Intracranial chordoma: radiosurgery,hypofractionated stereotactic radiotherapy and treatment outcomes

BackgroundThe aim of the study was to assess the results of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy (SRS/SRT) for skull base chordomas.Materials and methodsTwenty-three patients aged 12–75 were treated with SRS/SRT due to skull base chordoma. In 19 patients SRS/SRT was a part of the primary therapy, while in 4, a part of the treatment of recurrence. In 4 patients SRS/SRT was used as a boost after conventional radiotherapy and in 19 cases it was the only irradiation method applied. Patients were irradiated to total dose of 6–35 Gy and median total equivalent dose of 52 Gy.ResultsDuring median follow-up of 39 months, 4 patients died. One-, two- and five-year OS was 95%, 89% and 69%, respectively. In nine patients, progression of the disease was diagnosed during study period. One-, two- and five-year progression free survival (PFS) from the end of radiotherapy was 81%, 59% and 43%, respectively. Radiotherapy was well tolerated and only two patients in our group experienced moderate treatment-related toxicity.ConclusionSRS/SRT alone or in combination with surgery is a safe and effective method of irradiation of patients with skull base chordomas. High EQD₂ is necessary to achieve satisfactory treatment results.     

Stereotactic radiotherapy for bone oligometastases

About 60–90% of cancer patients are estimated to develop bone metastases, particularly in the spine.Bone scintigraphy, computed tomography (CT ) and magnetic resonance imaging (MRI ) are currently used to assess metastatic bone disease; positron emission tomography/computed tomography (PET-CT ) has become more widespread in clinical practice because of its high sensitivity and specificity with about 95% diagnostic accuracy. The most common and well-known radiotracer is 18F-fluorodeoxyglucose (¹⁸FDG); several other PET-radiotracers are currently under investigation for different solid tumors, such as ¹¹C or ¹⁸FDG-choline and prostate specific membrane antigen (PSMA)-PET/CT for prostate cancer. In treatment planning, standard and investigational imaging modalities should be registered with the planning CT so as to best define the bone target volume. For target volume delineation of spine metastases, the International Spine Radiosurgery Consortium (ISRC ) of North American experts provided consensus guidelines. Single fraction stereotactic radiotherapy (SRT ) doses ranged from 12 to 24 Gy; fractionated SRT administered 21–27 Gy in 3 fractions or 20–35 Gy in 5 fractions. After spine SRT, less than 5% of patients experienced grade ≥ 3 acute toxicity. Late toxicity included the extremely rare radiation-induced myelopathy and a 14% risk of de novo vertebral compression fractures.     

Impact of rotational errors of whole pelvis on the dose of prostate-based image-guided radiotherapy to pelvic lymph nodes and small bowel in high-risk prostate cancer

BackgroundThe target volume increases when the prostate and pelvic lymph nodes (PLNs) are combined, and the fiducial markers (FMs) are placed at the edge of the irradiation field. Thus, the position of FMs may be changed by the rotational errors (REs) of “whole pelvis”. The aim of this study was to examine the impact of REs of “whole pelvis” on the dose of FMs-based image-guided radiotherapy to the PLNs and the small bowel in prostate cancer including the PLNs.Materials and methodsWe retrospectively evaluated 10 patients who underwent prostate cancer radiotherapy involving the PLNs. The position of FMs was calculated from the radiographs obtained before and after the 6D correction of pelvic REs. We simulated the delivery dose considering the daily pelvic REs and calculated the difference from the planned dose in the D_98% of the PLN clinical target volume and the D_2cc, and V_45Gy of the small bowel.ResultThe position of FMs strongly correlated with the pelvic REs in the pitch direction (r = 0.7788). However, the mean delivered doses to PLNs for 10 patients were not significantly different from the planned doses (p = 0.625). Although the D_2cc and V_45Gy of the small bowel strongly correlated with the pitch rotation of the pelvis, there was no significant difference between the delivered and planned doses (p = 0.922 and p = 0.232, respectively).ConclusionThe dosimetric effect of pelvic REs on the dose to PLNs and the small bowel was negligible during the treatment course.     

Stereotactic radiotherapy for oligometastases in the lymph nodes

Even though systemic therapy is standard treatment for lymph node metastases, metastasis-directed stereotactic radiotherapy (SRT ) seems to be a valid option in oligometastatic patients with a low disease burden.Positron emission tomography-computed tomography (PET-CT ) is the gold standard for assessing metastases to the lymph nodes; co-registration of PET-CT images and planning CT images are the basis for gross tumor volume (GTV ) delineation. Appropriate techniques are needed to overcome target motion. SRT schedules depend on the irradiation site, target volume and dose constraints to the organs at risk (OARs) of toxicity. Although several fractionation schemes were reported, total doses of 48–60 Gy in 4–8 fractions were proposed for mediastinal lymph node SRT, with the spinal cord, esophagus, heart and proximal bronchial tree being the dose limiting OAR s. Total doses ranged from 30 to 45 Gy, with daily fractions of 7–12 Gy for abdominal lymph nodes, with dose limiting OARs being the liver, kidneys, bowel and bladder. SRT on lymph node metastases is safe; late side effects, particularly severe, are rare.     

Stereotactic radiotherapy for lung oligometastases

30–60% of cancer patients develop lung metastases, mostly from primary tumors in the colon-rectum, lung, head and neck area, breast and kidney. Nowadays, stereotactic radiotherapy (SRT ) is considered the ideal modality for treating pulmonary metastases.When lung metastases are suspected, complete disease staging includes a total body computed tomography (CT ) and/or positron emission tomography-computed tomography (PET -CT ) scan. PET -CT has higher specificity and sensitivity than a CT scan when investigating mediastinal lymph nodes, diagnosing a solitary lung lesion and detecting distant metastases. For treatment planning, a multi-detector planning CT scan of the entire chest is usually performed, with or without intravenous contrast media or esophageal lumen opacification, especially when central lesions have to be irradiated. Respiratory management is recommended in lung SRT, taking the breath cycle into account in planning and delivery. For contouring, co-registration and/or matching planning CT and diagnostic images (as provided by contrast enhanced CT or PET-CT ) are useful, particularly for central tumors. Doses and fractionation schedules are heterogeneous, ranging from 33 to 60 Gy in 3–6 fractions. Independently of fractionation schedule, a BED₁₀ > 100 Gy is recommended for high local control rates. Single fraction SRT (ranges 15–30 Gy) is occasionally administered, particularly for small lesions. SRT provides tumor control rates of up to 91% at 3 years, with limited toxicities.The present overview focuses on technical and clinical aspects related to treatment planning, dose constraints, outcome and toxicity of SRT for lung metastases.     

Prenatal,Perinatal and Neonatal Risk Factors for Intellectual Disability: A Systemic Review and Meta-Analysis

BackgroundThe etiology of non-genetic intellectual disability (ID) is not fully known, and we aimed to identify the prenatal, perinatal and neonatal risk factors for ID.MethodPubMed and Embase databases were searched for studies that examined the association between pre-, peri- and neonatal factors and ID risk (keywords “intellectual disability” or “mental retardation” or “ID” or “MR” in combination with “prenatal” or “pregnancy” or “obstetric” or “perinatal” or “neonatal”. The last search was updated on September 15, 2015. Summary effect estimates (pooled odds ratios) were calculated for each risk factor using random effects models, with tests for heterogeneity and publication bias.ResultsSeventeen studies with 55,344 patients and 5,723,749 control individuals were eligible for inclusion in our analysis, and 16 potential risk factors were analyzed. Ten prenatal factors (advanced maternal age, maternal black race, low maternal education, third or more parity, maternal alcohol use, maternal tobacco use, maternal diabetes, maternal hypertension, maternal epilepsy and maternal asthma), one perinatal factor (preterm birth) and two neonatal factors (male sex and low birth weight) were significantly associated with increased risk of ID.ConclusionThis systemic review and meta-analysis provides a comprehensive evidence-based assessment of the risk factors for ID. Future studies are encouraged to focus on perinatal and neonatal risk factors and the combined effects of multiple factors.     

Multimodality treatment of locally advanced soft-tissue sarcomas of the extremities

Background

Adjuvant radiotherapy (RTE) still has a fundamental role as a post-operative treatment of locally advanced soft tissues sarcomas of the extremities. Moreover the employment of combined modalities in locally advanced soft tissues sarcomas of the extremities allow to maximize the chance of local cure even in difficult presentation cases, and possibly improve survival, especially in high-risk disease patients. In patients with sarcomas of the extremities in which definitive surgery has not been radical (with positive or “close” margins) radiotherapy can improve the results in terms of Disease Free Survival (DFS) and, together with chemotherapy, of Overall Survival (OS). We recommend radiotherapy in case of deep tumor location, inadequate surgical margins and grade 3 tumour; for positive or “marginal (or close)” excision (that means inadequate surgery) or in selected patients with a bad prognosis, we believe that a multidisciplinary approach can be preferable.

Introduction

Adjuvant radiotherapy (RTE) still has a fundamental role as a post-operative treatment. In patients with sarcomas of the extremities in whom definitive surgery has been or not radical (positive or “close” margins), radiotherapy with chemotherapy can improve the results in terms of Disease Free Survival (DFS) and Overall Survival (OS), while RTE alone seems to improve local control.

Materials and methods

From 1/2000 to 12/2005 we treated 34 patients affected by locally advanced sarcomas of the upper or lower extremities with radiotherapy (doses ranging from 54 to 66 Gy) and chemotherapy in 18/34 with an adjuvant scheme that consisted in Epirubicine (120 mg/m²) plus Ifosfamide (7000–9000 mg/m²).

Results

Disease Free Survival (DFS) and the Overall Survival (OS) rates were 76% and 82%, respectively. Eighteen patients developed one or more long-term side effects. Most of these complications were mild: all patients experienced only erithema, edema, local sclerosis or moderate pain.

Conclusion

Radiotherapy has an important role as a post-operative treatment also when surgery was non-radical. It improves local control more in patients with high-grade sarcomas of the extremity with positive or close margins. It is still difficult to assess the role of adjuvant chemotherapy.     

Radionuclide Delivery Strategies in Tumor Treatment: A Systematic Review

The aim of this review was to assess recent progress in targeted radionuclide tumor therapy, focusing on the best delivery strategies. A literature search was conducted in PubMed, Web of Science, and Scopus using the terms “radionuclides”, “liposomes”, “avidin–biotin interaction”, “theranostic”, and “molecular docking”. The 10 year filter was applied, except for the avidin–biotin interaction. Data were retrieved from both preclinical and clinical settings. Three targeting strategies were considered: pretargeting, liposomes, and ligands. Pretargeting can be achieved by exploiting the avidin–biotin interaction. This strategy seems very promising, although it has been investigated mainly in resectable tumors. Radiolabeled liposomes have attracted new interest as probes to identify the most suitable patients for treatment with liposomal formulations of common chemotherapeutics. The use of ligands for the delivery of radiotherapeutics to a specific target is still the most appealing strategy for treating tumors. The most appropriate ligand can be identified by virtually simulating its interaction with the receptor. All strategies showed great potential for use in targeted radionuclide therapy, but they also have numerous drawbacks. The most promising option is probably the one based on the use of new ligands.     

Molecular Diagnostics of Fine Needle Aspiration for the Presurgical Screening of Thyroid Nodules

“The incidence of thyroid cancer, the most common endocrine malignancy, is rising. The two most common types of thyroid cancer are papillary and follicular” thyroid carcinomas. “Fine-needle aspiration (FNA) of thyroid nodules” can permit to detect many genetic mutations and other molecular alterations, including RAS and BRAF point mutations, PAX8/peroxisome proliferator-activated receptor (PPAR)γ and “RET/PTC rearrangements, occurring in thyroid papillary and follicular carcinomas” (more than 70% of cases), which can be used successfully to improve the diagnosis “and the management of patients with thyroid nodules”. The most extensive experience has been accumulated with “the diagnostic use of BRAF mutation”, which is highly specific for malignancy. “Testing FNA samples for a panel of mutations” that typically includes RAS, BRAF, PAX8/PPARγ and RET/PTC could permit to achieve the biggest diagnostic impact. “The accuracy of cancer diagnosis in thyroid nodules could be improved significantly using these and other emerging molecular markers”.     

Classification of Domain Movements in Proteins Using Dynamic Contact Graphs

A new method for the classification of domain movements in proteins is described and applied to 1822 pairs of structures from the Protein Data Bank that represent a domain movement in two-domain proteins. The method is based on changes in contacts between residues from the two domains in moving from one conformation to the other. We argue that there are five types of elemental contact changes and that these relate to five model domain movements called: “free”, “open-closed”, “anchored”, “sliding-twist”, and “see-saw.” A directed graph is introduced called the “Dynamic Contact Graph” which represents the contact changes in a domain movement. In many cases a graph, or part of a graph, provides a clear visual metaphor for the movement it represents and is a motif that can be easily recognised. The Dynamic Contact Graphs are often comprised of disconnected subgraphs indicating independent regions which may play different roles in the domain movement. The Dynamic Contact Graph for each domain movement is decomposed into elemental Dynamic Contact Graphs, those that represent elemental contact changes, allowing us to count the number of instances of each type of elemental contact change in the domain movement. This naturally leads to sixteen classes into which the 1822 domain movements are classified.     

Modeling spatial–temporal operations with context-dependent associative memories

We organize our behavior and store structured information with many procedures that require the coding of spatial and temporal order in specific neural modules. In the simplest cases, spatial and temporal relations are condensed in prepositions like “below” and “above”, “behind” and “in front of”, or “before” and “after”, etc. Neural operators lie beneath these words, sharing some similarities with logical gates that compute spatial and temporal asymmetric relations. We show how these operators can be modeled by means of neural matrix memories acting on Kronecker tensor products of vectors. The complexity of these memories is further enhanced by their ability to store episodes unfolding in space and time. How does the brain scale up from the raw plasticity of contingent episodic memories to the apparent stable connectivity of large neural networks? We clarify this transition by analyzing a model that flexibly codes episodic spatial and temporal structures into contextual markers capable of linking different memory modules.     

Acute Alcohol Consumption Impairs Controlled but Not Automatic Processes in a Psychophysical Pointing Paradigm

Numerous studies have investigated the effects of alcohol consumption on controlled and automatic cognitive processes. Such studies have shown that alcohol impairs performance on tasks requiring conscious, intentional control, while leaving automatic performance relatively intact. Here, we sought to extend these findings to aspects of visuomotor control by investigating the effects of alcohol in a visuomotor pointing paradigm that allowed us to separate the influence of controlled and automatic processes. Six male participants were assigned to an experimental “correction” condition in which they were instructed to point at a visual target as quickly and accurately as possible. On a small percentage of trials, the target “jumped” to a new location. On these trials, the participants’ task was to amend their movement such that they pointed to the new target location. A second group of 6 participants were assigned to a “countermanding” condition, in which they were instructed to terminate their movements upon detection of target “jumps”. In both the correction and countermanding conditions, participants served as their own controls, taking part in alcohol and no-alcohol conditions on separate days. Alcohol had no effect on participants’ ability to correct movements “in flight”, but impaired the ability to withhold such automatic corrections. Our data support the notion that alcohol selectively impairs controlled processes in the visuomotor domain.     

When Feelings Arise with Meanings: How Emotion and Meaning of a Native Language Affect Second Language Processing in Adult Learners

To determine when and how L2 learners start to process L2 words affectively and semantically, we conducted a longitudinal study on their interaction in adult L2 learners. In four test sessions, spanning half a year of L2 learning, we monitored behavioral and ERP learning-related changes for one and the same set of words by means of a primed lexical-decision paradigm with L1 primes and L2 targets. Sensitivity rates, accuracy rates, RTs, and N400 amplitude to L2 words and pseudowords improved significantly across sessions. A semantic priming effect (e.g, prime “driver”facilitating response to target “street”) was found in accuracy rates and RTs when collapsing Sessions 1 to 4, while this effect modulated ERP amplitudes within the first 300 ms of L2 target processing. An overall affective priming effect (e.g., “sweet” facilitating”taste”) was also found in RTs and ERPs (posterior P1). Importantly, the ERPs showed an L2 valence effect across sessions (e.g., positive words were easier to process than neutral words), indicating that L2 learners were sensitive to L2 affective meaning. Semantic and affective priming interacted in the N400 time-window only in Session 4, implying that they affected meaning integration during L2 immersion together. The results suggest that L1 and L2 are initially processed semantically and affectively via relatively separate channels that are more and more linked contingent on L2 exposure.     

How Watching Pinocchio Movies Changes Our Subjective Experience of Extrapersonal Space

The way we experience the space around us is highly subjective. It has been shown that motion potentialities that are intrinsic to our body influence our space categorization. Furthermore, we have recently demonstrated that in the extrapersonal space, our categorization also depends on the movement potential of other agents. When we have to categorize the space as “Near” or “Far” between a reference and a target, the space categorized as “Near” is wider if the reference corresponds to a biological agent that has the potential to walk, instead of a biological and non-biological agent that cannot walk. But what exactly drives this “Near space extension”? In the present paper, we tested whether abstract beliefs about the biological nature of an agent determine how we categorize the space between the agent and an object. Participants were asked to first read a Pinocchio story and watch a correspondent video in which Pinocchio acts like a real human, in order to become more transported into the initial story. Then they had to categorize the location ("Near" or "Far") of a target object located at progressively increasing or decreasing distances from a non-biological agent (i.e., a wooden dummy) and from a biological agent (i.e., a human-like avatar). The results indicate that being transported into the Pinocchio story, induces an equal “Near” space threshold with both the avatar and the wooden dummy as reference frames.     

Stereotactic radiotherapy for liver oligometastases

The liver is the first metastatic site in 15–25% of colorectal cancer patients and one of the first metastatic sites for lung and breast cancer patients.A computed tomography (CT ) scan with contrast medium is a standard procedure for assessing liver lesions but magnetic resonance imaging (MRI) characterizes small lesions better thanks to its high soft-tissue contrast. Positron emission tomography with computed tomography (PET-CT ) plays a complementary role in the diagnosis of liver metastases. Triphasic (arterial, venous and time-delayed) acquisition of contrast-medium CT images is the first step in treatment planning. Since the liver exhibits a relatively wide mobility due to respiratory movements and bowel filling, appropriate techniques are needed for target identification and motion management. Contouring requires precise recognition of target lesion edges. Information from contrast MRI and/or PET-CT is crucial as they best visualize metastatic disease in the parenchyma. Even though different fractionation schedules were reported, doses and fractionation schedules for liver stereotactic radiotherapy (SRT ) have not yet been established. The best local control rates were obtained with BED₁₀ values over 100 Gy. Local control rates from most retrospective studies, which were limited by short follow-ups and included different primary tumors with intrinsic heterogeneity, ranged from 60% to 90% at 1 and 2 years. The most common SRT-related toxicities are increases in liver enzymes, hyperbilirubinemia and hypoalbuminemia. Overall, late toxicity is mild even in long-term follow-ups.     

PAROTID TUMOR OPERATIONS—The Case Against Enucleation

So-called mixed “encapsulated” parotid tumors are best managed by surgical procedures which avoid contact with the “capsule.” Enucleation is often a hazardous and incomplete procedure. Subtotal or total parotidectomy with exposure of the facial nerve to avert accidental damage to it is the treatment of choice.Microscopic study of the periphery of such tumors reveals that the “capsule” does not fully encapsulate; hence, enucleation and lesser procedures may leave neoplastic tissue behind.Surgical procedures to achieve complete excision without endangering the facial nerve were carried out in 123 cases. There was local recurrence in one case.     

Nucleosome Remodeling and Epigenetics

Eukaryotic chromatin is kept flexible and dynamic to respond to environmental, metabolic, and developmental cues through the action of a family of so-called “nucleosome remodeling” ATPases. Consistent with their helicase ancestry, these enzymes experience conformation changes as they bind and hydrolyze ATP. At the same time they interact with DNA and histones, which alters histone–DNA interactions in target nucleosomes. Their action may lead to complete or partial disassembly of nucleosomes, the exchange of histones for variants, the assembly of nucleosomes, or the movement of histone octamers on DNA. “Remodeling” may render DNA sequences accessible to interacting proteins or, conversely, promote packing into tightly folded structures. Remodeling processes participate in every aspect of genome function. Remodeling activities are commonly integrated with other mechanisms such as histone modifications or RNA metabolism to assemble stable, epigenetic states.     

Radiobiology of stereotactic radiotherapy

This paper focuses on the radiobiological mechanisms underlying the effects of stereotactic radiotherapy (SRT ) which, despite SRT expansion, have not yet been fully elucidated. Some authors postulated that radiobiology principles, as applied to conventional fractionations (5R: reoxygenation, repair, repopulation, redistribution, radioresistence), suffice in themselves to account for the excellent clinical results of SRT; others argued that the role of the 5R was limited. Recent preclinical data showed that hypofractionated ablative treatments altered the microenvironment, thus determining cell death either directly or indirectly. Furthermore, dead tumor cells released quantities of antigens, which stimulated antitumor immunity, thus reducing the risk of relapse and metastasis. Better understanding of the radiobiological mechanisms underlying response to high-dose radiation treatment is essential for predicting its short- and long-term effects on the tumor and surrounding healthy tissues and, consequently, for improving its related therapeutic index.     

Could preoperative short-course radiotherapy be the treatment of choice for localized advanced rectal carcinoma?

Short-course preoperative radiotherapy (RT) is widely used in northern Europe for locally advanced resectable rectal cancer, but its role in the era of advanced imaging techniques is uncertain. Here, we reviewed articles and abstracts on SCRT published from 1974 through 2013 with the goal of identifying patients who might be best suited for short-course RT. We included relevant articles comparing surgery with or without preoperative radiation published before and after the advent of total mesorectal excision. We also analyzed two randomized trials directly comparing short-course RT with conventionally fractionated chemoradiation (the Polish Colorectal Study Group and the Trans-Tasman Radiation Oncology Group) that compared short-course RT with conventional chemoradiotherapy. We conclude from our review that short-course RT can be generally applied for operable rectal cancer and produces high rates of pelvic control with acceptable toxicity; it reduces local recurrence rates but does not increase overall survival. SCRT seems to be best used for tumors considered “low risk,” i.e., those that are >5 cm from the anal margin, without circumferential margin involvement, and involvement of fewer than 4 lymph nodes. Whether sequential chemotherapy can further improve outcomes remains to be seen, as does the best time for surgery (immediately or 6–8 weeks after RT). We further recommend that selection of patients for short-course RT should be based on findings from magnetic resonance imaging or transrectal ultrasonography.