Hemihypertrophy?

Background

Patients with Beckwith–Wiedemann syndrome (BWS) or isolated hemihypertrophy (HH) treated for a Wilms tumor (WT) carry an increased risk of developing metachronous lesion. There are no guidelines on precise indications for nephron sparing surgery (NSS) in unilateral WT (UWT). The objective of this retrospective study was to delineate the indications of NSS in patients with BWS/HH treated for WT and to evaluate their outcome.

Procedure

All cases of BWS/HH treated for a WT according to SIOP protocols from 1980 to 2013 were reviewed. Patients were divided into two groups (G): isolated UWT (G1) and bilateral lesions (G2) with two subgroups: bilateral tumors suspected of malignancy (G2a), and unilateral tumor suspected of malignancy with contralateral nephroblastomatosis (G2b).

Results

Forty-six patients were included (34 G1, three G2a, and nine G2b). Nine NSS and 25 total nephrectomies (TN) were performed in G1, two bilateral NSS and one NSS with contralateral TN in G2a, and eight NSS and one TN in G2b. The 3-year event-free survival was 92.3% (95% CI [77.9–97.5%]). One death occurred after a local relapse following a TN for a stage III stromal WT (G1) and another after a combined local and distant relapse following a NSS for a stage I diffuse anaplastic WT (G2b). There were two metachronous WT (4%), 3 years after a TN (G1) and 12 years after a NSS (G2b).

Conclusions

NSS is recommended in bilateral WT and may be an option in selected UWT patients with BWS/HH because it was not associated with an increased risk of local relapse.

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Surgical protocol violations in children with renal tumors provides an opportunity to improve pediatric cancer care: a report from the Children's Oncology Group

Abstract

Background

The purpose of this study was to evaluate the frequency and characteristics of surgical protocol violations (SPVs) among children undergoing surgery for renal tumors who were enrolled on the Children's Oncology Group (COG) renal tumor biology and classification study AREN03B2.

Methods

AREN03B2 was opened in February 2006, and as on March 31, 2013, there were 3,664 eligible patients. The surgical review forms for 3,536 patients with unilateral disease were centrally reviewed for SPVs. The frequency, type, number of violations, institutional prevalence, and quartiles for SPVs were assessed.

Results

Of the 3,536 patients, there were a total of 505 with at least one SPV (564 total SPVs reported), for an overall incidence of 14.28%. The types of SPVs included a lack of lymph node sampling in 365 (64.7%), avoidable spill in 61 (10.8%), biopsy immediately before nephrectomy in 89 (15.8%), an incorrect abdominal incision in 32 (5.7%), and unnecessary resection of organs in 17 (3.0%). The SPVs occurred in 163 of 215 participating institutions (75.8%). For centers with at least one SPV, the mean number of SPVs reported was 3.10 ± 2.39 (mean ± standard deviation). The incidence of protocol violation per institution ranged from 0 to 67%. Centers with an average of ≤1 case/year had an incidence of SPVs of 12.2 ± 3.8%, those with an average of >1 to <4 cases/year had an incidence of SPVs of 16.4 ± 3.6%, and those with an average of ≥4 cases/year had an incidence of SPVs of 12.6 ± 5.5% (P > 0.05).

Conclusions

SPVs that potentially result in additional exposure to chemotherapy and radiation therapy are not uncommon in children undergoing resection of renal malignancies.

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Chronic condition clusters and functional impairment in older cancer survivors: a population-based study

Abstract

Purpose

The purpose of the study is to identify chronic condition clusters at pre- and post-cancer diagnosis, evaluate predictors of developing clusters post-cancer, and examine the impact on functional impairment among older cancer survivors.

Methods

We identified 5991 survivors age 65 and older of prostate, breast, colorectal, lung, bladder, kidney, head and neck, and gynecologic cancer and non-Hodgkin lymphoma from the Surveillance, Epidemiology and End Results-Medicare Health Outcomes Survey resource. Survivors completed surveys pre- and post-cancer diagnosis on 13 chronic conditions and functional status. Among those with ≥2 conditions, exploratory factor analysis identified clusters of conditions. Differences in cluster frequency from pre- to post-cancer diagnosis were evaluated across the top five cancer types using chi-square tests. Modified Poisson regression models estimated the relative risk of developing clusters post-diagnosis. Chi-square tests evaluated associations between function and clusters.

Results

Clusters included the following: cardiovascular disease cluster (pre 6.1 % and post 7.7 %), musculoskeletal cluster (28.2 % and 29.3 %), metabolic cluster (14.9 % and 17.6 %), and the major depressive disorder risk (MDDr) + gastrointestinal (GI) + pulmonary condition cluster (5.8 % and 8.7 %). Increases in MDDr + GI + Pulmonary cluster from pre- to post-cancer diagnosis were observed for prostate, lung, and colorectal cancer survivors. Functional impairment was more prevalent in survivors with defined clusters, especially in MDDr + GI + pulmonary, compared to survivors with ≥2 un-clustered conditions.

Conclusions

Distinct condition clusters of two or more chronic conditions are prevalent among older cancer survivors. Cluster prevalence increases from pre- to post-cancer diagnosis and these clusters have a significant impact on functional limitations.

Implications for Cancer Survivors

Tailored management on specific multimorbidity patterns will have implications for functional outcomes among older survivors.

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Negative information-seeking experiences of long-term prostate cancer survivors

Abstract

Purpose

Many prostate cancer survivors have lasting symptoms and disease-related concerns for which they seek information. To understand survivors' information-seeking experiences, we examined the topics of their information searches, their overall perceptions of the search, and perceptions of their health information seeking self-efficacy (i.e., confidence in their ability to obtain information). We hypothesized that negative search experiences and lower health information seeking self-efficacy would be associated with certain survivor characteristics such as non-white race, low income, and less education.

Methods

This was a retrospective study using data from the Michigan Prostate Cancer Survivor Study (state-based survey of long-term prostate cancer survivor outcomes, N = 2499, response rate = 38 %). Participants recalled their last search for information and reported the topics and overall experience. We conducted multivariable regression to examine the association between survivor characteristics and the information-seeking experience.

Results

Nearly a third (31.7 %) of prostate cancer survivors (median age of 76 years and 9 years since diagnosis) reported having negative information-seeking experiences when looking for information. However, only 13.4 % reported having low health information-seeking self-efficacy. Lower income and less education were both significantly associated with negative information-seeking experiences.

Conclusions

Our findings suggest that many long-term prostate cancer survivors have negative experiences when searching for information, and lower income and less education were survivor factors related to negative information-seeking experiences.

Implications for cancer survivors

We advocate for ongoing, information needs assessment at the point-of-care as the survivorship experience progresses to assess and potentially improve survivors' quality of life.

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The use of mass spectrometry for analysing metabolite biomarkers in epidemiology: methodological and statistical considerations for application to large numbers of biological samples

Abstract

Data quality is critical for epidemiology, and as scientific understanding expands, the range of data available for epidemiological studies and the types of tools used for measurement have also expanded. It is essential for the epidemiologist to have a grasp of the issues involved with different measurement tools. One tool that is increasingly being used for measuring biomarkers in epidemiological cohorts is mass spectrometry (MS), because of the high specificity and sensitivity of MS-based methods and the expanding range of biomarkers that can be measured. Further, the ability of MS to quantify many biomarkers simultaneously is advantageously compared to single biomarker methods. However, as with all methods used to measure biomarkers, there are a number of pitfalls to consider which may have an impact on results when used in epidemiology. In this review we discuss the use of MS for biomarker analyses, focusing on metabolites and their application and potential issues related to large-scale epidemiology studies, the use of MS "omics" approaches for biomarker discovery and how MS-based results can be used for increasing biological knowledge gained from epidemiological studies. Better understanding of the possibilities and possible problems related to MS-based measurements will help the epidemiologist in their discussions with analytical chemists and lead to the use of the most appropriate statistical tools for these data.

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Diverse and Targetable Gene Rearrangements in Cancer

Triple-negative breast cancer (TNBC) and other molecularly heterogeneous malignancies present a significant clinical challenge due to a lack of high-frequency "driver" alterations amenable to therapeutic intervention. These cancers often exhibit genomic instability, resulting in chromosomal rearrangements that impact the structure and expression of protein-coding genes. However, identification of these rearrangements remains technically challenging. Using a newly developed approach that quantitatively predicts gene rearrangements in tumor-derived genetic material, we identified and characterized a novel oncogenic fusion involving the MER proto-oncogene tyrosine kinase (MERTK) and discovered a clinical occurrence and cell line model of the targetable FGFR3-TACC3 fusion in TNBC. Expanding our analysis to other malignancies, we identified a diverse array of novel and known hybrid transcripts, including rearrangements between non-coding regions and clinically relevant genes such as ALK, CSF1R, and CD274/PD-L1. The over 1000 genetic alterations we identified highlight the importance of considering non-coding gene rearrangement partners, and the targetable gene fusions identified in TNBC demonstrate the need to advance gene fusion detection for molecularly heterogeneous cancers.

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Metastasis suppression by E6AP

Metastatic disease is the major cause of breast cancer related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganisation to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonise distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors. We report that E6AP suppresses breast cancer invasiveness, colonisation and metastasis in mice, and in breast cancer patients, loss of E6AP associates with poor prognosis, particularly for basal breast cancer. E6AP regulates actin cytoskeletal remodelling via regulation of Rho-GTPases, acting as a negative regulator of ECT2, a GEF required for activation of Rho-GTPases. E6AP promotes ubiquitination and proteasomal degradation of ECT2 for which high expression predicts poor prognosis in breast cancer patients. We conclude that E6AP suppresses breast cancer metastasis by regulating actin cytoskeleton remodelling through the control of ECT2 and Rho-GTPase activity. These findings establish E6AP as a novel suppressor of metastasis and provide a compelling rationale for inhibition of ECT2 as a therapeutic approach for patients with metastatic breast cancer.

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telomerase activity in pancreatic cyst fluid

Purpose: Pancreatic cysts frequently pose clinical dilemmas. On one hand, cysts with high-grade dysplasia offer opportunities for cure, on the other hand, those with low-grade dysplasia are easily over treated. Cyst fluid markers have the potential to improve the evaluation of these cysts. Since telomerase activity is commonly activated in malignant cells, we evaluated the diagnostic performance of cyst fluid telomerase activity measurements for predicting histologic grade. Experimental design: Telomerase activity was measured using telomerase repeat amplification with digital-droplet PCR in surgically-aspirated cyst fluid samples from 219 patients who underwent pancreatic resection for a cystic lesion (184, discovery, 35 validation) and 36 patients who underwent endoscopic ultrasound fine needle aspiration. Methodological and clinical factors associated with telomerase activity were examined. Results: Telomerase activity was reduced in samples that had undergone prior thawing. Among 119 samples not previously thawed, surgical cyst fluids from cystic neoplasms with high-grade dysplasia +/- associated invasive cancer had higher telomerase activity (median [interquartile range], 1158 [295.9-13033] copies/μL of cyst fluid than those without (19.74 [2.58-233.6] copies/μL) (P < 0.001). Elevated cyst fluid telomerase activity had a diagnostic accuracy for invasive cancer/high-grade dysplasia of 88.1% (discovery), 88.6% (validation), and 88.2% (merged). Among cysts classified preoperatively as having "worrisome features", cyst fluid telomerase activity had high diagnostic performance (sensitivity 73.7%, specificity 90.6%, accuracy, 86.1%). In multivariate analysis, telomerase activity independently predicted the presence of invasive cancer/high-grade dysplasia. Conclusion: Cyst fluid telomerase activity can be a useful predictor of the neoplastic grade of pancreatic cysts.

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Breast Cancer Integrative Oncology Care and Its Costs

Background. Naturopathic oncology in conjunction with conventional treatment is commonly referred to as integrative oncology (IO). Clinics directed by oncology board certified NDs (Fellows of the American Board of Naturopathic Oncology or FABNOs) provide high-quality data for describing IO therapies, their costs and measuring clinical outcomes. Purpose. To describe the types of IO therapies prescribed to breast cancer patients by ND FABNO physicians. Study participants (n = 324). Women who sought care at 1 of 6 naturopathic oncology clinics in Washington State were asked to enroll in a prospective 5 year observational outcomes study. Methods. Medical records were abstracted to collect treatment recommendations and cost data. Results. More than 72 oral or topical, nutritional, botanical, fungal and bacterial-based medicines were prescribed to the cohort during their first year of IO care. Trametes versicolor was prescribed to 63% of the women. Mind-body therapy was recommended to 45% of patients, and 49% received acupuncture. Also, 26% were prescribed injectable therapy, including mistletoe, vitamin B complex (12%), IV ascorbate (12%), IV artesunate (7%), and IV nutrition and hydration (4%). Costs ranged from $1594/year for early-stage breast cancer to $6200/year for stage 4 breast cancer patients. Of the total amount billed for IO care for 1 year for breast cancer patients, 21% was out-of-pocket. Conclusions. IO care for women with breast cancer consists of botanical and mushroom oral therapies, parenteral botanical and nutrient therapy, mind-body medicine and acupuncture. IO clinic visits and acupuncture are partially paid for by medical insurance companies.

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