ATM Mutations in Cancer

Activation of checkpoint arrest and homologous DNA repair are necessary for maintenance of genomic integrity during DNA replication. Germ-line mutations of the ataxia telangiectasia mutated (ATM) gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Somatic ATM mutations or deletions are commonly found in lymphoid malignancies, as well as a variety of solid tumors. Such mutations may result in chemotherapy resistance and adverse prognosis, but may also be exploited by existing or emerging targeted therapies that produce synthetic lethal states. Mol Cancer Ther; 15(8); 1–11. ©2016 AACR.

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Smoking is a risk factor for development of adult T-cell leukemia/lymphoma in Japanese human T-cell leukemia virus type-1 carriers

Abstract

Background and purpose

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive hematological malignancy caused by human T-cell leukemia virus type-1 (HTLV-1); no effective methods have yet been identified to prevent development of ATLL in carriers of HTLV-1. This study investigated the association between cigarette smoking and the risk of ATLL development among Japanese carriers of HTLV-1.

Methods

This study examined the association between smoking and development of ATLL in a cohort of 1,332 Japanese HTLV-1 carriers aged 40–69 years free of ATLL at baseline from two different HTLV-1-endemic areas of Japan. Cox proportional hazards models adjusted for sex, geographic area, age at baseline, and alcohol drinking were used to estimate the effect of cigarette smoking on ATLL development.

Results

Between 1993 and 2012, 25 new ATLL cases were identified among these subjects. The overall crude incidence rate for ATLL was 1.08 per 1,000 person-years among HTLV-1 carriers and was higher among male carriers than among female carriers (2.21 vs. 0.74). The risk of ATLL development increased significantly with increasing numbers of cigarettes smoked per day (hazard ratio for every increment of 20 cigarettes, 2.03; 95 % confidence interval (CI) 1.13–3.66 overall, 2.07 (95 % CI 1.13–3.73) in male carriers).

Conclusions

Cigarette smoking may influence ATLL development among HTLV-1 carriers in Japan.

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Knockdown of Immature Colon Carcinoma Transcript 1 Inhibits Proliferation and Promotes Apoptosis of Non-Small Cell Lung Cancer Cells

Non–small cell lung cancer, as the most frequent type lung cancer, has lower survival rate of 5 years, despite improvements in surgery and chemotherapy. Previous studies showed immature colon carcinoma transcript 1 is closely related to tumorigenesis of human cancer cells. In the present study, we found immature colon carcinoma transcript 1 was overexpressed in lung cancer tissues using Oncomine database mining, and the biological effect of immature colon carcinoma transcript 1 was investigated in non–small cell lung cancer cell lines 95D and A549. Lentivirus-mediated RNA interference was used to knock down immature colon carcinoma transcript 1 expression in 95D and A549 cells in vitro, and the knockdown efficiency was determined using quantitative real-time polymerase chain reaction and Western blot assay. Knockdown of immature colon carcinoma transcript 1 significantly suppressed non–small cell lung cancer cell proliferation and colony formation ability confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assay. Flow cytometry was applied to measure cell cycle arrest, and the result showed the cell cycle arrested in G₂/M phase in 95D cells and arrested in G₀/G₁ phase in A549 cells. Furthermore, we measured the levels of cell cycle–associated proteins by Western blot analysis and found immature colon carcinoma transcript 1–mediated cell proliferation inhibition appeared due to downregulation of cell cycle activator cyclin D1 and upregulation of cell cycle inhibitor p21. In addition, immature colon carcinoma transcript 1 silencing significantly induced non–small cell lung cancer cell apoptosis by annexin V/7-amino-actinomycin D double-staining assay. All our data suggest that immature colon carcinoma transcript 1 may play an important role for non–small cell lung cancer cell proliferation and could be a potential molecular target for diagnosing and treating human non–small cell lung cancer.

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Alectinib for ALK-Positive Non-Small Cell Lung Cancer

On December 11, 2015, the FDA granted accelerated approval to alectinib (ALECENSA®; Genentech, Inc.) for the treatment of patients with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This approval was based on two single-arm trials including 225 patients treated with alectinib 600 mg orally twice daily. The objective response rates (ORR) by independent review committee in these studies were 38% (95% CI, 36-52) and 44% (95% CI 36-53); the median durations of response (DOR) were 7.5 months and 11.2 months. In a pooled analysis of 51 patients with measurable disease in the central nervous system (CNS) at baseline, the CNS ORR was 61% (95% CI 46-74); the CNS DOR was 9.1 months. The primary safety analysis population included 253 patients. The most common adverse reactions were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). The most common laboratory abnormalities were anemia (56%), increased aspartate aminotransferase (51%), increased alkaline phosphatase (47%), increased creatine phosphokinase (43%), hyperbilirubinemia (39%), hyperglycemia (36%), increased alanine aminotransferase (34%), and hypocalcemia (32%). Dose reductions due to adverse reactions occurred in 12% of patients, while 27% of patients had alectinib dosing interrupted for adverse reactions. Permanent discontinuation of alectinib due to adverse reactions occurred in only 6% of patients. With the clinically meaningful ORR and DOR and the safety profile observed in these trials, alectinib was determined to have a favorable benefit-risk profile for the treatment of the indicated population.

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Low Expression LncRNA TUBA4B is a Poor Predictor of Prognosis and Regulates Cell Proliferation in Non-Small Cell Lung Cancer

Abstract

We aimed to unveil the clinical roles and biological function of lncRNA TUBA4B in on-small cell lung cancer (NSCLC). The relative expression level of TUBA4B was estimated by qPCR in 114 pairs of NSCLC and NT samples and the relation of TUBA4B to clinical data of NSCLC patients was analyzed. We found TUBA4B was lower expressed in NSCLC and five cell lines. The lower expression of TUBA4B was remarkably correlated with advanced TNM stage and lymph node metastasis and served as a predictor for overall survival of NSCLC. After overexpression of TUBA4B, cell proliferation ability of A549 and NCI-H1299 remarkably decreased. Our study ascertained low expression TUBA4B in NSCLC tissue, cell lines and is a poor predictor for prognosis and can regulate cell proliferation in NSCLC.

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Biologic Evaluation of Diabetes and Local Recurrence in Non-Small Cell Lung Cancer

Abstract

A recent multicenter study led by our institution demonstrated that local recurrence of non-small cell lung cancer (NSCLC) was significantly more frequent in patients with diabetes, raising the possibility of different tumor biology in diabetics. Epithelial-to-mesenchymal transition (EMT) plays a key role in local tumor recurrence and metastasis. In the present study, we investigated differences of tumor microenvironment between patients with and without diabetes by examining expression of EMT markers. Seventy-nine NSCLC patients were selected from the cohort of our early multicenter study. These patients were classified into 4 groups: 39 with adenocarcinoma with (n = 19) and without (n = 20) diabetes, and 40 with squamous cell carcinoma with (n = 20) and without (n = 20) diabetes. Immunohistochemical expression of eight EMT markers was analyzed, including transforming growth factor-beta (TGF-β), epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF-1R), vimentin, E-cadherin, N-cadherin, HtrA1, and beta-catenin. Five markers (E-cadherin, HtrA1, TGF-β, IGF-1R and vimentin) demonstrated significantly higher expression in diabetics than in non-diabetics in both histology types. N-cadherin had higher expression in diabetics, though the difference did not reach statistical significance. EGFR showed a higher expression in diabetics in squamous cell carcinoma only. Beta-catenin was the only marker with no difference in expression between diabetics versus non-diabetics. Our findings suggest that diabetes is associated with enhanced EMT in NSCLC, which may contribute to growth and invasiveness of NSCLC.

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The Expression of Checkpoint and DNA Repair Genes in Head and Neck Cancer as Possible Predictive Factors

Abstract

DNA damage response failure may influence the efficacy of DNA-damaging treatments. We determined the expression of 16 genes involved in distinct DNA damage response pathways, in association with the response to standard therapy. Twenty patients with locoregionally advanced, squamous cell head and neck carcinoma were enrolled. The treatment included induction chemotherapy (iChT) with docetaxel, cisplatin and 5-fluorouracil followed by concomitant chemoradiotherapy (ChRT) or radiotherapy (RT) alone. The volumetric metabolic therapeutic response was determined by [18F]FDG-PET/CT. In the tumor and matched normal tissues collected before treatment, the gene expressions were examined via the quantitative real-time polymerase chain reaction (qRT-PCR). The down-regulation of TP53 was apparently associated with a poor response to iChT, its up-regulation with complete regression in 2 cases. 7 cases with down-regulated REV1 expression showed complete regression after ChRT/RT, while 1 case with REV1 overexpression was resistant to RT. The overexpression of WRN was an independent predictor of tumor relapse. Our results suggest that an altered expression of REV1 predicts sensitivity to RT, while WRN overexpression is an unfavorable prognostic factor.

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The effect of non-small cell lung cancer histology on survival as measured by the graded prognostic assessment in patients with brain metastases treated by hypofractionated stereotactic radiotherapy

The purpose of this study was to investigate the impact of histology on survival stratified by the Graded Prognostic Assessment (GPA) for non-small cell lung cancer (NSCLC) in a group of selected patients trea...

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Anti-Estrogen Withdrawal Effect With Raloxifene? A Case Report

A 66-year-old patient presented with acute recurrent metastatic estrogen and progesterone receptor–positive, Her-2/neu-negative breast cancer, bone lesions (lumbar spine, pelvis), pulmonary nodules, hepatic metastasis, elevated cancer antigen 15 and liver enzymes, dyspepsia, and diarrhea. The patient had been taking raloxifene for approximately 8 years. After discontinuation, clinical parameters and symptoms improved rapidly without oncological therapy or other forms of treatment. Three months after raloxifene discontinuation, capecitabine was initiated by the treating oncologist who deemed an anti-estrogen withdrawal effect (AEWE) implausible. However, the lasting regression was more indicative of a raloxifene rebound effect than chemotherapy or other interventions. Today, the patient is asymptomatic with a good performance status. Hepatic metastatic regression has been confirmed, without any oncological treatment administered in the past 16 months and approximately 23 months following the withdrawal of raloxifene. This case highlights the need to screen breast cancer patients for the possibility of an AEWE if they are using raloxifene and possibly similar selective estrogen receptor modulators (SERMs) which includes tamoxifen, when diagnosed with advanced breast cancer, especially in the recurrent disease setting.

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The emerging roles of Jab1/CSN5 in cancer

Abstract

C-Jun activation domain-binding protein-1 (Jab1) not only is full but also a subunit (CSN5) of the constitutive photomorphogenesis 9 signalosome (CSN), which is an evolutionarily conserved and multifunctional protein that involves in controlling cellular proliferation and apoptosis, affecting a series of pathways, as well as regulating genomic instability and DNA damage and repair. The CSN is a highly conservative protein from yeast to human and interacts with the cullin-RING family of ubiquitin ligases so that it could be execute a process of removing NEDD8, a ubiquitin-like polypeptide (deneddylase activity). The role of Jab1/CSN5's multi-function has been proved as being oncogenic in nature, what is more, Jab1/CSN5 has been confirmed by much evidence that it participates in the carcinogenesis progression and is tightly associated with poor prognosis. However, the biologic implication of Jab1/CSN5 activity during the cancer's development is unclear. We performed a systematic literature review and assessment from PubMed and Medline databases in this article. Jab1/CSN5 is participate in a lot of biologic responses, including cell proliferation, apoptosis, cell cycle regulation, DNA metabolism, invasion, DNA damage and repair, and recurrence. It also promotes cell transformation and tumorigenesis. In this review, we mainly expound the progress in the function and research advances of Jab1/CSN5 and in untangling the Jab1/CSN5 signaling pathway. Based on these bases, its potential as a therapeutic target for cancer can play a greater role in future cancer treatment.

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Prenatal presentation of pyruvate dehydrogenase complex deficiency

Abstract

We present the case of a female infant referred for prenatal MR evaluation of ventriculomegaly, which had been attributed by the referring obstetrician to aqueductal stenosis. Fetal MR confirmed ventriculomegaly but also demonstrated cerebral volume loss and white matter abnormalities. After birth, the infant developed persistent lactic acidosis. A diagnosis of pyruvate dehydrogenase complex deficiency was made on the basis of metabolic and molecular genetic studies. Ventriculomegaly is a common referral reason for fetal MR, yet there are few published reports of the radiographic findings that accompany inborn errors of metabolism, one potentially under-recognized cause of enlarged ventricles. This case contributes to this small body of literature on the imaging features of pyruvate dehydrogenase complex deficiency by describing pre- and postnatal MR findings and key clinical details. Our report emphasizes the necessity of considering pyruvate dehydrogenase complex deficiency and other metabolic disorders as potential etiologies for fetal ventriculomegaly since prompt diagnosis may allow for early initiation of treatment and improve outcome.

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Hermes

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Radiation exposure contribution of the scout abdomen radiograph in common pediatric fluoroscopic procedures

Abstract

Background

Contrast enema, voiding cystourethrography and upper gastrointestinal studies are the most common fluoroscopic procedures in children. Scout abdomen radiographs have been routinely obtained prior to fluoroscopy and add to the radiation exposure from these procedures. Elimination of unnecessary routine scout radiographs in select studies might significantly reduce radiation exposure to children and improve the overall benefit-to-risk ratio of these fluoroscopic procedures.

Objective

To determine the radiation exposure contribution of the preliminary/scout abdomen radiographs with respect to the radiation exposure of the total procedure.

Materials and methods

We retrospectively collected demographic information and radiation exposure values of dose area product (in Gy-cm²) and entrance air kerma (in mGy) — initially for the scout abdomen radiographs done prior to fluoroscopy and subsequently the total procedural radiation values (the combined values of the scout radiograph and fluoroscopic radiation exposure) — in children who underwent contrast enemas, voiding cystourethrograms and upper gastrointestinal studies in a 4-month period. The radiation parameters, including fluoroscopy time, dose area product and entrance air kerma, were available in the log book maintained in the fluoroscopy suite. Fluoroscopy procedures were performed on a single fluoroscopy machine using four frames per second pulse rate and other radiation-minimizing techniques. Usage of the grid to obtain scout radiographs was also recorded. The proportion of radiation exposure from the scout radiograph relative to that of the total procedure was calculated by dividing the individual parameters of the scout to the total procedural values and multiplied by 100 to express these values as a percentage. We calculated mean, median and range and performed statistical analysis of the data.

Results

A total of 151 procedures performed on 71 males and 80 females qualified for the study. The age range of the patients was 2 days to 18 years, with a mean of nearly 3.5 years (40 months) and median of 15 months. There were 63 upper gastrointestinal studies, 65 voiding cystourethrography studies and 23 contrast enema studies. The fluoroscopy time for all procedures combined ranged from 0.1 min (6 s) to 2 min, with mean and median values of 0.4 min and 0.3 min, respectively. The fractional radiation exposure contribution for the dose area product of scout abdomen radiograph to the total procedure ranged from 4% to 98%, with mean and median values of 51% and 49%, respectively. The fractional contribution of the scout radiograph to the total procedure for the entrance air kerma values ranged from 6% to 97%, with mean and median values of 29% and 26%, respectively. There was a significant negative correlation (P<0.001) between fluoroscopy radiation time and the proportion of radiation parameters of scout radiograph to total procedural values.

Conclusion

Scout radiographs can contribute a significant proportion (median values of approximately 50% for the dose area product and 26% for the entrance air kerma) of radiation exposure in common fluoroscopy procedures in children.

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ESPR postmortem imaging task force: where we begin

Abstract

A new task force on postmortem imaging was established at the annual meeting of the European Society of Paediatric Radiology (ESPR) in Graz, Austria, in 2015. The postmortem task force is separate from the child abuse task force as it covers all aspects of fetal, neonatal and non-forensic postmortem imaging. The main focus of the task force is the guidance and standardization of non-radiographic postmortem imaging, particularly postmortem CT and postmortem MRI. This manuscript outlines the starting point of the task force, with a mission statement, outline of current experience, and short- and long-term goals.

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Non-sclerotic bone involvement in Erdheim–Chester: PET/CT and MRI findings in a 15-year-old boy

Abstract

Erdheim–Chester disease is a rare form of non-Langerhans cell histiocytosis with multi-organ infiltration that occurs mainly in adults. Pediatric cases are extremely rare. Here we report a case of multisystemic Erdheim–Chester disease in a 15-year-old boy with central nervous system involvement and skeletal findings. Positron emission tomography (PET) and MRI were used to demonstrate characteristic bilateral, symmetrical medullary involvement of the metadiaphyses of long bones in the absence of the classic sclerotic radiographic appearance. This illustrates the potential for earlier diagnosis and visualization of therapeutic response in children.

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Is lipoprotein (a) protective of dementia?

Abstract

Lipoprotein(a) [Lp(a)]–an established risk factor for vascular disease, has been suggested to be associated with risk of dementia, however no prospective evidence exists to support this finding. We aimed to assess the association of Lp(a) with dementia risk. Lp(a) concentration was assessed at baseline in a prospective cohort of 2532 men aged 42–61 years. During a median follow-up of 24.9 years, 228 new cases of dementia were recorded. Lp(a) was approximately log-linearly associated with dementia risk. In age-adjusted analysis, the hazard ratio for dementia in a comparison of extreme quartiles of Lp(a) levels was 0.68 (95 % CI: 0.47–0.99), which persisted after adjustment for several physical measures, history of coronary heart disease, smoking status, history of diabetes, serum lipids, alcohol consumption, and socio-economic status 0.68 (0.46–0.99). Lp(a) is protective of future dementia risk in a middle-aged male Caucasian population. Further research is needed replicate these findings.

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Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma

Durable responses in metastatic cancers have been achieved with a variety of immunotherapies such as interleukin-2, adoptive cell transfer of tumor-infiltrating lymphocytes, antibodies that block cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), and antibodies that block programmed death 1 (PD-…

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Randomized Phase 3 Trials of Accelerated Partial Breast Irradiation: A Trickle Before the Deluge

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Atif J. Khan, Yazid Belkacemi




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Meetings

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4





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Editorial Statement on Gleason Scoring for Prostate Cancer

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Anthony L. Zietman, Joseph Smith, Eric Klein, Michael Droller, Prokar Dasgupta, James Catto




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Radiation Therapy Did Not Induce Long-Term Changes in Rectal Mucosa: Results From the Randomized Scandinavian Prostate Cancer Group 7 Trial

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Jens Erik Slagsvold, Trond Viset, Arne Wibe, Stein Kaasa, Anders Widmark, Jo-Åsmund Lund
PurposeTo investigate long-term changes in the rectal mucosa after curative external beam radiation therapy in the treatment of prostate cancer.Methods and MaterialsIn the Scandinavian Prostate Cancer Group 7 trial, 880 men with locally advanced prostate cancer were randomized to hormonal therapy alone versus hormonal therapy plus radiation therapy to 70 Gy. A subcohort from this trial being randomized at our center (n=178) was invited to a study on late anorectal side effects during 2003-2005, approximately 5 years after treatment, including measuring health-reported quality of life and physician-assessed toxicity score by the Late Effects Normal Tissue Task Force/Subjective, Objective, Management, Analytic (LENT/SOMA) and European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group score. Sixty-seven patients had a rectal mucosa biopsy. Sixty-four biopsies were included in the final analysis, of which 33 patients were randomized to hormonal treatment and 31 to hormonal treatment plus radiation therapy. The presence of fibrosis, number of capillaries, and lymphocyte infiltration was then evaluated by light microscopy.ResultsThe group receiving radiation therapy had significantly higher LENT/SOMA and function/bother scale scores than the group that only received hormonal treatment, but there was no significant difference in the presence of fibrosis, ectasia, number of capillaries in the lamina propria, or lymphocyte infiltration between the groups.ConclusionRadiation therapy to 70 Gy to the prostate does not induce long-term microscopic mucosal changes in the rectum 5 years after treatment. This is in contrast to the general assumption that structural changes, including fibrosis, seen after radiation therapy include the mucosa. We speculate that the main late effects of radiation therapy on the structure of the rectum are located in the deeper layers of the rectal wall than the mucosa.



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Trends in Disclosures of Industry Sponsorship

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Awad A. Ahmed, Emma B. Holliday, Mohamad Fakhreddine, Stella K. Yoo, Curtiland Deville, Reshma Jagsi
PurposeTo examine trends in the reporting of industry funding of oncology trials by primary therapeutic intervention studied: local, targeted, or nontargeted systemic.Methods and MaterialsWe reviewed oncologic trials published in 10 journals for the years 1994, 2004, and 2014 to determine the frequency of declarations of industry funding for cancer research. Logistic modeling was used to assess associations between reported industry funding and investigation characteristics, such as type of primary intervention, cancer site, study endpoint, number of participants, geographic location of corresponding author, journal impact factor, trial phase, and year of publication.ResultsReporting of industry funding increased over time (odds ratio [OR] 6.8; 95% confidence interval [CI] 3.82-12.35). Compared with systemic trials, those investigating local therapies were less likely to report industry funding (OR 0.08; 95% CI 0.14-0.15), whereas studies examining targeted interventions were more likely to report industry funding (OR 2.24; 95% CI 1.38-3.66). Studies investigating gynecologic (OR 0.37; 95% CI 0.15-0.88) and pediatric cancers (OR 0.08; 95% CI 0.02-0.27) were less likely to report funding by industry when compared with hematologic cancers. Phase 2 (OR 0.32, 95% CI 0.19-0.52) and phase 3 (OR 0.39, 95% CI 0.17-0.37) studies were less likely to report industry funding than phase 1 studies. Trials investigating interventions for metastatic disease (OR 2.55; 95% CI 1.73-3.79) were more likely to have reported industry funding compared with studies examining the primary/definitive disease setting.ConclusionIndustry funding was reported in more than one-third of oncology trials examined in this study, and the proportion of trials reporting industry funding increased over time. The potential ramifications for these patterns of funding for the future direction of cancer research should be examined, especially given the disproportionate distribution of industry funding among therapeutic intentions, cancer types, and treatment modalities.



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In Regard to Kubicek et al

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Filippo Alongi, Alba Fiorentino




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Issue Highlights

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4





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Protons for Oropharyngeal Cancer Have Not Yet Justified Their Promise

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Jonathan J. Beitler, Bhishamjit S. Chera




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Image Guided Radiation Therapy Using Synthetic Computed Tomography Images in Brain Cancer

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Ryan G. Price, Joshua P. Kim, Weili Zheng, Indrin J. Chetty, Carri Glide-Hurst
PurposeThe development of synthetic computed tomography (CT) (synCT) derived from magnetic resonance (MR) images supports MR-only treatment planning. We evaluated the accuracy of synCT and synCT-generated digitally reconstructed radiographs (DRRs) relative to CT and determined their performance for image guided radiation therapy (IGRT).Methods and MaterialsMagnetic resonance simulation (MR-SIM) and CT simulation (CT-SIM) images were acquired of an anthropomorphic skull phantom and 12 patient brain cancer cases. SynCTs were generated using fluid attenuation inversion recovery, ultrashort echo time, and Dixon data sets through a voxel-based weighted summation of 5 tissue classifications. The DRRs were generated from the phantom synCT, and geometric fidelity was assessed relative to CT-generated DRRs through bounding box and landmark analysis. An offline retrospective analysis was conducted to register cone beam CTs (n=34) to synCTs and CTs using automated rigid registration in the treatment planning system. Planar MV and KV images (n=37) were rigidly registered to synCT and CT DRRs using an in-house script. Planar and volumetric registration reproducibility was assessed and margin differences were characterized by the van Herk formalism.ResultsBounding box and landmark analysis of phantom synCT DRRs were within 1 mm of CT DRRs. Absolute planar registration shift differences ranged from 0.0 to 0.7 mm for phantom DRRs on all treatment platforms and from 0.0 to 0.4 mm for volumetric registrations. For patient planar registrations, the mean shift differences were 0.4 ± 0.5 mm (range, −0.6 to 1.6 mm), 0.0 ± 0.5 mm (range, −0.9 to 1.2 mm), and 0.1 ± 0.3 mm (range, −0.7 to 0.6 mm) for the superior-inferior (S-I), left-right (L-R), and anterior-posterior (A-P) axes, respectively. The mean shift differences in volumetric registrations were 0.6 ± 0.4 mm (range, −0.2 to 1.6 mm), 0.2 ± 0.4 mm (range, −0.3 to 1.2 mm), and 0.2 ± 0.3 mm (range, −0.2 to 1.2 mm) for the S-I, L-R, and A-P axes, respectively. The CT-SIM and synCT derived margins were <0.3 mm different.ConclusionDRRs generated by synCT were in close agreement with CT-SIM. Planar and volumetric image registrations to synCT-derived targets were comparable with CT for phantom and patients. This validation is the next step toward MR-only planning for the brain.



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In Regard to Chapman et al

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Angeles Rovirosa, Antonio Herreros




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High E6 Gene Expression Predicts for Distant Metastasis and Poor Survival in Patients With HPV-Positive Oropharyngeal Squamous Cell Carcinoma

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Shariq S. Khwaja, Callie Baker, Wesley Haynes, Christopher R. Spencer, Hiram Gay, Wade Thorstad, Douglas R. Adkins, Brian Nussenbaum, Rebecca D. Chernock, James S. Lewis, Xiaowei Wang
PurposePatients with human papillomavirus (HPV)–positive oropharyngeal squamous cell carcinoma (OPSCC) have a favorable prognosis. As a result, de-escalation clinical trials are under way. However, approximately 10% of patients will experience distant recurrence even with standard-of-care treatment. Here, we sought to identify novel biomarkers to better risk-stratify HPV-positive patients with OPSCC.Methods and MaterialsGene expression profiling by RNA sequencing (RNA-seq) and quantitative polymerase chain reaction was performed on HPV-positive OPSCC primary tumor specimens from patients with and without distant metastasis (DM).ResultsRNA-seq analysis of 39 HPV-positive OPSCC specimens revealed that patients with DM had 2-fold higher E6 gene expression levels than did patients without DM (P=.029). This observation was confirmed in a validation cohort comprising 93 patients with HPV-positive OPSCC. The mean normalized E6 expression level in the 17 recurring primary specimens was 13 ± 2 compared with 8 ± 1 in the remaining 76 nonrecurring primaries (P=.001). Receiver operating characteristic analysis established an E6 expression level of 7.3 as a cutoff for worse recurrence-free survival (RFS). Patients from this cohort with high E6 gene expression (E6-high) (n=51, 55%) had more cancer-related deaths (23% vs 2%, P<.001) and DM (26% vs 5%, P<.001) than did patients with low E6 gene expression (E6-low) (n=42, 45%). Kaplan-Meier survival analysis revealed that E6-high had worse RFS (95% vs 69%, P=.004) and cancer-specific survival (97% vs 79%, P=.007). E6-high maintained statistical significance in multivariate regression models balancing surgery, chemotherapy, nodal stage, and smoking status. Gene set enrichment analysis demonstrated that tumors with high E6 expression were associated with P53, epidermal growth factor receptor, activating transcription factor-2, and transforming growth factor-β signaling pathways.ConclusionHigh E6 gene expression level identifies HPV-positive OPSCC patients with 5-fold greater risk of distant disease recurrence and worse cancer-specific survival. Validation in a multi-institutional prospective clinical trial is required to assess the utility of E6 gene expression as a clinically useful prognostic biomarker.



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In Regard to Nagata et al

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Yasushi Nagata, Taro Shibata, Satoshi Ishikura




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Fast MVCT: A rapid imaging method for total body or marrow irradiation in helical tomotherapy

Publication date: Available online 6 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Taiki Magome, Akihiro Haga, Yutaka Takahashi, Keiichi Nakagawa, Kathryn E. Dusenbery, Susanta K. Hui
PurposeMegavoltage computed tomography (MVCT) imaging has been widely used for three-dimensional (3-D) setup of patients treated with helical tomotherapy (HT). One drawback of MVCT is it's very long imaging time, owing to slow couch speeds of approximately 1 mm/s, which can be difficult for the patient to tolerate. We sought to develop an MVCT imaging method allowing faster couch speeds, and to assess its accuracy for image guidance for HT.Methods and MaterialsThree cadavers were scanned four times with couch speeds of 1, 2, 3, and 4 mm/s. The resulting MVCT images were reconstructed using an iterative reconstruction (IR) algorithm with a penalty term of total variation, as well as with a conventional filtered back projection (FBP) algorithm. The MVCT images were registered with kilovoltage CT images, and the registration errors from the two reconstruction algorithms were compared. This fast MVCT imaging was tested in three cases of total marrow irradiation as a clinical trial.ResultsThree-dimensional registration errors of the MVCT images reconstructed with the IR algorithm were smaller than the errors of images reconstructed with the FBP algorithm at fast couch speeds (2, 3, 4 mm/s). The scan time and imaging dose at a speed of 4 mm/s were reduced to 30% of those from a conventional coarse mode scan. For the patient imaging, faster MVCT (3 mm/s couch speed) scanning reduced imaging time and still generated images useful for anatomical registration.ConclusionsFast MVCT with IR algorithm is clinically feasible for large 3-D target localization, which may reduce overall time for treatment procedure. This technique may also be useful for calculating daily dose distributions or organ motion analyses in HT treatment over a wide area. Automated integration of this imaging is at least needed to further assess its clinical benefits.

Teaser

We report the feasibility of a new "Fast MVCT" imaging modality to improve total marrow irradiation (TMI) treatment management. Using human cadavers, we acquired multiple whole-body megavoltage CT images with iterative reconstruction (IR) algorithm at increasing couch speeds in helical tomotherapy. The scanning time and the imaging radiation dose could both be reduced by employing the IR algorithm with minimal registration error. We also confirmed these findings in three TMI patients.


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The Short-Term and Intermediate-Term Risk of Second Neoplasms After Diagnosis and Treatment of Unilateral Vestibular Schwannoma: Analysis of 9460 Cases

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Matthew L. Carlson, Amy E. Glasgow, Jeffrey T. Jacob, Elizabeth B. Habermann, Michael J. Link
PurposeTo determine the incidence of second intracranial neoplasms after the diagnosis and treatment of sporadic vestibular schwannoma (VS).Methods and MaterialsAnalysis of the Surveillance, Epidemiology, and End Results (SEER) database including all patients identified with a diagnosis of VS and a second intracranial tumor. The Kaplan-Meier method was used to determine the incidence of second tumors while allowing for censoring at loss to follow-up or death. Multivariable associations between treatment modality and second tumor formation were explored using Cox proportional hazards regression analysis. Two illustrative cases are also presented.ResultsIn all, 9460 patients with unilateral VS were identified between 2004 and 2012. Overall, 66 (0.7%) patients experienced a separate intracranial tumor, benign or malignant, after treatment of VS. Kaplan-Meier estimates for time to second neoplasm at 1, 3, and 5 years were 0.3%, 0.7%, and 0.8%, respectively. Multivariable comparison between VS treatment modalities revealed that the risk of second tumor formation was similar between radiation and surgery (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.36-1.51; P=.93) but greater for tumors managed with observation alone compared with radiation (HR 2.48; 95% CI 1.31-4.71; P<.01). A total of 6 (0.06%) intracranial malignancies were diagnosed after VS treatment. Kaplan-Meier estimates for time to malignancy at 1, 3, and 5 years were 0%, 0.1%, and 0.1%, respectively. After adjustment for age at diagnosis, sex, and treatment modality, the probability of malignancy after radiation was not greater than after observation alone or microsurgery (HR 4.88; 95% CI 0.85-28.14; P=.08) during the study period.ConclusionsThe risk for the development of a second intracranial neoplasm, benign or malignant, at 5 years after treatment of unilateral VS is approximately 0.8%, whereas the risk of acquiring a separate malignancy is 0.1%, or approximately 1 per 1000 cases. The short-term and intermediate-term incidence of second neoplasm after radiation of VS is not greater than the incidence after microsurgery or observation.



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Influence of Comorbidity on the Risk of Mortality in Men With Unfavorable-Risk Prostate Cancer Undergoing High-Dose Radiation Therapy Alone

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Mai Anh Huynh, Ming-Hui Chen, Jing Wu, Michelle H. Braccioforte, Brian J. Moran, Anthony V. D'Amico
PurposeTo explore whether a subgroup of men with unfavorable-risk prostate cancer (PC) exists in whom high-dose radiation therapy (RT) alone is sufficient to avoid excess PC death due to competing risk from cardiometabolic comorbidity.Methods and MaterialsThis was a cohort study of 7399 men in whom comorbidity (including congestive heart failure, diabetes mellitus, or myocardial infarction) was assessed and recorded with T1-3NxM0 PC treated with brachytherapy with or without neoadjuvant RT, October 1997 to May 2013 at a single providing institution. Cox and competing risks regression analyses were used to assess whether men with unfavorable–intermediate/high-risk versus favorable–intermediate/low-risk PC were at increased risk of PC-specific, all-cause, or other-cause mortality (PCSM, ACM, OCM), adjusting for number of comorbidities, age at and year of brachytherapy, RT use, and an RT treatment propensity score.ResultsAfter a median follow-up of 7.7 years, 935 men died: 80 of PC and 855 of other causes. Among men with no comorbidity, PCSM risk (adjusted hazard ratio [AHR] 2.74 [95% confidence interval (CI) 1.49-5.06], P=.001) and ACM risk (AHR 1.30 [95% CI 1.07-1.58], P=.007) were significantly increased in men with unfavorable–intermediate/high-risk PC versus favorable–intermediate/low-risk PC, with no difference in OCM (P=.07). Although PCSM risk was increased in men with 1 comorbidity (AHR 2.87 [95% CI 1.11-7.40], P=.029), ACM risk was not (AHR 1.03 [95% CI 0.78-1.36], P=.84). Neither PCSM risk (AHR 4.39 [95% CI 0.37-51.98], P=.24) or ACM risk (AHR 1.43 [95% CI 0.83-2.45], P=.20) was increased in men with 2 comorbidities.ConclusionsTo minimize death from PC, high-dose RT alone may be sufficient treatment in men with 2 or more cardiometabolic comorbidities and unfavorable–intermediate- and high-risk PC.



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N08C9 (Alliance): A Phase 3 Randomized Study of Sulfasalazine Versus Placebo in the Prevention of Acute Diarrhea in Patients Receiving Pelvic Radiation Therapy

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Robert C. Miller, Daniel G. Petereit, Jeff A. Sloan, Heshan Liu, James A. Martenson, James D. Bearden, Ronald Sapiente, Grant R. Seeger, Rex B. Mowat, Ben Liem, Matthew J. Iott, Charles L. Loprinzi
PurposeTo provide confirmatory evidence on the use of sulfasalazine to reduce enteritis during pelvic radiation therapy (RT), following 2 prior single-institution trials suggestive that benefit existed.Methods and MaterialsA multi-institution, randomized, double-blind, placebo-controlled phase 3 trial was designed to assess the efficacy of sulfasalazine versus placebo in the treatment of RT-related enteritis during RT including the posterior pelvis (45.0-53.5 Gy) and conducted through a multicenter national cooperative research alliance. Patients received 1000 mg of sulfasalazine or placebo orally twice daily during and for 4 weeks after RT. The primary endpoint was maximum severity of diarrhea (Common Terminology Criteria for Adverse Events version 4.0). Toxicity and bowel function were assessed by providers through a self-administered bowel function questionnaire taken weekly during RT and for 6 weeks afterward.ResultsEighty-seven patients were enrolled in the trial between April 29, 2011, and May 13, 2013, with evenly distributed baseline factors. At the time of a planned interim toxicity analysis, more patients with grade ≥3 diarrhea received sulfasalazine than received placebo (29% vs 11%, P=.04). A futility analysis showed that trial continuation would be unlikely to yield a positive result, and a research board recommended halting study treatment. Final analysis of the primary endpoint showed no significant difference in maximum diarrhea severity between the sulfasalazine and placebo arms (P=.41).ConclusionsSulfasalazine does not reduce enteritis during pelvic RT and may be associated with a higher risk of adverse events than placebo. This trial illustrates the importance of confirmatory phase 3 trials in the evaluation of symptom-control agents.



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Regional Lung Function Profiles of Stage I and III Lung Cancer Patients: An Evaluation for Functional Avoidance Radiation Therapy

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Yevgeniy Vinogradskiy, Leah Schubert, Quentin Diot, Timothy Waxweiller, Phillip Koo, Richard Castillo, Edward Castillo, Thomas Guerrero, Chad Rusthoven, Laurie Gaspar, Brian Kavanagh, Moyed Miften
PurposeThe development of clinical trials is underway to use 4-dimensional computed tomography (4DCT) ventilation imaging to preferentially spare functional lung in patients undergoing radiation therapy. The purpose of this work was to generate data to aide with clinical trial design by retrospectively characterizing dosimetric and functional profiles for patients with different stages of lung cancer.Methods and MaterialsA total of 118 lung cancer patients (36% stage I and 64% stage III) from 2 institutions were used for the study. A 4DCT-ventilation map was calculated using the patient's 4DCT imaging, deformable image registration, and a density-change–based algorithm. To assess each patient's spatial ventilation profile both quantitative and qualitative metrics were developed, including an observer-based defect observation and metrics based on the ventilation in each lung third. For each patient we used the clinical doses to calculate functionally weighted mean lung doses and metrics that assessed the interplay between the spatial location of the dose and high-functioning lung.ResultsBoth qualitative and quantitative metrics revealed a significant difference in functional profiles between the 2 stage groups (P<.01). We determined that 65% of stage III and 28% of stage I patients had ventilation defects. Average functionally weighted mean lung dose was 19.6 Gy and 5.4 Gy for stage III and I patients, respectively, with both groups containing patients with large spatial overlap between dose and high-function regions.ConclusionOur 118-patient retrospective study found that 65% of stage III patients have regionally variant ventilation profiles that are suitable for functional avoidance. Our results suggest that regardless of disease stage, it is possible to have unique spatial interplay between dose and high-functional lung, highlighting the importance of evaluating the function of each patient and developing a personalized functional avoidance treatment approach.



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Spatial Precision in Magnetic Resonance Imaging–Guided Radiation Therapy: The Role of Geometric Distortion

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Joseph Weygand, Clifton David Fuller, Geoffrey S. Ibbott, Abdallah S.R. Mohamed, Yao Ding, Jinzhong Yang, Ken-Pin Hwang, Jihong Wang
Because magnetic resonance imaging–guided radiation therapy (MRIgRT) offers exquisite soft tissue contrast and the ability to image tissues in arbitrary planes, the interest in this technology has increased dramatically in recent years. However, intrinsic geometric distortion stemming from both the system hardware and the magnetic properties of the patient affects MR images and compromises the spatial integrity of MRI-based radiation treatment planning, given that for real-time MRIgRT, precision within 2 mm is desired. In this article, we discuss the causes of geometric distortion, describe some well-known distortion correction algorithms, and review geometric distortion measurements from 12 studies, while taking into account relevant imaging parameters. Eleven of the studies reported phantom measurements quantifying system-dependent geometric distortion, while 2 studies reported simulation data quantifying magnetic susceptibility–induced geometric distortion. Of the 11 studies investigating system-dependent geometric distortion, 5 reported maximum measurements less than 2 mm. The simulation studies demonstrated that magnetic susceptibility–induced distortion is typically smaller than system-dependent distortion but still nonnegligible, with maximum distortion ranging from 2.1 to 2.6 mm at a field strength of 1.5 T. As expected, anatomic landmarks containing interfaces between air and soft tissue had the largest distortions. The evidence indicates that geometric distortion reduces the spatial integrity of MRI-based radiation treatment planning and likely diminishes the efficacy of MRIgRT. Better phantom measurement techniques and more effective distortion correction algorithms are needed to achieve the desired spatial precision.



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In Reply to Rovirosa and Herreros

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Christina Hunter Chapman, Shruti Jolly




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The 2-Year Cosmetic Outcome of a Randomized Trial Comparing Prone and Supine Whole-Breast Irradiation in Large-Breasted Women

Publication date: 15 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 95, Issue 4
Author(s): Liv Veldeman, Kimberly Schiettecatte, Charlotte De Sutter, Christel Monten, Annick van Greveling, Patrick Berkovic, Thomas Mulliez, Wilfried De Neve
PurposeTo report the 2-year cosmetic outcome of a randomized trial comparing prone and supine whole-breast irradiation in large-breasted patients.Methods and MaterialsOne hundred patients with a (European) cup size ≥C were included. Before and 2 years after radiation therapy, clinical endpoints were scored and digital photographs were taken with the arms alongside the body and with the arms elevated 180°. Three observers rated the photographs using the 4-point Harvard cosmesis scale. Cosmesis was also evaluated with the commercially available Breast Cancer Conservation Treatment.cosmetic results (BCCT.core) software.ResultsTwo-year follow-up data and photographs were available for 94 patients (47 supine treated and 47 prone treated). Patient and treatment characteristics were not significantly different between the 2 cohorts. A worsening of color change occurred more frequently in the supine than in the prone cohort (19/46 vs 10/46 patients, respectively, P=.04). Five patients in the prone group (11%) and 12 patients in the supine group (26%) presented with a worse scoring of edema at 2-year follow-up (P=.06). For retraction and fibrosis, no significant differences were found between the 2 cohorts, although scores were generally worse in the supine cohort. The cosmetic scoring by 3 observers did not reveal differences between the prone and supine groups. On the photographs with the hands up, 7 patients in the supine group versus none in the prone group had a worsening of cosmesis of 2 categories using the BCCT.org software (P=.02).ConclusionWith a limited follow-up of 2 years, better cosmetic outcome was observed in prone-treated than in supine-treated patients.



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A Validated Risk Score for Venous Thromboembolism Is Predictive of Cancer Progression and Mortality

Background.

Retrospective studies have suggested an association between cancer-associated venous thromboembolism (VTE) and patient survival. We evaluated a previously validated VTE Clinical Risk Score in also predicting early mortality and cancer progression.

Methods.

A large, nationwide, prospective cohort study of adults with solid tumors or lymphoma initiating chemotherapy was conducted from 2002 to 2006 at 115 U.S. practice sites. Survival and cancer progression were estimated by the method of Kaplan and Meier. Multivariate analysis was based on Cox regression analysis adjusted for major prognostic factors including VTE itself.

Results.

Of 4,405 patients, 134 (3.0%) died and 330 (7.5%) experienced disease progression during the first 4 months of therapy (median follow-up 75 days). Patients deemed high risk (n = 540, 12.3%) by the Clinical Risk Score had a 120-day mortality rate of 12.7% (adjusted hazard ratio [aHR] 3.00, 95% confidence interval [CI] 1.4–6.3), and intermediate-risk patients (n = 2,665, 60.5%) had a mortality rate of 5.9% (aHR 2.3, 95% CI 1.2–4.4) compared with only 1.4% for low-risk patients (n = 1,200, 27.2%). At 120 days of follow-up, cancer progression occurred in 27.2% of high-risk patients (aHR 2.2, 95% CI 1.4–3.5) and 16.4% of intermediate-risk patients (aHR 1.9, 95% CI 1.3–2.7) compared with only 8.5% of low-risk patients (p < .0001).

Conclusion.

The Clinical Risk Score, originally developed to predict the occurrence of VTE, is also predictive of early mortality and cancer progression during the first four cycles of outpatient chemotherapy, independent from other major prognostic factors including VTE itself. Ongoing and future studies will help determine the impact of VTE prophylaxis on survival.

Implications for Practice:

The risk of venous thromboembolism (VTE) is increased in patients receiving cancer chemotherapy. In this article, the authors demonstrate that a popular risk score for VTE in patients with cancer is also associated with the risk of early mortality in this setting. It is important that clinicians evaluate the risk of VTE in patients receiving cancer treatment and discuss the risk and associated symptoms of VTE with patients. Individuals at increased risk should be advised that VTE is a medical emergency and should be urgently diagnosed and appropriately treated to reduce the risk of serious and life-threatening complications.

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Treatment Summaries and Follow-Up Care Instructions for Cancer Survivors: Improving Survivor Self-Efficacy and Health Care Utilization

Background.

Treatment summaries and follow-up care plan information should be provided to cancer survivors. This study examines the association of receiving summaries and care plans with cancer survivor self-efficacy for chronic illness management, and whether self-efficacy was associated with health care utilization.

Methods.

Four hundred forty-one cancer survivors (≥2 years from diagnosis and had completed treatment) ≥65 years old from 12 cancer centers across 5 states completed telephone surveys. Survivors responded to three questions about receiving a written treatment summary, written follow-up plan, and an explanation of follow-up care plans. Respondents completed the Stanford Chronic Illness Management Self-Efficacy Scale and reported emergency room visits and hospitalizations in the past year. Three multiple linear regression models estimated the association of written treatment summary, written follow-up care plan, and verbal explanation of follow-up plan with total self-efficacy score. Log-binomial models estimated the association of self-efficacy scores with emergency room visits and hospitalizations (yes/no).

Results.

Among survivors, 40% and 35% received a written treatment summary and follow-up care plan, respectively. Seventy-nine percent received an explanation of follow-up care plans. Receiving a verbal explanation of follow-up care instructions was significantly associated with higher self-efficacy scores (β = 0.72, p = .009). Higher self-efficacy scores were significantly associated with lower prevalence ratios of emergency room visits (prevalence ratio, 0.92; 95% confidence interval, 0.88–0.97) and hospitalizations (prevalence ratio, 0.94; 95% confidence interval, 0.89–0.99).

Conclusion.

Explanation of the follow-up care plan, beyond the written component, enhances survivor self-efficacy for managing cancer as a chronic condition—an important mediator for improving health care utilization outcomes.

Implications for Practice:

Older cancer survivors (>65 years) are especially vulnerable to poor outcomes in survivorship because of the complexity of follow-up care and other chronic conditions. Delivering written treatment summaries, written follow-up care plans, and verbal explanations of follow-up care plans all independently increased the self-efficacy for chronic illness management among older survivors. In particular, delivering this information in the verbal format was significantly associated with higher self-efficacy and, subsequently, a lower likelihood of emergency room visits. Understanding the mechanism through which summaries and follow-up care plans may positively influence survivor health is critical to increasing the delivery of the information.

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Cancer Incidence in First- and Second-Degree Relatives of BRCA1 and BRCA2 Mutation Carriers

Background.

Mutations in the BRCA1 and BRCA2 genes are associated with increased risk of breast, ovarian, and several other cancers. The purpose of the present study was to evaluate the incidence of cancer in first- and second-degree relatives of BRCA mutation carriers compared with the general population.

Materials and Methods.

A total of 1,086 pedigrees of BRCA mutation carriers was obtained from a prospectively maintained, internal review board-approved study of persons referred for clinical genetic counseling at the University of Texas MD Anderson Cancer Center. We identified 9,032 first- and second-degree relatives from 784 pedigrees that had demonstrated a clear indication of parental origin of mutation. Standardized incidence ratios (SIRs) were used to compare the observed incidence of 20 primary cancer sites to the expected incidence of each cancer based on the calculated risk estimates according to each subject's age, sex, and ethnicity.

Results.

BRCA1 families had increased SIRs for breast and ovarian cancer (p < .001) and decreased SIRs for kidney, lung, prostate, and thyroid cancer and non-Hodgkin's lymphoma (p < .001). BRCA2 families had increased SIRs for breast, ovarian, and pancreatic cancer (p < .001) and decreased SIRs for kidney, lung, thyroid, and uterine cancer and non-Hodgkin's lymphoma (p < .0025). Analysis of only first-degree relatives (n = 4,099) identified no decreased SIRs and agreed with the increased SIRs observed in the overall study population.

Conclusion.

We have confirmed previous reports of an association between breast, ovarian, and pancreatic cancers with BRCA mutations. Additional research to quantify the relative risks of these cancers for BRCA mutation carriers can help tailor recommendations for risk reduction and enhance genetic counseling.

Implications for Practice:

BRCA gene mutations have been well described to carry an increased risk of both breast and ovarian cancer. However, the implications and risks of other cancers continues to be investigated. Evaluating the risks for other cancers further is key in identifying and managing risk reduction strategies.

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Evaluation of careHPV, Cervista Human Papillomavirus, and Hybrid Capture 2 Methods in Diagnosing Cervical Intraepithelial Neoplasia Grade 2+ in Xinjiang Uyghur Women

Objective.

The study aimed to evaluate the value of the Cervista human papillomavirus (HPV), Hybrid Capture 2 (HC-2), and careHPV tests in diagnosing cervical intraepithelial neoplasia grade 2 (CIN2) or worse in Xinjiang Uyghur women.

Methods.

Three high-risk human papillomavirus (HR-HPV) detection methods were studied on two different populations by different combination modes; a cytology specimen was obtained at the same time. An abnormal result of any test resulted in referral to colposcopy. Cervical biopsy was also performed.

Results.

In population 1, HR-HPV-positive rates were 57.6% and 54.3% as detected by HC-2 and Cervista, respectively; = 0.892 for consistency check of HC-2 and Cervista (p < .001). Area under the receiver operating characteristic curve (AUC) of HC-2 and Cervista was 0.744 (95% confidence interval [CI]: 0.664~0.824, p < .001) and 0.786 (95% CI: 0.715~0.858, p < .001), respectively, for diagnosing CIN2+. The A9 probe can detect six subtypes of HPV, including HPV16, HPV31, HPV33, HPV35, HPV52, and HPV58. If one or more of these subtypes are postitive, then A9 will be positive. A diagnosis of class A9 by the Cerevista test correlated with pathological interpretations (chi-square = 43.063, p < .001). In population 2, HR-HPV-positive rates were 40.1% and 34.4%, respectively, by HC-2 and careHPV; value was 0.779 for the two tests (p < .001). AUC of HC-2 was 0.895 (95% CI: 0.849~0.940, p < .001), and careHPV was 0.841 (95% CI: 0.770~0.899, p < .001) for diagnosing CIN2+.

Conclusion.

Good consistency was shown between HC-2 and Cervista tests and also between the HC-2 and careHPV tests. In the detection of CIN2+, Cervista showed better specificity than HC-2, and interpretation of the A9 subgroup showed high predicted value. The HC-2 test demonstrated better sensitivity than careHPV in detection of CIN2+. HC-2, Cervista, and careHPV may be applied as a triage test for visual inspection with acetic acid/Lugol's iodine-positive or ThinPrep cytologic test-positive women. The careHPV test was comparatively economical and efficient and may be more suitable for resource-limited regions, such as Xinjiang.

Implications for Practice:

This study was designed to evaluate the value of the Cervista human papillomavirus (HPV), Hybrid Capture 2 (HC-2), and careHPV tests in diagnosing cervical intraepithelial neoplasia grade 2 (CIN2) or worse (CIN2+) lesions in Xinjiang Uyghur women. Results showed that there was good consistency between the HC-2 and Cervista tests, as well as between the HC-2 and careHPV tests. In detecting CIN2+, Cervista had higher specificity than HC-2, whereas analysis of the A9 subgroup had high predictive value. (The A9 probe can detect six subtypes of HPV, including HPV16, HPV31, HPV33, HPV35, HPV52, and HPV58. If one or more of these subtypes are postitive, then A9 will be positive.) The HC-2 test demonstrated better sensitivity than careHPV in detecting CIN2+. HC-2, Cervista, and careHPV could be applied as a triage test for visual inspection with acetic acid/Lugol's iodine-positive or ThinPrep cytologic test-positive women. The careHPV test was comparatively economical and efficient and may be more suitable for resource-limited regions, such as Xinjiang.

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Early Recurrence After Hepatectomy for Colorectal Liver Metastases: What Optimal Definition and What Predictive Factors?

Background.

The purpose of this study was to determine the optimal definition and elucidate the predictive factors of early recurrence after surgery for colorectal liver metastases (CRLM).

Methods.

Among 987 patients who underwent curative surgery for CRLM from 1990 to 2012, 846 with a minimum follow-up period of 24 months were eligible for this study. The minimum p value approach of survival after initial recurrence was used to determine the optimal cutoff for the definition of early recurrence. The predictive factors of early recurrence and prognostic factors of survival were analyzed.

Results.

For 667 patients (79%) who developed recurrence, the optimal cutoff point of early recurrence was determined to be 8 months after surgery. The impact of early recurrence on survival was demonstrated mainly in patients who received preoperative chemotherapy. Among the 691 patients who received preoperative chemotherapy, recurrence was observed in 562 (81%), and survival in patients with early recurrence was significantly worse than in those with late recurrence (5-year survival 18.5% vs. 53.4%, p < .0001). Multivariate logistic analysis identified age ≤57 years (p = .0022), >1 chemotherapy line (p = .03), disease progression during last-line chemotherapy (p = .024), >3 tumors (p = .0014), and carbohydrate antigen 19-9 >60 U/mL (p = .0003) as independent predictors of early recurrence. Salvage surgery for recurrence significantly improved survival, even in patients with early recurrence.

Conclusion.

The optimal cutoff point of early recurrence was determined to be 8 months. The preoperative prediction of early recurrence is possible and crucial for designing effective perioperative chemotherapy regimens.

Implications for Practice:

In this study, the optimal cutoff point of early recurrence was determined to be 8 months after surgery based on the minimum p value approach, and its prognostic impact was demonstrated mainly in patients who received preoperative chemotherapy. Five factors, including age, number of preoperative chemotherapy lines, response to last-line chemotherapy, number of tumors, and carbohydrate antigen 19-9 concentrations, were identified as predictors of early recurrence. Salvage surgery for recurrence significantly improved survival, even in patients with early recurrence. For better selection of patients who could truly benefit from surgery and should also receive strong postoperative chemotherapy, the accurate preoperative prediction of early recurrence is crucial.

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Founder and Recurrent Mutations in BRCA1 and BRCA2 Genes in Latin American Countries: State of the Art and Literature Review

Background.

Numerous epidemiological factors affect the probability of developing breast or ovarian cancer, but no predictor is as determinant as inheriting a mutation in BRCA1 or BRCA2. The concept of the founder effect explains the reduced genetic variability in some populations, according to the theory that new populations can be formed from a reduced number of individuals, so the new population would carry only a small fraction of the genetic variability of the original population. The main purpose of this review is to provide an update on the state of the art in founder mutations and some recurrent mutations that have recently been described in Latin America.

Methods.

A literature search was performed in the electronic databases of PUBMED, EMBASE, LILACS, and BIREME using the terms BRCA1, BRCA2, founder mutation, Latin American population, and Hispanic. Sixty-two papers were identified, of which 38 were considered relevant for this review. Each result is shown per country.

Results.

In Latin America, clear founder effects have been reported in Mexico (BRCA1 del exons 9–12), Brazil (BRCA1 5382insC and BRCA2 c.156_157insAlu), and Colombia (BRCA1 3450del4, A1708E, and BRCA2 3034del4) and in Latinas residing in Southern California (BRCA1 185delAG, IVS5+1G>A, S955x, and R1443x). Of these, mutation BRCA1 3450del4 has also been reported in Brazil and Chile, whereas mutation BRCA2 3034del4 has been reported in Argentina and Peru. These data support the idea that although most Hispanic populations are the result of a mixture between Europeans, Africans, and Amerindians, the relative proportion of each genetic component varies throughout the Hispanic populations, making it necessary to identify the mutations characteristic of each population to generate mutation profiles adjusted to each one of them.

Conclusion.

In Latin American countries, and even among regions of the same country, there is great heterogeneity of ancestors. Therefore, Latinas should not be analyzed like other population groups without taking into account their genetic ancestry. The presence of founder mutations in specific population groups represents a cost-effective analysis. The importance of determining the founder mutations lies mainly in the decrease in costs. If we manage to decrease costs, screenings could be offered more widely and cover a larger number of women.

Implications for Practice:

Hispanic and African-American populations are four to five times less likely than other populations worldwide to receive screening for BRCA mutations, a main reason being the high costs of these tools. The present study seeks to identify the prevalent mutations and the founder effect in the BRCA gene in the Hispanic population to address specific panels for this population group in the future and develop strategies for population screening.

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Establishing stereotactic body radiotherapy with flattening filter free techniques in the treatment of pulmonary lesions - initial experiences from a single institution

Abstract

Background

Stereotactic body radiotherapy (SBRT) using flattening filter free (FFF)-techniques has been increasingly applied during the last years. However, clinical studies investigating this emerging technique are still rare. Hence, we analyzed toxicity and clinical outcome of pulmonary SBRT with FFF-techniques and performed dosimetric comparison to conventional techniques using flattening filters (FF).

Materials and methods

Between 05/2014 and 06/2015, 56 consecutive patients with 61 pulmonary lesions were treated with SBRT in FFF-mode. Central lesions received 8 × 7.5 Gy delivered to the conformally enclosing 80 %-isodose, while peripheral lesions were treated with 3 × 15 Gy, prescribed to the 65 %-isodose. Early and late toxicity (after 6 months) as well as initial clinical outcomes were evaluated. Furthermore, [deleted] plan quality and efficiency were evaluated by analyzing conformity, beam- on and total treatment delivery times in comparison to plans with FF-dose application.

Results

Median follow-up time was 9.3 months (range 1.5–18.0 months). Early toxicity was low with only 5 patients (8.9 %) reporting CTCAE 2° or higher side-effects. Only one patient (1.8 %) was diagnosed with radiation-induced pneumonitis CTCAE 3°, while 2 (3.6 %) patients suffered from pneumonitis CTCAE 2°. After 6 months, no toxicity greater than CTCAE 2° was reported. 1-year local progression-free survival, distant progression-free survival and overall survival were 92.8 %, 78.0 %, and 94.4 %, respectively. While plan quality was similar for FFF- and FF-plans in respect to conformity (p = 0.275), median beam-on time as well as total treatment time were significantly reduced for SBRT in FFF-mode compared to FF-mode (p ≤ 0.001, p ≤ 0.001).

Conclusions

Patient treatment with SBRT using FFF-techniques is safe and provides promising clinical results with only modest toxicity at significantly increased dose delivery speed.

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The incidence and significance of multicentric noncontrast-enhancing lesions distant from a histologically-proven glioblastoma

Abstract

Improvements in imaging are increasing the detection of multiple lesions in the setting of glioblastoma. Occasionally distant non-enhancing lesions may be identified which have the appearances of a multicentric low-grade glioma. We aimed to determine the incidence, prognostic significance and diagnostic value of this appearance in new glioblastoma patients. Pre-operative MRIs of patients with a new diagnosis of glioblastoma were reviewed to identify multicentric non-enhancing lesions, defined as areas of FLAIR hyperintensity and mass effect, without post-contrast enhancement, separate from the histologically-proven glioblastoma. Patient survival was compared to glioblastoma patients without these appearances, and follow-up imaging was reviewed. Nine of 151 patients (6 %) had multicentric non-enhancing lesions. Their median survival of 183 days was significantly worse than the 278 days for patients without multicentric nonenhancing lesions (p = 0.025). Follow-up MRIs were performed in four patients. In one patient, there were several additional lesions, one of which developed evidence of necrosis within 22 days of presentation. In the other three patients, the multicentric lesions developed enhancement and evidence of necrosis within 1 year, and became confluent on FLAIR with the dominant lesion. The appearance of a multicentric non-enhancing lesion is an uncommon finding in glioblastoma, but a poor prognostic feature. These lesions progress faster than expected for a low-grade glioma and are thus likely to represent more advanced lesions than their appearances suggest. Confluence with the dominant lesion developing with time suggests that the tumor is more extensive than appreciated on imaging.

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COX-2 rs689466, rs5275, and rs20417 polymorphisms and risk of head and neck squamous cell carcinoma: a meta-analysis of adjusted and unadjusted data

Abstract

Background

Numerous case–control studies have been performed to investigate the association between three cyclooxygenase-2 (COX-2) polymorphisms (rs20417 (−765G > C), rs689466 (−1195G > A), and rs5275 (8473 T > C)) and the risk of head and neck squamous cell carcinoma (HNSCC). However, the results were inconsistent. Therefore, we conducted this meta-analysis to investigate the association.

Methods

We searched in PubMed, Embase, and Web of Science up to January 20, 2015 (last updated on May 12, 2016). Two independent reviewers extracted the data. Odds ratios (ORs) with their 95 % confidence intervals (CIs) were used to assess the association. All statistical analyses were performed using the Review Manager (RevMan) 5.2 software.

Results

Finally 8 case–control studies were included in this meta-analysis. For unadjusted data, an association with increased risk was observed in three genetic models in COX-2 rs689466 polymorphism; however, COX-2 rs5275 and rs20417 polymorphisms were not related to HNSCC risk in this study. The pooled results from adjusted data all revealed non-significant association between these three polymorphisms and risk of HNSCC. We also found a similar result in the subgroup analyses, based on both unadjusted data and adjusted data.

Conclusion

Current results suggest that COX-2 rs689466, rs5275, and rs20417 polymorphisms are not associated with HNSCC. Further large and well-designed studies are necessary to validate this association.

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Health professionals and the early detection of head and neck cancers: a population-based study in a high incidence area

Abstract

Background

In the context of early detection of head and neck cancers (HNC), the aim of this study was to describe how people sought medical consultation during the year prior to diagnosis and the impact on the stage of the cancer.

Methods

Patients over 20 years old with a diagnosis of HNC in 2010 were included from four French cancer registries. The medical data were matched with data regarding uptake of healthcare issued from French National Health Insurance General Regime.

Results

In 86.0 % of cases, patients had consulted a general practitioner (GP) and 21.1 % a dentist. Consulting a GP at least once during the year preceding diagnosis was unrelated to Charlson index, age, sex, département, quintile of deprivation of place of residence. Patients from the 'quite privileged', 'quite underprivileged' and 'underprivileged' quintiles consulted a dentist more frequently than those from the 'very underprivileged' quintile (p = 0.007).

The stage was less advanced for patients who had consulted a GP (OR = 0.42 [0.18–0.99]) - with a dose–response effect.

Conclusions

In view of the frequency of consultations, the existence of a significant association between consultations and a localised stage at diagnosis and the absence of a socio-economic association, early detection of HNC by GPs would seem to be the most appropriate way.

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