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Selenium (Se) has been known for many years to have played a role in boosting the immune function, but the manner in which this element acts at the molecular level in host defence and inflammatory diseases is poorly understood. To elucidate the role of Se-containing proteins in the immune function, we knocked out the expression of this protein class in T-cells or macrophages of mice by targeting the removal of the selenocysteine tRNA gene using loxP-Cre technology. Mice with selenoprotein-less T-cells manifested reduced pools of mature and functional T-cells in lymphoid tissues and an impairment in T-cell-dependent antibody responses. Furthermore, selenoprotein deficiency in T-cells led to an inability of these cells to suppress reactive oxygen species production, which in turn affected their ability to proliferate in response to T-cell receptor stimulation. Selenoprotein-less macrophages, on the other hand, manifested mostly normal inflammatory responses, but this deficiency resulted in an altered regulation in extracellular matrix-related gene expression and a diminished migration of macrophages in a protein gel matrix. These observations provided novel insights into the role of selenoproteins in the immune function and tissue homeostasis. [ABSTRACT FROM AUTHOR]

Thoracic radiotherapy decisions in patients with interstitial lung disease (ILD) are complex due to concerns about severe or even fatal radiation pneumonitis. This systematic review analysed the published evidence regarding the incidence of radiation pneumonitis and mortality after thoracic radiotherapy and investigated clinical and dosimetric predictors of radiation pneumonitis in lung cancer patients with ILD. A systematic search was carried out in PubMed, Medline, Embase and the Cochrane database for articles published between January 2000 and April 2021. Two authors independently screened eligible studies that met our predefined criteria. Studies were assessed for design and quality and a qualitative data synthesis was carried out. The search strategy resulted in 1750 articles. After two rounds of screening, 24 publications were included. The median overall incidence of grade ≥3 radiation pneumonitis was 19.7% (range 8-46%). The incidence was greater in conventional radical radiotherapy-treated patients (median 31.8%) compared with particle beam therapy- or stereotactic ablative radiotherapy-treated patients (median 12.5%). The median rate of grade 5 radiation pneumonitis was 11.9% (range 0-60%). The presence of ILD was an independent predictor of severe radiation pneumonitis. Severe radiation pneumonitis was more common in the presence of usual interstitial pneumonia (UIP) pattern or idiopathic pulmonary fibrosis (IPF) than non-UIP or non-IPF subtype. Several other clinical predictors were reported in the literature. V5, V10, V20 and mean lung dose were the most common dosimetric predictors for severe radiation pneumonitis, often with stricter dose constraints than conventionally used. Patients with lung cancer associated with ILD had a poorer overall survival compared with patients without ILD. In conclusion, patients with lung cancer associated with ILD have a poor prognosis. They are at high risk of severe and even fatal radiation pneumonitis. Careful patient selection is necessary, appropriate high-risk consenting and strict lung dose-volume constraints should be used, if these patients are to be treated with thoracic radiotherapy., (Copyright © 2022 The Royal College of Radiologists. All rights reserved.)

This document aims to assist oncologists in making clinical decisions encountered while managing their patients with hepatocellular carcinoma (HCC), specific to Indian practice, based on consensus among experts. Most patients are staged by Barcelona Clinic Liver Cancer (BCLC) staging system which comprises patient performance status, Child-Pugh status, number and size of nodules, portal vein invasion and metastasis. Patients should receive multidisciplinary care. Surgical resection and transplant forms the mainstay of curative treatment. Ablative techniques are used for small tumours (<3 cm) in patients who are not candidates for surgical resection (Child B and C). Patients with advanced (HCC should be assessed on an individual basis to determine whether targeted therapy, interventional radiology procedures or best supportive care should be provided. In advanced HCC, immunotherapy, newer targeted therapies and modern radiation therapy have shown promising results. Patients should be offered regular surveillance after completion of curative resection or treatment of advanced disease., Competing Interests: None

Context: Stereotactic body radiotherapy (SBRT) is increasingly being used for early-stage lung cancer and lung oligometastases., Aims: To report our experience of setting up lung SBRT and early clinical outcomes., Settings and Design: This was a retrospective, interventional, cohort study., Subjects and Methods: Patients were identified from multidisciplinary tumor board meetings. They underwent four-dimensional computed tomography-based planning. The ROSEL trial protocol, the Radiation Therapy Oncology Group (RTOG) 0236, and the UK-Stereotactic Ablative Body Radiotherapy Consortium guidelines were used for target volume and organs-at-risks (OARs) delineation, dosimetry, and plan quality assessment. Each SBRT plan underwent patient-specific quality assurance (QA). Daily online image guidance using KVCT or MVCT was done to ensure accurate treatment delivery., Statistical Analysis Used: Microsoft Excel 2010 was used for data analysis., Results: Fifteen patients were treated to one or more lung tumors. One patient received helical tomotherapy in view of bilateral lung oligometastases at similar axial levels. All the remaining patients received volumetric modulated arc therapy (VMAT)-based treatment. The prescription dose varied from 40 to 60 Gy in 5-8 fractions with alternate-day treatment. The mean and median lung V20 was 5.24% and 5.16%, respectively (range, 1.66%-9.10%). The mean and median conformity indexes were 1.02 and 1.06, respectively (range, 0.70-1.18). After a median follow-up of 17 months, the locoregional control rate was 93.3%., Conclusions: SBRT was implemented using careful evaluation of OAR dose constraints, dosimetric accuracy and plan quality, patient-specific QA, and online image guidance for accurate treatment delivery. It was safe and effective for early-stage nonsmall cell lung cancer and lung metastases. Prospective data were collected to audit our outcomes., Competing Interests: None

Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1 + CD38 hi CD8 + cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1 + CD38 hi CD8 + cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1 + CD38 + CD8 + cells in tumor and blood than responders. In conclusion, the status of CD8 + T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1 + CD38 hi CD8 + cells that is reversed by optimal priming. PD-1 + CD38 hi CD8 + cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.

Background: Medical decisions made by oncology clinicians have serious implications, even when made collaboratively with the patient. Clinicians often use the Eastern Clinical Oncology Group (ECOG) performance status (PS) scores to help them make treatment-related decisions., Methods: The current study explores the variability of the ECOG score when applied to 12 predetermined specially designed clinical case vignettes presented to a group of oncology clinicians ( n = 72). The quantitative analysis included evaluation of variability of ECOG PS scores and exploration of rater and patient-related factors which may influence the final ECOG rating. In-depth interviews were conducted with oncology clinicians to ascertain factors that they felt were important while making treatment-related decisions. Basic and global themes were generated following qualitative data analysis., Results: Quantitative results showed that there was poor agreement in ECOG rating between raters. Overall concordance with the gold standard rating ranged between 19.4% and 56.9% for the vignettes. Moreover, patients deemed to have socially desirable qualities ( p < 0.004) were rated to have better PS and women patients ( p < 0.004) to have worse PS. Clinicians having international work experience had increased concordance with ECOG PS rating. Qualitative results showed that 'perceived socio-economic background of the patient', 'age of the patient', 'patient's and family's preferences' and 'past treatment response' were the major themes highlighted by respondents that influenced the treatment-related decisions made by clinicians., Conclusion: There is considerable variability in ECOG PS determined by clinicians. Decision-making in oncology is complex, multifactorial and is influenced by rater and patient-related factors., Competing Interests: The authors do not have any conflicts of interest to declare.

Objective:: Intensity modulated radiotherapy (IMRT) is used, where necessary, for bulky or complex-shaped, locally advanced, non-small cell lung cancer (NSCLC). We evaluate our real-world experience with radical radiotherapy including concurrent chemoradiation (CCRT), and analyse the impact of IMRT on survival outcomes in patients with larger volume disease., Methods:: All patients treated between May 2011 and December 2017 were included. Analyses were conducted for factors affecting survival, including large volume disease that was defined as planning target volume (PTV) > 500 cc., Results:: In 184 patients with large volume disease, the median overall survival was 19.2 months, compared to 22 months seen with the overall cohort of 251 patients who received radical radiotherapy. PTV and using CCRT were significant predictors for survival. IMRT was used in 93 (50.5%) of 184 patients with large PTV. The patients treated using IMRT had significantly larger disease volume (median PTV = 859 vs 716 cc; p-value = 0.009) and more advanced stage (proportion of Stage IIIB: 56 vs 29%; p-value = 0.003) compared to patients treated with three-dimensional conformal radiotherapy. Yet, the outcomes with IMRT were non-inferior to those treated with 3DCRT. CCRT was used in 103 (56%) patients with large volume disease and resulted in a significantly better median survival of 24.9 months. The proportional benefit from CCRT was also greater than in the overall cohort., Conclusion:: Despite being used for larger volume and more advanced NSCLC, inverse-planned IMRT resulted in non-inferior survival., Advances in Knowledge:: IMRT enables the safe use of curative CCRT for large-volume, locally-advanced NSCLC.

Objective:: Radiation planning for locally-advanced non-small cell lung cancer (NSCLC) can be time-consuming and iterative. Many cases cannot be planned satisfactorily using multisegment three-dimensional conformal radiotherapy (3DCRT). We sought to develop and validate a predictive model which could estimate the probability that acceptable target volume coverage would need intensity modulated radiotherapy (IMRT)., Methods:: Variables related to the planning target volume (PTV) and topography were identified heuristically. These included the PTV, it's craniocaudal extent, the ratio of PTV to total lung volume, distance of the centroid of the PTV from the spinal canal, and the extent PTV crossed the midline. Metrics were chosen such that they could be measured objectively, quickly and reproducibly. A logistic regression model was trained and validated on 202 patients with NSCLC. A group of patients who had both complex 3DCRT and IMRT planned was then used to derive the utility of the use of such a model in the clinic based on the time taken for planning such complex 3DCRT., Results:: Of the 202 patients, 93 received IMRT, as they had larger volumes crossing midline. The final model showed a good rank discrimination (Harrell's C-index 0.84) and low calibration error (mean absolute error of 0.014). Predictive accuracy in an external dataset was 92%. The final model was presented as a nomogram. Using this model, the dosimetrist can save a median planning time of 168 min per case., Conclusion:: We developed and validated a data-driven, decision aid which can reproducibly determine the best planning technique for locally-advanced NSCLC., Advances in Knowledge:: Our validated, data-driven decision aid can help the planner to determine the need for IMRT in locally advanced NSCLC saving significant planning time in the process.

Introduction: Use of deep inspiration breath hold (DIBH) radiation therapy may reduce long-term cardiac mortality. The resource and time commitments associated with DIBH are impediments to its widespread adoption. We report the dosimetric benefits, workforce requirements, and potential reduction in cardiac mortality when DIBH is used for left-sided breast cancers., Methods and Materials: Data regarding the time consumed for planning and treating 50 patients with left-sided breast cancer with DIBH and 20 patients treated with free breathing (FB) radiation therapy were compiled prospectively for all personnel (regarding person-hours [PH]). A second plan was generated for all DIBH patients in the FB planning scan, which was then compared with the DIBH plan. Mortality reduction from use of DIBH was calculated using the years of life lost resulting from ischemic heart disease for Indians and the postulated reduction in risk of major cardiac events resulting from reduced cardiac dose., Results: The median reduction in mean heart dose between the DIBH and FB plans was 166.7 cGy (interquartile range, 62.7-257.4). An extra 6.76 PH were required when implementing DIBH as compared with FB treatments. Approximately 3.57 PH were necessary per Gy of reduction in mean heart dose. The excess years of life lost from ischemic heart disease if DIBH was not done in was 0.95 per 100 patients, which translates into a saving of 12.8 hours of life saved per PH of work required for implementing DIBH. DIBH was cost effective with cost for implementation of DIBH for all left-sided breast cancers at 2.3 times the annual per capita gross domestic product., Conclusion: Although routine implementation of DIBH requires significant resource commitments, it seems to be worthwhile regarding the projected reductions in cardiac mortality., (Copyright © 2018 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Introduction: Radical radiotherapy (RT) with curative intent, with or without chemotherapy, is the standard treatment for inoperable, locally advanced nonsmall cell lung cancer (NSCLC)., Materials and Methods: We retrospectively reviewed the data for all 288 patients who presented with inoperable, locally advanced NSCLC at our institution, between May 2011 and December 2016., Results: RT alone or sequential chemoradiotherapy (SCRT) or concurrent chemoradiotherapy (CCRT) was used for 213 patients. Median age was 64 years (range: 27-88 years). Stage-III was the biggest stage group with 189 (88.7%) patients. Most patients with performance status (PS) 0 or 1 received CCRT, whereas most patients with PS 2 received RT alone (P < 0.001). CCRT, SCRT, and RT alone were used for 120 (56.3%), 24 (11.3%), and 69 (32.4%) patients, respectively. A third of all patients (32.4%) required either volumetric-modulated arc radiotherapy (VMAT) or tomotherapy. Median follow-up was 16 months. The median progression-free survival and median overall survival (OS) were 11 and 20 months, respectively. One-year OS and 2-year OS were 67.9% and 40.7%, respectively. Patients treated using CCRT lived significantly longer with a median survival of 28 months, compared with 13 months using SCRT and RT alone (P < 0.001). On multivariate analysis, OS was significantly affected by age, stage group, treatment approach, and response to treatment., Conclusion: RT including CCRT is feasible, safe, and well tolerated in our patient population and results in survival benefits comparable with published literature. CCRT should be considered for all patients with inoperable, locally advanced NSCLC, who are fit and have good PS., Competing Interests: None

Combination therapies that depend on checkpoint inhibitor antibodies (Abs) such as for PD-1 or its ligand (PD-L1) together with immune stimulatory agonist Abs like anti-OX40 are being tested in the clinic to achieve improved antitumor effects. Here, we studied the potential therapeutic and immune effects of one such combination: Ab to PD-1 with agonist Ab to OX40/vaccine. We tested the antitumor effects of different treatment sequencing of this combination. We report that simultaneous addition of anti-PD-1 to anti-OX40 negated the antitumor effects of OX40 Ab. Antigen-specific CD8 + T-cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival reduced. Although we observed an increase in IFNγ-producing E7-specifc CD8 + T cells in the spleens of mice treated with the combination of PD-1 blockade with anti-OX40/vaccine, these cells underwent apoptosis both in the periphery and the tumor. These results indicate that anti-PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist Ab. These findings have important implications on the design of combination immunotherapy for cancer, demonstrating the need to test treatment combination and sequencing before moving to the clinic. Cancer Immunol Res; 5(9); 755-66. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Aims: To evaluate the effect of radiotherapy dose-volume parameters of neural stem cell (NSC) compartment on progression-free survival (PFS) and overall survival after post-resection chemoradiation in newly diagnosed glioblastoma., Materials and Methods: Sixty-one patients with unifocal glioblastoma were included. Ipsilateral (NSC&#95;Ipsi), contralateral (NSC&#95;Contra) and combined NSC (NSC&#95;Combined) were contoured on radiotherapy planning computerised tomography datasets. NSC dose-volume parameters were correlated with PFS and overall survival. Serial magnetic resonance imaging scans were assessed to understand the frequency of pre- and post-treatment involvement of the NSC by contrast enhancing lesions (CELs)., Results: Baseline involvement of NSC with CELs was seen in 67.2% and 95.9% had CELs and FLAIR abnormalities at progression. With a median follow-up of 14.1 months (interquartile range 9.4-20.6 months), median PFS and overall survival were 14.5 (95% confidence interval 11.6-17.5) and 16.2 (95% confidence interval 13.3-19.2) months, respectively. Poor Eastern Cooperative Oncology Group performance score, advanced recursive partitioning analysis class, unmethylated O6-methylguanine methyltransferase (MGMT) status, higher than median of mean NSC&#95;Ipsi dose were associated with significantly inferior PFS and overall survival on univariate analysis. On multivariate analysis, unmethylated MGMT status, higher than median of mean doses to NSC&#95;Ipsi and poor compliance to adjuvant temozolomide were independent predictors of inferior survival., Conclusions: In this cohort, 67.2% of newly diagnosed glioblastoma patients had NSC involved with CELs at presentation and 95.9% at progression. This might be an imaging surrogate of the current notion of gliomagenesis and progression from NSC rests. A high radiation dose to NSC&#95;Ipsi was significantly associated with inferior survival. This could be a function of larger tumours and planning target volumes in those with pre-treatment NSC involvement. Methylated MGMT and good compliance to adjuvant temozolomide were independent predictors of better survival. Until further evidence brings hope for glioblastoma, elective, partial NSC irradiation remains experimental., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: To report the acute toxicity and the dosimetric correlates after moderately hypofractionated radiotherapy for localized prostate cancer., Methods: A total of 101 patients with localized prostate cancer were treated with image-guided intensity-modulated radiation therapy. Patients were treated to 65Gy/25Fr/5 weeks (n = 18), or 60Gy/20Fr/4 weeks (n = 83). Most (82.2%) had high-risk or pelvic node-positive disease. Acute toxicity was assessed using Radiation Therapy Oncology Group (RTOG) acute morbidity scoring criteria. Dose thresholds for acute rectal and bladder toxicity were identified., Results: The incidence of acute grade 2 GI toxicity was 20.8%, and grade 2 genitourinary (GU) toxicity was 6.9%. No Grade 3 to 4 toxicity occurred. Small bowel toxicity was uncommon (Gr 2 = 4%). The 2Gy equivalent doses (EQD2) to the rectum and bladder (α/β = 3) calculated showed that the absolute doses were more consistent predictors of acute toxicities than the relative volumes. Those with grade 2 or more GI symptoms had significantly higher V EQD2-60Gy (13.2 vs 9.9cc, p = 0.007) and V EQD2-50Gy (20.6 vs 15.4cc, p = 0.005). Those with grade 2 or more GU symptoms had significantly higher V EQD2-70Gy (30.4 vs 18.4cc, p = 0.001) and V EQD2-65Gy (44.0 vs 28.8cc, p = 0.001). The optimal cutoff value for predicting grade 2 acute proctitis, for V EQD2-60Gy was 9.7cc and for V EQD2-50Gy was 15.9cc. For grade 2 GU symptoms, the threshold values were 23.6cc for V EQD2-70Gy and 38.1cc for V EQD2-65Gy ., Conclusions: Hypofractionated radiotherapy for prostate cancer is well tolerated and associated with manageable acute side effects. The absolute dose-volume parameters of rectum and bladder predict for acute toxicities., (Copyright © 2017 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Aims: Breast cancer is the most common cancer in women. Western data have confirmed hypofractionated radiation therapy to be safe and effective in the adjuvant radiation therapy of breast cancers. We report the disease-related outcomes in a non-Caucasian, unscreened population treated with hypofractionated radiation., Materials and Methods: Unselected case notes of patients presenting to a tertiary cancer centre between June 2011 and December 2013 were reviewed from the electronic hospital case records. Patients with a diagnosis of non-metastatic invasive non-sarcomatous breast cancer were identified. Demographic information, oestrogen receptor (ER), progesterone receptor (PR), HER2 status, pathological tumour, nodal stage at diagnosis and outcomes of treatment, including systemic therapies, surgery and hypofractionated radiation, were documented. Local recurrence rates, disease-free survival (DFS) and overall survival were calculated., Results: Overall 925 patents were identified, median age 53.0 years (interquartile range 45-61), 330 of whom had neoadjuvant chemotherapy. The median follow-up time was 22.6 months and 23.5 months for overall and neoadjuvant chemotherapy groups, respectively. ER, PR and HER2 status was available in 788 patients, 77.2% of whom were ER/PR positive, 14.7% had triple negative disease, while 9.5% were HER2 rich. Overall, 34.2% (113 patients) underwent breast conservation surgery; 744 (80.4%) patients were treated with systemic chemotherapy and 878 (94.9%) patients received adjuvant radiation therapy, of whom 407 (44.0%) received supraclavicular-fossa radiotherapy. Overall survival, DFS and locoregional recurrence-free survival (LRRFS) for the overall group were 93%, 86.9% and 97.1%, respectively. LRRFS in the breast conservation surgery versus mastectomy groups were 99% versus 95.5% (P=0.003), with more node-positive patients in the mastectomy group. Stage N0/1 had better LRRFS compared with N2/2 (99.1% versus 95.7%); 94.3% versus 82.3%; P=0.005, 0.000. Grade 3 (53.8%) tumours had worse overall survival compared with grade 1 or grade 2 disease (89.6% versus 100% and 96.4%; P<0.001) although the LRRFS was not significantly different between the groups (98.9% versus 97.8%; P=0.37). There was no difference in LRRFS based on molecular subtypes., Conclusion: Local recurrence rates following hypofractionated radiation in our population were comparable with those reported by the START trialists and were found to be safe in the medium term for patients irrespective of breast conservation surgery/mastectomy or radiotherapy to the supraclavicular field. Molecular group frequencies were comparable with Western populations but did not affect LRRFS., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: Clinical implementation of image-guided intensity-modulated radiotherapy is rapidly evolving. Helical tomotherapy treatment delivery involves daily imaging before intensity-modulated radiotherapy delivery. This can be a time consuming resource-intensive process, which may not be essential in head and neck radiotherapy, where effective immobilisation is possible. This study aimed to evaluate whether an offline protocol implementing the shifts derived from the first few fractions can be an acceptable alternative to daily imaging for helical tomotherapy., Materials and Methods: We retrospectively analysed the set-up data of 2858 fractions of 100 head and neck cancer patients who were treated with daily online image guidance. Using summary data from all treatment fractions, we calculated the systematic error (∑) and random error (σ) in each of the three axes, i.e. mediolateral (x), craniocaudal (y), anteroposterior (z). We also calculated the translational vector of each fraction of individual patients. We then simulated two no-action-level offline protocols where set-up errors of the first three (protocol F3) or five fractions (protocol F5) were averaged and implemented for the remaining fractions. The residual errors in each axis for these fractions were determined together with the residual ∑ and σ. Planning target volume (PTV) margins using the van Herk formula were generated based on the uncorrected errors as well as for the F3 and F5 protocols. For each scenario, we tabulated the number of fractions where the residual errors were more than 5 mm (our default PTV margin). We also tried to evaluate whether errors tended to differ based on intent (radical or adjuvant), anatomical subsite or weight loss during treatment., Results: Analysis from this large dataset revealed that in the tomotherapy platform, the highest set-up errors were in the anteroposterior (z) axis. The global mean was 5.4 mm posterior shift, which can be partly attributed to couch sag on this system. Uncorrected set-up errors resulted in systematic and random errors of ∑x,y,z of 1.8, 1.7 and 2 mm and σx,y,z of 1.7, 1.5 and 1.9 mm, with a required PTV margin in x, y, z axes of 5.7, 5.3 and 6.2 mm. Implementing average shifts from the first three or five fractions resulted in a substantial reduction in the residual systematic errors, whereas random errors remained constant. The PTV margins required for the residual errors after three and five fraction corrections were 3.8, 3.4 and 5.1 mm for F3 and 3.3, 2.9, 4.8 mm for F5. The proportions of fractions where there was >5 mm residual error were 1.6%, 1.1%, 2.9% in x, y and z axes in the F3 protocol and 1.5%, 0.8% and 2.6% with the F5 protocol. Although there was no difference in residual shifts > 5 mm, there was a statistically higher chance of residual errors > 3 mm larynx/hypopharynx subsites versus other sites. In patients who had more than 5% weight loss, there was no significant increase in residual errors with the F5 protocol and the required PTV margin was within our default PTV margins expansion., Conclusions: Correction of systematic errors by implementing average shifts from the first five fractions enables us to safely avoid daily imaging in this retrospective analysis. If this is validated in a prospective group it could lead to implementation of a resource sparing image-guided radiotherapy protocol both in terms of time and imaging dose. Patients with larynx/hypopharynx subsites may require more careful evaluation and daily online matching., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Intensity-modulated radiotherapy (IMRT) is being increasingly used for the treatment of non-small cell lung cancer (NSCLC), despite the absence of published randomised controlled trials. Planning studies and retrospective series have shown a decrease in known predictors of lung toxicity (V20 and mean lung dose) and the maximum spinal cord dose. Potential dosimetric advantages, accessibility of technology, a desire to escalate dose or a need to meet normal organ dose constraints are some of the factors recognised as supporting the use of IMRT. However, IMRT may not be appropriate for all patients being treated with radical radiotherapy. Unique problems with using IMRT for NSCLC include organ and tumour motion because of breathing and the potential toxicity from low doses of radiotherapy to larger amounts of lung tissue. Caution should be exercised as there is a paucity of prospective data regarding the efficacy and safety of IMRT in lung cancer when compared with three-dimensional conformal radiotherapy and IMRT data from other cancer sites should not be extrapolated. This review looks at the use of IMRT in NSCLC, addresses the challenges and highlights the potential benefits of using this complex radiotherapy technique., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD-1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit.

Introduction: Malignant struma ovarii is an extremely rare ovarian tumour containing malignant thyroid carcinoma within differentiated thyroid tissue, as the predominant tissue type. Surgery for suspected ovarian tumour and incidental pathological diagnosis is the most common presentation. Evidence supporting any particular approach to the clinical management of this condition is limited, mainly consisting of case reports, small series or pathological case series. There is no randomised evidence for postoperative management in view of the rarity of this condition. The opinion is divided between conservative management versus total thyroidectomy and radio-iodine ablation., Methods: We carried out a retrospective review of our series with focus on postoperative management of this rare condition. A review of existing literature was also carried out., Results: Six patients with a median age of 52 years presented with various symptoms of abdominal pain, pressure or menstrual problems. After the initial gynaecological resection and specialised pathology review, they were subsequently treated with total thyroidectomy and administration of radioactive iodine. All of these six patients are in remission at a median follow up of 60 months., Conclusion: We favour aggressive postoperative management with total thyroidectomy and radioactive iodine, and long-term follow up of these patients., (© 2012 The Authors. Journal of Medical Imaging and Radiation Oncology © 2012 The Royal Australian and New Zealand College of Radiologists.)

Small cell carcinomas of the ovary (SCCO) are rare and aggressive malignant neoplasms carrying a poor prognosis. Although multi-modality treatment including chemotherapy leads to a high initial response rate, the majority of these patients relapse quickly and die within 2 years of diagnosis. Because these tumours are rare, there is no consensus to support any particular approach to management. We present 2 cases and review the relevant literature to make a number of recommendations. The treatment of these unusual cases should to be individually discussed in a multi-disciplinary team and multi-modality treatment including surgery, chemotherapy and radiotherapy should be considered for patients with limited disease. Conservative, fertility-preserving surgery may be considered in younger women with early-stage disease. Induction chemotherapy with weekly dose-dense and dose-intense carboplatin and taxane is useful. Prophylactic cranial irradiation (PCI) may be considered in patients in remission after primary treatment with chemotherapy or surgery.

Immunotherapies based on adoptive cell transfer are highly effective in the treatment of metastatic melanoma, but the use of this approach in other cancer histologies has been hampered by the identification of appropriate target molecules. Immunologic approaches targeting tumor vasculature provide a means for the therapy of multiple solid tumor types. We developed a method to target tumor vasculature, using genetically redirected syngeneic or autologous T cells. Mouse and human T cells were engineered to express a chimeric antigen receptor (CAR) targeted against VEGFR-2, which is overexpressed in tumor vasculature and is responsible for VEGF-mediated tumor progression and metastasis. Mouse and human T cells expressing the relevant VEGFR-2 CARs mediated specific immune responses against VEGFR-2 protein as well as VEGFR-2-expressing cells in vitro. A single dose of VEGFR-2 CAR-engineered mouse T cells plus exogenous IL-2 significantly inhibited the growth of 5 different types of established, vascularized syngeneic tumors in 2 different strains of mice and prolonged the survival of mice. T cells transduced with VEGFR-2 CAR showed durable and increased tumor infiltration, correlating with their antitumor effect. This approach provides a potential method for the gene therapy of a variety of human cancers.

Adoptive cell transfer using autologous tumor infiltrating lymphocytes or lymphocytes transduced with antitumor T-cell receptor (TCR) is an effective therapy for patients with metastatic melanoma. A limiting factor in the effectiveness of this treatment is the apoptosis of the transferred cells when Interleukin-2 (IL-2) administration is withdrawn. In an attempt to improve persistence of the transferred lymphocytes, we cotransduced human peripheral blood lymphocytes with retroviruses encoding Bcl-2 or Bcl-xL, antiapoptotic genes of the BCL2 family, and the MART-1 melanoma tumor antigen-specific TCR, DMF5. Lymphocytes were cotransduced with 38% to 64% cotransduction efficiency, and exhibited a marked delay in apoptosis after IL-2 withdrawal. Cotransduction with Bcl-2 or Bcl-xL did not affect cytokine secretion or lytic ability of the DMF5-transduced lymphocytes. After 5 days of IL-2 withdrawal, cotransduced lymphocytes produced similar levels of IFN-γ per cell as DMF5-alone transduced lymphocytes in response to tumor cells. Cotransduction did not alter the phenotype of lymphocytes with respect to a panel of T-cell differentiation markers. In a mouse model of melanoma, adoptively transferred T cells transduced with Bcl-2 persisted better in vivo at the site of tumor, 13 and 21 days after adoptive transfer (P=0.0064 and 0.041, respectively), with evidence of enrichment of the Bcl-2-transduced population over time (P<0.0001). Thus, by coexpressing Bcl-2 or Bcl-xL with a tumor-specific TCR, we have engineered a lymphocyte that resists apoptosis owing to IL-2 withdrawal without altering its tumor-specific function or phenotype, and thus may show improved antitumor effectiveness in vivo after cell transfer.

Adoptive cell transfer (ACT)-based immunotherapies can mediate objective cancer regression in animal models and in up to 70% of patients with metastatic melanoma; however, it remains unclear whether the tumor vasculature impedes the egress of tumor-specific T cells, thus hindering this immunotherapy. Disruption of the proangiogenic interaction of vascular endothelial growth factor (VEGF) with its receptor (VEGFR-2) has been reported to "normalize" tumor vasculature, enhancing the efficacy of chemotherapeutic agents by increasing their delivery to the tumor intersitium. We thus sought to determine whether disrupting VEGF/VEGFR-2 signaling could enhance the effectiveness of ACT in a murine cancer model. The administration of an antibody against mouse VEGF synergized with ACT to enhance inhibition of established, vascularized, B16 melanoma (P = 0.009) and improve survival (P = 0.003). Additive effects of an antibody against VEGFR-2 in conjunction with ACT were seen in this model (P = 0.013). Anti-VEGF, but not anti-VEGFR-2, antibody significantly increased infiltration of transferred cells into the tumor. Thus, normalization of tumor vasculature through disruption of the VEGF/VEGFR-2 axis can increase extravasation of adoptively transferred T cells into the tumor and improve ACT-based immunotherapy. These studies provide a rationale for the exploration of combining antiangiogenic agents with ACT for the treatment of patients with cancer.

A case of solitary bone metastasis from breast cancer, where MRI assessment of treatment response was inaccurate and whole-body fluorodeoxyglucose ((18)FDG) positron emission tomography with computed tomography (PET-CT) proved more reliable and objective, is presented.

STAF [Sec (selenocysteine) tRNA gene transcription activating factor] is a transcription activating factor for a number of RNA Pol III- and RNA Pol II-dependent genes including the Trsp [Sec tRNA gene], which in turn controls the expression of all selenoproteins. Here, the role of STAF in regulating expression of Sec tRNA and selenoproteins was examined. We generated transgenic mice expressing the Trsp transgene lacking the STAF-binding site and made these mice dependent on the transgene for survival by removing the wild-type Trsp. The level of Sec tRNA was unaffected or slightly elevated in heart and testis, but reduced approximately 60% in liver and kidney, approximately 70% in lung and spleen and approximately 80% in brain and muscle compared with the corresponding organs in control mice. Moreover, the ratio of the two isoforms of Sec tRNA that differ by methylation at position 34 (Um34) was altered significantly, and the Um34-containing form was substantially reduced in all tissues examined. Selenoprotein expression in these animals was most affected in tissues in which the Sec tRNA levels were most severely reduced. Importantly, mice had a neurological phenotype strikingly similar to that of mice in which the selenoprotein P gene had been removed and their life span was substantially reduced. The results indicate that STAF influences selenoprotein expression by enhancing Trsp synthesis in an organ-specific manner and by controlling Sec tRNA modification in each tissue examined.

Selenium is an essential dietary element with antioxidant roles in immune regulation, but there is little understanding of how this element acts at the molecular level in host defense and inflammatory disease. Selenium is incorporated into the amino acid selenocysteine (Sec), which in turn is inserted into selenoproteins in a manner dependent on Sec tRNA([Ser]Sec). To investigate the molecular mechanism that links selenium to T cell immunity, we generated mice with selenoprotein-less T cells by cell type-specific ablation of the Sec tRNA([Ser]Sec) gene (trsp). Herein, we show that these mutant mice exhibit decreased pools of mature T cells and a defect in T cell-dependent antibody responses. We also demonstrate that selenoprotein deficiency leads to oxidant hyperproduction in T cells and thereby suppresses T cell proliferation in response to T cell receptor stimulation. These findings offer novel insights into immune function of selenium and physiological antioxidants.

LoxP-Cre technology was used to remove the selenocysteine tRNA gene, trsp, in either endothelial cells or myocytes of skeletal and heart muscle to elucidate the role of selenoproteins in cardiovascular disease. Loss of selenoprotein expression in endothelial cells was embryonic lethal. A 14.5-day-old embryo had numerous abnormalities including necrosis of the central nervous system, subcutaneous hemorrhage and erythrocyte immaturity. Loss of selenoprotein expression in myocytes manifested no apparent phenotype until about day 12 after birth. Affected mice had decreased mobility and an increased respiratory rate, which proceeded rapidly to death. Pathological analysis revealed that mice lacking trsp had moderate to severe myocarditis with inflammation extending into the mediastinitis. Thus, ablation of selenoprotein expression demonstrated an essential role of selenoproteins in endothelial cell development and in proper cardiac muscle function. The data suggest a direct connection between the loss of selenoprotein expression in these cell types and cardiovascular disease.

Characterizing Sec tRNAs that decode UGA provides one of the most direct and easiest means of determining whether an organism possesses the ability to insert selenocysteine (Sec) into protein. Herein, we used a combination of two techniques, computational to identify Sec tRNA genes and RT-PCR to sequence the gene products, to unequivocally demonstrate that two widely studied, model protozoans, Dictyostelium discoideum and Tetrahymena thermophila, encode Sec tRNA in their genomes. The advantage of using both procedures is that computationally we could easily detect potential Sec tRNA genes and then confirm by sequencing that the Sec tRNA was present in the tRNA population, and thus the identified gene was not a pseudogene. Sec tRNAs from both organisms decode UGA. T. thermophila Sec tRNA, like all other sequenced Sec tRNAs, is 90 nucleotides in length, while that from D. discoideum is 91 nucleotides long making it the longest eukaryotic sequenced to date. Evolutionary analyses of known Sec tRNAs reveal the two forms identified herein are the most divergent eukaryotic Sec tRNAs thus far sequenced.

Purpose: This study was conducted to assess the value of sonographically guided core biopsy in the evaluation of thyroid nodules by comparison with fine-needle aspiration cytology (FNAC) performed with and without sonographic guidance., Methods: We performed a retrospective analysis of a consecutive series of 645 thyroid samples obtained at a single center. Samples came from 422 patients who underwent FNAC (with or without sonographic guidance), sonographically guided core biopsy, or excision of thyroid tissue with or without prior frozen sectioning. Final diagnoses were obtained from surgery or clinical follow-up. Initial and final diagnoses were compared., Results: Adequate samples for assessment were obtained in 87% of core biopsies, compared with 60% of cytology aspirates (p <0.001). Sonographically guided core biopsy and sonographically guided FNAC both had zero false-negative rates for the diagnosis of malignancy, compared with a 7.0% false-negative rate (95% confidence interval, 2.0-12.0%) for aspiration cytology when sonography was not used. With core biopsy, 11% of patients required surgical confirmation of the diagnosis, compared with 43% of patients following FNAC (p <0.001). There were no major complications following core biopsy., Conclusions: Sonographically guided core biopsy provides an accurate and safe alternative to FNAC in the assessment of thyroid nodules., (2005 Wiley Periodicals, Inc.)

Fertilization includes sperm-egg recognition, adhesion, binding, fusion and egg activation. Integrin (ITG) receptors which are adhesion molecules are expressed on mouse, hamster and human gametes and their potential ligands also have been identified. Role of ITGs during fertilization is supported by inhibition of sperm-egg adhesion and/or fusion by means of anti-ITG mAbs, Arg-Gly-Asp (RGD) or disintegrin-like peptides. This review includes the current understanding of the molecular mechanism that regulates sperm-egg interaction and implications of this knowledge for assessing the fertility potential of men and immunocontraceptive method.