Applicator visualization using ultrashort echo time MRI for high-dose-rate endorectal brachytherapy.

PURPOSE: The individual channels in an endorectal applicator for high-dose-rate endorectal brachytherapy are not visible on standard MRI sequences. The aim of this study was to test whether an ultrashort echo time (UTE) MRI sequence could be used to visualize the individual channels to enable MR-only treatment planning for rectal cancer. METHODS AND MATERIALS: We used a radial three-dimensional (3D) UTE pulse sequence and acquired images of phantoms and two patients with rectal cancer. We rigidly registered a UTE image and CT scan of an applicator phantom, based on the outline of the applicator. One observer compared channel positions on the UTE image and CT scan in five slices spaced 25 mm apart. To quantify geometric distortions, we scanned a commercial 3D geometric quality assurance phantom and calculated the difference between detected marker positions on the UTE image and corresponding marker positions on two 3D T1-weighted images with opposing readout directions. RESULTS: On the UTE images, there is sufficient contrast to discern the individual channels. The difference in channel positions on the UTE image compared with the CT was on average -0.1 ± 0.1 mm (left-right) and 0.1 ± 0.3 mm (anteroposterior). After rigid registration to the 3D T1-weighted sequences, the residual 95th percentile of the geometric distortion inside a 550-mm-diameter sphere was 1.0 mm (left-right), 0.9 mm (anteroposterior), and 0.9 mm (craniocaudal). CONCLUSIONS: With a UTE sequence, the endorectal applicator and individual channels can be adequately visualized in both phantom and patients. The geometrical fidelity is within an acceptable range.

Radiotherapy quality assurance for mesorectum treatment planning within the multi-center phase II STAR-TReC trial: Dutch results.

BACKGROUND: The STAR-TReC trial is an international multi-center, randomized, phase II study assessing the feasibility of short-course radiotherapy or long-course chemoradiotherapy as an alternative to total mesorectal excision surgery. A new target volume is used for both (chemo)radiotherapy arms which includes only the mesorectum. The treatment planning QA revealed substantial variation in dose to organs at risk (OAR) between centers. Therefore, the aim of this study was to determine the treatment plan variability in terms of dose to OAR and assess the effect of a national study group meeting on the quality and variability of treatment plans for mesorectum-only planning for rectal cancer. METHODS: Eight centers produced 25 × 2 Gy treatment plans for five cases. The OAR were the bowel cavity, bladder and femoral heads. A study group meeting for the participating centers was organized to discuss the planning results. At the meeting, the values of the treatment plan DVH parameters were distributed among centers so that results could be compared. Subsequently, the centers were invited to perform replanning if they considered this to be necessary. RESULTS: All treatment plans, both initial planning and replanning, fulfilled the target constraints. Dose to OAR varied considerably for the initial planning, especially for dose levels below 20 Gy, indicating that there was room for trade-offs between the defined OAR. Five centers performed replanning for all cases. One center did not perform replanning at all and two centers performed replanning on two and three cases, respectively. On average, replanning reduced the bowel cavity V20Gy by 12.6%, bowel cavity V10Gy by 22.0%, bladder V35Gy by 14.7% and bladder V10Gy by 10.8%. In 26/30 replanned cases the V10Gy of both the bowel cavity and bladder was lower, indicating an overall lower dose to these OAR instead of a different trade-off. In addition, the bowel cavity V10Gy and V20Gy showed more similarity between centers. CONCLUSIONS: Dose to OAR varied considerably between centers, especially for dose levels below 20 Gy. The study group meeting and the distribution of the initial planning results among centers resulted in lower dose to the defined OAR and reduced variability between centers after replanning. TRIAL REGISTRATION: The STAR-TReC trial, ClinicalTrials.gov Identifier: NCT02945566. Registered 26 October 2016, https://clinicaltrials.gov/ct2/show/NCT02945566).

EUS-guided fiducial marker placement for radiotherapy in rectal cancer: feasibility of two placement strategies and four fiducial types.

Background and study aims To facilitate image guidance during radiotherapy of rectal cancer, we investigated the feasibility of fiducial marker placement. This study aimed to evaluate technical success rate and safety of two endoscopic ultrasound (EUS)-guided placement strategies and four fiducial types for rectal cancer patients. Patients and methods This prospective multicenter study included 20 participants who were scheduled to undergo rectal cancer treatment with neoadjuvant short-course radiotherapy or chemoradiation. EUS-guided endoscopy was used for fiducial placement at the tumor site (n = 10) or in the mesorectal fat and in the tumor (n = 10). Four fiducial types were used (Visicoil 0.75 mm, Visicoil 0.50 mm, Cook, Gold Anchor). The endpoints were technical success rate and retention of fiducials, the latter of which was evaluated on cone-beam computed tomography scans during the first five radiotherapy fractions. Results A total of 64 fiducials were placed in 20 patients. For each fiducial type, at least three fiducials were successfully placed in all patients. Technical failure consisted of fiducial blockage within the needle (n = 2) and ejection of two preloaded fiducials at once (n = 4). No serious adverse events were reported. In three patients, one of the fiducials was misplaced without clinical consequences; two in the prostate and one in the intraperitoneal cavity. After a median time of 17 days after placement (range 7 - 47 days), a total of 42/64 (66 %) fiducials were still present (24/44 intratumoral vs. 18/20 mesorectal fiducials, P  = 0.009). Conclusions Placement of fiducials in rectal cancer patients is feasible, however, retention rates for intratumoral fiducials were lower (55 %) than for mesorectal fiducials (90 %).

Feasibility of Gold Fiducial Markers as a Surrogate for Gross Tumor Volume Position in Image-Guided Radiation Therapy of Rectal Cancer.

PURPOSE: To evaluate the feasibility of fiducial markers as a surrogate for gross tumor volume (GTV) position in image-guided radiation therapy of rectal cancer. METHODS AND MATERIALS: We analyzed 35 fiducials in 19 patients with rectal cancer who received short-course radiation therapy or long-course chemoradiation therapy. Magnetic resonance imaging examinations were performed before and after the first week of radiation therapy, and daily pre- and postirradiation cone beam computed tomography scans were acquired in the first week of radiation therapy. Between the 2 magnetic resonance imaging examinations, the fiducial displacement relative to the center of gravity of the GTV (COGGTV) and the COGGTV displacement relative to bony anatomy were determined. Using the cone beam computed tomography scans, inter- and intrafraction fiducial displacement relative to bony anatomy were determined. RESULTS: The systematic error of the fiducial displacement relative to the COGGTV was 2.8, 2.4, and 4.2 mm in the left-right, anterior-posterior (AP), and craniocaudal (CC) directions, respectively. Large interfraction systematic errors of up to 8.0 mm and random errors up to 4.7 mm were found for COGGTV and fiducial displacements relative to bony anatomy, mostly in the AP and CC directions. For tumors located in the mid and upper rectum, these errors were up to 9.4 mm (systematic) and 5.6 mm (random) compared with 4.9 mm and 2.9 mm for tumors in the lower rectum. Systematic and random errors of the intrafraction fiducial displacement relative to bony anatomy were ≤2.1 mm in all directions. CONCLUSIONS: Large interfraction errors of the COGGTV and the fiducials relative to bony anatomy were found. Therefore, despite the observed fiducial displacement relative to the COGGTV, the use of fiducials as a surrogate for GTV position reduces the required margins in the AP and CC directions for a GTV boost using image-guided radiation therapy of rectal cancer. This reduction in margin may be larger in patients with tumors located in the mid and upper rectum compared with the lower rectum.

Predictive factors for response and toxicity after brachytherapy for rectal cancer; results from the HERBERT study.

PURPOSE: The HERBERT study was a dose-finding feasibility study of a high-dose rate endorectal brachytherapy (HDREBT) boost after external beam radiotherapy (EBRT) in elderly patients with rectal cancer who were unfit for surgery. This analysis evaluates the association of patient, tumor and dosimetric parameters with tumor response and toxicity after HDREBT in definitive radiotherapy for rectal cancer. PATIENTS AND METHODS: The HERBERT study included 38 inoperable patients with T2-3N0-1 rectal cancer. Thirteen fractions of 3 Gy EBRT were followed by three weekly HDREBT applications of 5-8 Gy per fraction. Clinical and dosimetric parameters were tested for correlation with clinical complete response (cCR), sustained partial/complete response (SR), patient reported bowel symptoms, physician reported acute and late proctitis (CTCAE v3) and endoscopically scored toxicity. RESULTS: Thirty-five patients completed treatment and were included in the current analyses. Twenty of 33 evaluable patients achieved a cCR, the median duration of a sustained response was 32 months. Tumor volume at diagnosis showed a strong association with clinical complete response (OR 1.15; p = 0.005). No dose-response correlation was observed in this cohort. Prescribed dose to the brachytherapy CTV (D90) correlated with acute and late physician reported proctitis while CTV volume, CTV width and high dose regions in the CTV (D1cc/D2cc) were associated with endoscopic toxicity at the tumor site. CONCLUSION: Tumor volume is the most important predictive factor for tumor response and a higher dose to the brachytherapy CTV increases the risk of severe clinically and endoscopically observed proctitis after definitive radiotherapy in elderly patients with rectal cancer.

MRI visibility of gold fiducial markers for image-guided radiotherapy of rectal cancer.

BACKGROUND AND PURPOSE: A GTV boost is suggested to result in higher complete response rates in rectal cancer patients, which is attractive for organ preservation. Fiducials may offer GTV position verification on (CB)CT, if the fiducial-GTV spatial relationship can be accurately defined on MRI. The study aim was to evaluate the MRI visibility of fiducials inserted in the rectum. MATERIALS AND METHODS: We tested four fiducial types (two Visicoil types, Cook and Gold Anchor), inserted in five patients each. Four observers identified fiducial locations on two MRI exams per patient in two scenarios: without (scenario A) and with (scenario B) (CB)CT available. A fiducial was defined to be consistently identified if 3 out of 4 observers labeled that fiducial at the same position on MRI. Fiducial visibility was scored on an axial and sagittal T2-TSE sequence and a T1 3D GRE sequence. RESULTS: Fiducial identification was poor in scenario A for all fiducial types. The Visicoil 0.75 and Gold Anchor were the most consistently identified fiducials in scenario B with 7 out of 9 and 8 out of 11 consistently identified fiducials in the first MRI exam and 2 out of 7 and 5 out of 10 in the second MRI exam, respectively. The consistently identified Visicoil 0.75 and Gold Anchor fiducials were best visible on the T1 3D GRE sequence. CONCLUSION: The Visicoil 0.75 and Gold Anchor fiducials were the most visible fiducials on MRI as they were most consistently identified. The use of a registered (CB)CT and a T1 3D GRE MRI sequence is recommended.

Benefit of adaptive CT-based treatment planning in high-dose-rate endorectal brachytherapy for rectal cancer.

PURPOSE: In this planning study, we investigated the dosimetric benefit of repeat CT-based treatment planning at each fraction vs. the use of a single CT-based treatment plan for all fractions for high-dose-rate endorectal brachytherapy (HDREBT) for rectal cancer. METHODS AND MATERIALS: We included 11 patients that received a CT scan with applicator in situ for all three fractions. The treatment plan of the first fraction was projected on the repeat CT scans to simulate the use of a single treatment plan. In addition, replanning was performed on the repeat CT scans, and these were compared to the corresponding projected treatment plans. RESULTS: Repeat CT-based treatment planning resulted on average in a 21% higher (p = 0.01) conformity index compared to single CT-based treatment planning. Projecting the initial treatment plan to the repeat CT scans of fraction two and three, 12/22 fractions reached a CTV D98 of 85% of the prescribed dose of 7 Gy, which increased to 14/22 using replanning. For the remaining fractions, median CTV D98 was 4.2 Gy, and an intervention would be necessary to correct applicator balloon setup or to remove remaining air and/or feces between the CTV and the applicator. CONCLUSIONS: Using a single CT-based treatment plan for all fractions may result in a suboptimal treatment at later fractions. Therefore, repeat CT imaging should be the minimal standard practice in HDREBT for rectal cancer to determine whether an intervention would be necessary. Replanning based on repeat CT imaging resulted in more conformal treatment plans and is therefore recommended.

Clinical pedicle screw accuracy and deviation from planning in robot-guided spine surgery: robot-guided pedicle screw accuracy.

STUDY DESIGN: A retrospective chart review was performed for 112 consecutive minimally invasive spinal surgery patients who underwent pedicular screw fixation in a community hospital setting. OBJECTIVE: To assess the clinical accuracy and deviation in screw positions in robot-assisted pedicle screw placement. SUMMARY OF BACKGROUND DATA: Accuracy of pedicle screw placement in in vivo studies varies widely, especially when minimally invasive techniques are used. Robotic guidance was recently introduced to increase screw placement accuracy but still reported accuracies vary. METHODS: Reproducibility of the surgeon's plan using robotic guidance was assessed by fusing individual vertebras from the preoperative computed tomography (CT) containing the planning with a postoperative CT. Deviation in entry point and difference in angle of insertion was measured on axial and sagittal planes. Grading of pedicle screw placement was performed on postoperative CTs using the Gertzbein-Robbins classification. RESULTS: CT-to-CT fusion succeeded for 178 screws, but these appeared to be random, with no apparent selection bias. Mean deviation in entry point was 2.0 ± 1.2 mm. Mean difference in angle of insertion was 2.2° ± 1.7° on the axial plane and 2.9° ± 2.4° on the sagittal plane. Assessment of pedicle screw accuracy showed that 477 of 487 screws (97.9%) were safely placed (<2 mm, category A+B), 8 screws in category C and 1 in category D. None of the screws necessitated resurgery for revised placement. CONCLUSION: Preoperative planning of robotic guidance is reproduced intraoperatively within acceptable deviations. We conclude that robotic guidance allows for highly accurate execution of the preoperative plan, leading to accurate screw placement. LEVEL OF EVIDENCE: 3.

The forkhead transcription factor UNC-130 is required for the graded spatial expression of the UNC-129 TGF-beta guidance factor in C. elegans.

Secreted proteins required for cellular movements along the circumference of the body wall in Caenorhabditis elegans include UNC-6/netrin and the novel TGF-beta UNC-129. Expression of these proteins is graded along the dorsoventral (D/V) axis, providing polarity information to guide migrations. Here we show that the graded expression of UNC-129 in dorsal but not ventral body muscles depends on unc-130, which encodes a Forkhead transcription factor. The phenotype of unc-130 mutants closely mimics the reported effects of ectopically expressing unc-129 in both dorsal and ventral body muscles (). This fits our present finding that unc-130 cell autonomously represses unc-129 expression in the ventral body muscles. Thus the cell-specific effects of unc-130 on ventral, but not dorsal, body muscle expression of unc-129 accounts for the D/V polarity information required for UNC-129-mediated guidance. Genetic interactions between unc-130 and other guidance genes show that several molecular pathways function in parallel to guide the ventral to dorsal migration of distal tip cells (DTCs) and axonal growth cones in C. elegans. Genetic interactions confirm that UNC-129 does not require the only known type II TGF-beta receptor in C. elegans (DAF-4) for its guidance functions. Also, unc-130 is partially required for male tail morphogenesis and for embryogenesis.

mab-20 encodes Semaphorin-2a and is required to prevent ectopic cell contacts during epidermal morphogenesis in Caenorhabditis elegans.

The Semaphorins are a family of secreted and transmembrane proteins known to elicit growth cone repulsion and collapse. We made and characterized a putative null mutant of the C. elegans gene semaphorin-2a (Ce-sema-2a). This mutant failed to complement mutants of mab-20 (Baird, S. E., Fitch, D. H., Kassem, I. A. A. and Emmons, S. W. (1991) Development 113, 515-526). In addition to low-frequency axon guidance errors, mab-20 mutants have unexpected defects in epidermal morphogenesis. Errant epidermal cell migrations affect epidermal enclosure of the embryo, body shape and sensory rays of the male tail. These phenotypic traits are explained by the formation of inappropriate contacts between cells of similar type and suggest that Ce-Sema-2a may normally prevent formation or stabilization of ectopic adhesive contacts between these cells.

A BMP homolog acts as a dose-dependent regulator of body size and male tail patterning in Caenorhabditis elegans.

We cloned the dbl-1 gene, a C. elegans homolog of Drosophila decapentaplegic and vertebrate BMP genes. Loss-of-function mutations in dbl-1 cause markedly reduced body size and defective male copulatory structures. Conversely, dbl-1 overexpression causes markedly increased body size and partly complementary male tail phenotypes, indicating that DBL-1 acts as a dose-dependent regulator of these processes. Evidence from genetic interactions indicates that these effects are mediated by a Smad signaling pathway, for which DBL-1 is a previously unidentified ligand. Our study of the dbl-1 expression pattern suggests a role for neuronal cells in global size regulation as well as male tail patterning.

Multiple ephrins control cell organization in C. elegans using kinase-dependent and -independent functions of the VAB-1 Eph receptor.

Eph receptor (EphR) tyrosine kinases and their ephrin ligands mediate direct cell-to-cell signaling. The C. elegans genome encodes four potential GPI-modified ephrins (EFN-1 to -4) and one EphR (VAB-1). Single and multiple ephrin mutants reveal functions for EFN-1, EFN-2, and EFN-3 in epidermal cell organization that, in aggregate, mirror those of VAB-1. Ephrin mutants have defects in head morphology and enclosure of the embryo by the epidermis and identify ephrin-EphR signaling functions involved in aligning and fusing tail and head epidermal cells, respectively. Biochemical analyses indicate that EFN-1, EFN-2, and EFN-3 jointly activate the VAB-1 tyrosine kinase in vivo. Mutant phenotypes and expression pattern analysis suggest that multiple ephrins are involved in distinct aspects of kinase-dependent and kinase-independent VAB-1 signaling required for proper cell organization during development in C. elegans.

Cloning and sequencing of an alpha-tubulin cDNA from Artemia franciscana: evidence for translational regulation of alpha-tubulin synthesis.

The brine shrimp, Artemia franciscana, exhibits a limited number of tubulin isotypes which change little during early postgastrula growth. In order to better understand the synthesis of alpha-tubulins during Artemia development, a cDNA termed alphaAT1 was cloned and sequenced. Alignment analyses revealed that the polypeptide encoded by alphaAT1 is similar to alpha-tubulins from other species. Hybridization of alphaAT1 to restriction-digested DNA on Southern blots produced a simple banding pattern, indicating that Artemia have a small number of alpha-tubulin genes. Probing of Northern blots demonstrated an abundant supply of alpha-tubulin mRNA in dormant cysts, emerging nauplii and instar I larvae. However, it was not until instar I larvae were produced that the amount of polysomal alpha-tubulin mRNA increased, suggesting that synthesis of the tubulin corresponding to alphaAT1 is translationally controlled. This work provides one of the few examples where tubulin synthesis is thought to be translationally regulated. Moreover, when considered in the light of previous analyses, the findings imply that cell differentiation in postgastrula Artemia and the diversification of microtubule function certain to accompany this process occur with little or no change in alpha-tubulin composition.