Distal Point Research Articles

When are all closed subsets recurrent?

In the paper we study relations of rigidity, equicontinuity and pointwise recurrence between an invertible topological dynamical system (t.d.s.)$(X,T)$and the t.d.s. $(K(X),T_{K})$induced on the hyperspace$K(X)$of all compact subsets of$X$, and provide some characterizations. Among other examples, we construct a minimal, non-equicontinuous, distal and uniformly rigid t.d.s. and a weakly mixing t.d.s. which induces dense periodic points on the hyperspace$K(X)$but itself does not have dense distal points, solving in that way a few open questions from earlier articles by Dong, and Li, Yan and Ye.

Qualitative Assessment and Quantitative Analysis of the Long Head of the Biceps Tendon in Relation to the Pectoralis Major Tendon Humeral Insertion: An Anatomic Study

To qualitatively assess and to quantitatively analyze the long head of the biceps tendon (LHBT) in the region of the pectoralis major (PM). From 11 fresh cadaveric donors, 20 cadaveric shoulders without operative scars were dissected-mean age, 76.9years (range, 61 to 93years); male, 75%; left-sided, 55%; mean height, 67.8 inches (range, 61 to 71 inches); mean weight, 148.1 pounds (range, 106 to 176 pounds). Two specimens with discovered ruptures were excluded. The LHBT circumference was measured at the anterior edge of supraspinatus, suprapectorally, midpectorally, and subpectorally. The muscle was then removed from the LHBT and the circumference was again measured at the supra-, mid-, and subpectoral levels. These data were used to calculate the area of the tendon. All measurements were performed by 2 independent observers. Statistical analysis was performed to assess reliability of data and the difference between serial measurements. The mean calculated percentage tendon decreased from 86.7% at the superior edge of the PM to 49.8% at the midpoint of the PM and to 17.5% at the inferior edge of the PM. Distal to the PM, the LHBT was composed of a small percentage of tendon to muscle, which may have implications for the mechanical strength of fixation of tenodesis. The anatomic location of the musculotendinous junction of the LHBT began proximal to the superior edge of the PM tendon, which implies that restoration of anatomic tensioning may require a more proximal docking site than previously described. Tenodesis performed between the midpoint of the PM insertion and more distal points involves a significant portion of muscle, which may not be optimal. Tenodesis performed between the midpoint of the PM insertion and more distal points involves a significant portion of muscle, which may affect the mechanical strength or optimal choice of fixation location.

Traditional Chinese Medicine acupuncture and myofascial trigger needling: The same stimulation points?

BackgroundAcupuncture originates in China, and its effectiveness has been well documented in musculoskeletal pain disorders and other conditions. A widely accepted contemporary medical treatment option for myofascial pain is trigger point needling. Although there are many differences between Traditional Chinese Medicine acupuncture theory and the myofascial trigger point needling framework, it is argued that the stimulation sites for these two needling modalities are similar. DiscussionIn this paper we examined the correspondence between Traditional Chinese Medicine acupoints and myofascial trigger points. Based on this correspondence, we considered exploration of Ah-shi points from four aspects: pain recognition, distal Ah-shi points, Anti-Ah-shi points, and management approaches.Summary: The extent of correspondence is influenced by definitions of acupoints. Myofascial trigger points are significantly correlated to Traditional Chinese Medicine acupoints, including primary channel acupoints, extra acupoints, and Ah-shi points. Considering the correlation between MTrPs and acupoints and the rarely-studied research area of Ah-shi points, it may be reasonable to incorporate research findings of myofascial trigger points into further investigations into Ah-shi points. Correspondence between myofascial trigger points and acupoints enhances contemporary understanding of the mechanism of action of acupuncture, and may serve to facilitate increased integration of acupuncture into clinical management.

How to drill the talar tunnel in ATFL reconstruction?

Reconstruction of the anterior talofibular ligament may be indicated in cases of residual instability after conservative treatment. Often, a bone tunnel is used for fixation in the talar bone. The purpose of this study is to evaluate possible routes for drilling the talar tunnel. Virtual tunnels were generated in a 3D bone model, oriented towards the following external landmarks: the talar neck, the most anterior point of the medial malleolus (MM), the most distal point of the MM, the most medial point of the MM, and the most posterior point of the MM. The parameters analysed for tunnels with lengths of 20, 25, and 30mm were the maximum distance inside the bone and the distance from the tunnel to the bone surface. A minimal safe distance (MSD) was calculated for a tunnel with a diameter of 5mm. The shortest measured distance before arriving outside the talar bone was 16.7mm. The longest distances were obtained in the tunnels oriented towards the talar neck (mean value of 36.6, SD 2.8) and towards the most posterior point of the MM (mean value of 35.8, SD 0.3). Only one tunnel, measuring 20mm in depth and oriented towards the most posterior point of the MM, revealed no individual values below the MSD. External landmarks are useful for drilling a talar tunnel during reconstruction of the anterior talofibular ligament. Only one tunnel, oriented towards the most posterior point of the MM, measuring 5mm in diameter and with a maximum depth of 20mm, was safe in all individuals. Surgeons should be aware of these limits when treating patients with ankle instability.

Are stainless steel elastic nails the solution to heavier children with femoral shaft fractures?

Background: The use of titanium elastic intramedullary nails for the treatment of femoral shaft fractures, in children weighing 45 kg, has been questioned due to the increased rates of malunion. Our aim was to see if the mechanical properties of stainless steel elastic nails provided enough fracture stability to justify their use in heavier children. Materials and Methods: Twenty pediatric femoral Sawbones®, fixed with titanium or stainless steel elastic nails, were tested. The bending stiffness and moments of the constructs were calculated at increasing loads, along with the angle of fracture deformation. From these estimates of maximum permitted body weight for each nail type were extrapolated. Results: Steel nails created significantly stiffer constructs than titanium in both the coronal and sagittal planes (P < 0.0001). Steel nails allowed bigger sagittal bending moments before losing acceptable alignment, compared to titanium (P < 0.0001). However, in the coronal plane, the difference was not statistically significant (P = 0.457). The estimated body weights extrapolated in the sagittal plane were 45 and 61 kg, in titanium and steel, respectively. In the coronal plane, they were 42 and 44 kg. Discussion: As steel has nearly twice the Young's modulus of titanium, it seems logical that fractures fixed with steel nails would be stiffer and fail at higher loads. However, it is unclear why steel did not outperform titanium in the coronal plane. A theory was proposed that unequal nail slip from the insertion sites might be a contributing factor to these findings. Conclusion: Pediatric femoral shaft fractures fixed with elastic steel nails provide significantly stiffer constructs than those fixed with titanium. However, there is an increased risk of malunion in the coronal plane, in children weighing 45 kg, regardless of material used, possibly due to unequal nail slip at the distal entry points.

Incidence of palamris longus muscle and tendon variations: a cadaveric study

Introduction: Palmaris longus muscle is one of the most variable muscles of the human body. Complete agenesis, variation in the location and form of the fleshy portion, aberrancy in attachment, duplication or triplication, accessory tendinous slips, replacing elements are some of the variations commonly encountered. Due to the large variability of the Palmaris longus muscle, we had undertaken this study to estimate the prevalence of this variation in our geographical area. Materials and Methods: A total of 32 cadavers, i.e. 64 upper limbs were dissected for the assessment of Palmaris longus muscle. The length and the circumference of the muscle belly of the Palmaris longus muscle, was noted. The most distal point on the muscle tendon to the point where the tendon crosses the line joining the pisiform bone and the tubercle of the scaphoid bone was measured to assess the length of the muscle. The width of the tendon was measured based on the aponeurosis. Finally, the length of the forearm was measured from the tip of the olecranon process to the styloid process of the ulna. Results: Out of the 32 cadavers, 23 were males with a total of 46 upper limbs which were used for discussion, 9 were females with 18 upper limbs. The mean length of the muscle in males was 124mm while in females, it was only 86.2mm. There was not much difference in the length and width of the tendon in both the sexes. 4.3% of males and 5.5% of the females had Palmaris longus muscle agenesis. Other deformities were high aponeurosis, slender long Palmaris longus tendon, digastric palmaris longus muscle with a single tendon, fusion of palmaris longus muscle belly with the flexor digitorum superficialis muscle with one case each. Conclusion: The Palmaris longus muscle is quite prevalent among the population in our area, as observed by the dissection of the cadavers. As Palmaris muscle and the tendon is normally used for tendon replacement, a proper understanding of the variations in the muscle is impor

Radiographic cephalometry analysis of condylar position after bimaxillary osteotomy in patients with mandibular prognathism.

Postoperative condylar position is a substantial concern in surgical correction of mandibular prognathism. Orthognathic surgery may change condylar position and this is considered a contributing factor for early skeletal relapse and the induction of temporomandibular disorders. The purpose of this study was to evaluate changes in condylar position, and to correlate angular skeletal measurements following bimaxillary surgery. On profile teleradiographs of 21 patients with mandibular angular and linear parametres, the changes in condylar position, were measured during preoperative orthodontic treatment and 6 months after the surgical treatment. A statistically significant difference in values between the groups was found. The most distal point on the head of condyle point (DI) moved backward for 1.38 mm (p = 0.02), and the point of center of collum mandibulae point (DC) moved backward for 1.52 mm (p = 0.007). The amount of upward movement of the point DI was 1.62 mm (p = 0.04). In the patients with mandibular prognathism, the condyles tend to migrate upward and forward six months after bimaxillary surgery.

Nonrecurrent Laryngeal Nerve in the Era of Intraoperative Nerve Monitoring.

Nonrecurrent laryngeal nerve (non-RLN) is an anatomical variation increasing the risk of vocal cord palsy. Prediction and early identification of non-RLN may minimize such a risk of injury. This study assessed the effect of intraoperative neuromonitoring (IONM) on the detection of non-RLN. A total of 462 (236 right) nerves in 272 patients were identified and totally exposed, and all intraoperative steps of IONM were sequentially applied on the vagus nerve (VN) and RLN. Right predissection VN stimulation at a distal point did not create a sound signal in three cases (3/236; 1.27%). Proximal dissection of the right VN under IONM guidance established a proximal point, creating a positive signal. The separation point of non-RLN from VN was discovered in all three patients. Non-RLNs were exposed from separation to laryngeal entry. Positive IONM signals were obtained after resection of thyroid lobes, and postoperative period was uneventful in patients with non-RLN. Absence of distal VN signal is a precise predictor of the non-RLN. IONM-guided proximal dissection of the right VN leads to identification of the non-RLN. The prediction of non-RLN by the absence of the VN signal at an early stage of surgery may prevent or minimize the risk of nerve injury.

Facial nerve stimulation as a future treatment for ischemic stroke.

Stimulation of the autonomic parasympathetic fibers of the facial nerve system (hereafter simply “facial nerve”) rapidly dilates the cerebral arteries and increases cerebral blood flow whether that stimulation is delivered at the facial nerve trunk or at distal points such as the sphenopalatine ganglion. Facial nerve stimulation thus could be used as an emergency treatment of conditions of brain ischemia such as ischemic stroke. A rich history of scientific research has examined this property of the facial nerve, and various means of activating the facial nerve can be employed including noninvasive means. Herein, we review the anatomical and physiological research behind facial nerve stimulation and the facial nerve stimulation devices that are in development for the treatment of ischemic stroke.

CT Angiography Analysis of Axillary Artery Diameter versus Common Femoral Artery Diameter: Implications for Axillary Approach for Transcatheter Aortic Valve Replacement in Patients with Hostile Aortoiliac Segment and Advanced Lung Disease.

Objective. The use of the axillary artery as an access site has lost favor in percutaneous intervention due to the success of these procedures from a radial or brachial alternative. However, these distal access points are unable to safely accommodate anything larger than a 7-French sheath. To date no studies exist describing the size of the axillary artery in relation to the common femoral artery in a patient population. We hypothesized that the axillary artery is of comparable size to the CFA in most patients and less frequently diseased. Methods. We retrospectively reviewed 110 CT scans of the thoracic and abdominal aorta done at our institution to rule out aortic dissection in which the right axillary artery, right CFA, left axillary artery, and left CFA were visualized. Images were then reconstructed using commercially available TeraRecon software and comparative measurements made of the axillary and femoral arteries. Results. In 96 patients with complete data, the mean sizes of the right and left axillary artery were slightly smaller than the left and right CFA. A direct comparison of the sizes of the axillary artery and CFA in the same patient yielded a mean difference of 1.69 mm ± 1.74. In all patients combined, the mean difference between the axillary artery and CFA was 1.88 mm on the right and 1.68 mm on the left. In 19 patients (19.8%), the axillary artery was of the same caliber as the associated CFA. In 8 of 96 patients (8.3%), the axillary artery was larger compared to the CFA. Conclusions. Although typically smaller, the axillary artery is often of comparable size to the CFA, significantly less frequently calcified or diseased, and in almost all observed cases large enough to accommodate a sheath with up to 18 French.

Regression equation for estimation of total humeral length using measurements of its proximal segments among Indian population

Abstract Background: The aim of the present study was to calculate regression equation for the estimation of total length of the humerus using the measurements of its proximal fragments in Indian population. This equation is essential for forensic investigators for estimating the humeral length and also height of individual using humeral length when fragments ofhumerus are available in forensic investigation. Materials and Methods: In the present study 150 (75 left and 75 right) adult, fully ossified, dry and processed humerii were taken to analyze the morphometric details of the humeral segments which were measured using osteometric board and scale. The distance between three different segments namely, from most proximal point in the head to most distal point of the circumference of the head (segment­1), from most distal point of the circumference of the head to the convergence of two areas of muscle attachment (segment-2), the convergence of two areas of muscle attachment to the deltoid tuberosity (segment-3) and maximum length of humerus were measured to the nearest millimeter. The association between the humeral segments and maximum humeral length was calculated using Pearson's correlation coefficient (r) and later linear regression was applied considering left and right humerii separately. Results: The regression equation of humerus segments -1, 2 and 3 were MHL­ Maximum humeral length= 175.05 + [3.58(Hl)], MHL = 185.80 + [2.18(H2)], MHL = 161.44 + [2.18(H3)] on left and MHL = 171.91 + [3.74(Hl)], MHL = 195.54 + [1.95(H2)], MHL = 229.03 + [1.24(H3)] on right side of humerus respectively. This regression equation of Mean total length of humerus using its proximal fragmentary bone length will help for the stature estimation of individual Conclusion: This study helps in forensic, anatomic and archeological fields in order to identify human remains of unknown persons.

An anatomical and histological study of the vascularized iliotibial tract graft.

An examination of the vascular anatomy of the iliotibial tract (IT) has not been previously reported. Because a flap resists infection better than an avascular graft, a vascularized IT graft is useful for reconstructive surgeries pertaining to infected wounds or wounds in contact with artificial material. The purpose of this study was to examine the vascular anatomy of the IT. The study sample consisted of 39 limbs of freshly frozen cadavers. The study was divided into three parts. The ascending and transverse branches of the lateral circumflex femoral artery (LCFA) of all cadavers were injected with latex. Distance from the tensor fasciae latae muscle and the most distal point at which the vessel on the IT was stained by latex was recorded. A microscopic observation was performed for these limbs. The deep femoral artery (DFA) or superior lateral genicular artery (SLGA) was also observed. The length of the IT fed by the LCFA was 162.3 ± 36.2 mm. The IT vascularity was located between the layered structure of the fascia and there was a vascular source for the IT within 1 mm above the IT by optical microscopy. The vascularity derived from the DFA or SLGA was not confirmed in any specimens. Blood supply of the IT was derived from the LCFA and a vascularized IT graft could be elevated in length to approximately 16 cm. This knowledge may be useful for improving the safety of surgery when transferring an IT flap. © 2015 Wiley Periodicals, Inc. Microsurgery 36:325-329, 2016.

Solitaire salvage: a stent retriever-assisted catheter reduction technical report

The endovascular management of giant aneurysms often proves difficult with standard techniques. Obtaining distal access to allow catheter reduction is often key to approaching these aneurysms, but several anatomic challenges...

Joint kinematics of surgeons during lumbar pedicle screw placement.

A surgical robot for spine surgery has recently been developed. The objective is to assess the joint kinematics of the surgeon during spine surgery. We enrolled 18 spine surgeons, who each performed pedicle screw placement, and used an optoelectronic motion analysis system. Using three-dimensional (3D) motion images, distance changes in five joints and angle changes in six joints were calculated during surgery. Distance fluctuations increased gradually from the proximal to the distal joint. Angle fluctuations were largest at the distal point but did not gradually increase, and the elbow showed the second largest fluctuation. Changes along the X axis were larger than those of the Y and Z axes. The distances gradually increased from proximal portions of the body to the hand. In angle changes, the elbow was most dynamic during pedicle screw placement. The surgeons' whole joints carry out a harmonic role during lumbar pedicle screw placement. Copyright © 2015 John Wiley & Sons, Ltd.

Commentary on ‘Same Site Recurrence is More Frequent After Endovenous Laser Ablation Compared with High Ligation and Stripping of the Great Saphenous Vein: 5 Year Results of a Randomized Clinical Trial (RELACS Study)’

Recurrence after “curative” procedures for varicose veins due to great saphenous vein (GSV) incompetence is widely considered the Achilles heel of all types of intervention, including the “radical” gold standard of high ligation and stripping of the GSV accompanied by phlebectomies. Although the introduction of minimally invasive endovenous thermal methods has challenged this traditional gold standard, further information on the long-term recurrence rates of the two methods is required to adequately inform decision making. In this issue, the RELACS (Randomized Study Comparing Endovenous Laser Ablation With Crossectomy and Stripping of the Great Saphenous Vein) investigators report on the 5 year results of a randomized controlled trial (RCT) comparing endovenous laser ablation (EVLA) with saphenofemoral junction (SFJ) flush ligation (with a non-absorbable 0-0 suture and stump oversewing with a 40 polypropylene suture to reduce groin neovascularization) and invaginated stripping of the GSV to just below the knee. Three similar RCTs on 542 patients have already reported 5 year results. These trials compared EVLA, performed with bare tip 810 nm or 980 nm diode laser, with stripping. Of note, the surgical technique was different in all four RCTs. SFJ flush ligation and GSV cryostripping to 5 cm below the knee was performed in the first trial; SFJ flush ligation and GSV PIN (perforateeinvaginate) stripping to just below the knee, in the second one; and SFJ flush ligation (with a non-absorbable 0-0 suture and stump intimal destruction with bipolar cautery to reduce groin neovascularization) and invaginated stripping of the GSV to the distal point of reflux in the third. Unlike these RCTs, RELACS included mainly patients with chronic venous insufficiency [clinical, etiologic, anatomic, and pathological (CEAP) clinical class C3eC6]. Consistent with other RCTs, venous severity scores and quality of life measures were equally improved with EVLA and stripping in RELACS. Also, in agreement with the other RCTs, recurrent varicose veins were reported to be equally frequent 5 years after EVLA and stripping (45% vs. 54%; p 1⁄4 .15) in RELACS; however, clinical recurrence in the operated region was more frequent after EVLA (18% vs. 5% for stripping; p < .001), and different site recurrence was more frequent after stripping (50% vs. 31% for EVLA; p 1⁄4 .002). Neovascularization and recurrence unrelated to

Acupuncture combined with medicated cupping for temporomandibular disorders

ObjectiveTo observe the application of acupuncture at distal points combined with medicated cupping on the affected parts in the treatment of temporomandibular disorders (TMD) and to evaluate its effectiveness. MethodsA total of 120 patients with TMD were randomly divided into two groups according to the random number table and random number remainder method. Sixty-two patients in acupuncture combined with cupping group (group A) were treated with acupuncture at Hégŭ (▪ LI 4) and Tàichōng (▪ LR 3) combined with medicated cupping on the affected parts with Sānqī (▪Radix et Rhizoma Notoginseng) and Báizh▪ (▪Radix Angelicae Dahuricae). Fifty-eight patients in cupping group (group B) were just treated with medicated cupping. Patients were treated for 30 min each time, once daily, and 10 times were considered as one course of treatment. After one course of treatment, the therapeutic effect was evaluated. Before and after treatment, craniomandihular index (CMI), dysfunction index (DI), palpation index(PI) and changes in pain degree (VAS score) were compared. ResultsBefore and after treatment, CMI in group A were 0.27±0.02 and 0.04±0.01, respectively, and in group B were 0.29±0.02 and 0.06±0.01, respectively; PI in group A were 0.19±0.01 and 0.05±0.03, respectively, and in group B were 0.18±0.02 and 0.11±0.02, respectively; DI in group A were 0.33±0.04 and 0.06±0.02, respectively, and in group B were 0.34±0.05 and 0.11±0.04, respectively; VAS in group A were 5.39±0.24 and 2.13±0.47, respectively, and in group B were 5.70±0.31 and 3.97±0.26, respectively. After treatment, CMI, DI, PI and VAS in both groups significantly decreased when compared with those before treatment (all P<0.01), and the indices in group A were significantly lower than that in group B after treatment (all P<0.05), indicating that the difference was significant. ConclusionThe therapeutic effect of acupuncture at distal points combined with cupping at adjacent points in treatment of TMD is superior to that of single medicated cupping therapy.

Comunicação entre os nervos musculocutâneo e mediano no braço: estudo anatômico e implicações clínicas

ObjectiveTo determine the frequency and features of communication between the musculocutaneous nerve (MCN) and median nerve (MN) in a sample of the Colombian population, and assess its clinical implication. MethodsThe arms of 53 cadaver specimens that had been subjected to necropsy at the National Institute of Forensic Medicine, in Bucaramanga, Colombia, were studied. The structures of the anterior compartment of the arm were dissected and characterized regarding the presence of communication between the MCN and MN. ResultsA communicating branch was found in 21/106 upper limbs (19.8%), occurring bilaterally in 10 (47.6%) and unilaterally in 11 (52.4%), without significant difference regarding the side of occurrence (p=0.30). In 17% of the cases, there was MCN‐MN communication in which the communicating branch was seen leaving the MCN after piercing the coracobrachialis muscle (Type I). In 2.8%, the connection was from the MN to the MCN (Type II). The length of the communicating branch was 57.8±33.4mm. The distances from the proximal and distal points of this branch to the coracoid process were 138±39.4mm and 188±48.3mm, respectively. The communicating branch was located mostly in the middle third of the arm. ConclusionsThe frequency of MCN‐MN communication observed in the present study is in the middle of the range of what was reported in previous studies. MCN‐MN connections need to be taken into account in diagnosing and managing peripheral nerve lesions of the upper limbs

Determination of the Central Axis of the Scaphoid.

Purpose Determine the central axis of the scaphoid and its relation to surrounding anatomic landmarks to facilitate internal fixation of the scaphoid. Methods Seventeen cadaveric dissections of the wrist were performed. Measurements of the height and width of the proximal pole, waist, and distal pole were made. The midpoint of the height and width of each measurement were plotted on a scatter plot graph and a forecast line was developed. The formula of the resultant line was used to calculate the position of the central axis at the proximal pole, waist, and distal pole. The inverse tangent of the slope of the line was then used to determine the angle of the line from proximal to distal. Results The average central axis fell along a line measuring at points from the ulnar to the radial border and from the dorsal to the volar border of the proximal pole, waist, and distal pole at 7.86 mm, 7.61 mm, and 7.31 mm respectively; an angle of 13.78 degrees from ulnar to radial and dorsal to volar. The proximal point can be determined by measuring ∼44 mm radially from the ulnar styloid along the watershed line of the radius and 14 mm volar from the dorsal tip of the Lister tubercle. The distal point can be determined by measuring ∼4 mm ulnar from a line extending distally from the volar radial corner, and 7 mm volar from the most dorsal point of the combined surface of the trapezium and triquetrum. No significant difference existed between male and female specimens. Conclusions The central axis of the scaphoid can be described to exist along a line extending from the relative central point of the proximal pole, measured 7.86 mm radial from the scapholunate ligament and 8.31 mm volar of the most dorsal point; through the waist, and extending to the relative central point of the distal pole measured 3.77 mm ulnar of the volar radial corner and 7.36 mm volar of the most dorsal point at an angle directed radially and volarly at 13.78 degrees. Level of Evidence Level III Type of Study Diagnostic/ therapeutic.

Real-Time MRI-Guided Catheter Tracking Using Hyperpolarized Silicon Particles.

Visualizing the movement of angiocatheters during endovascular interventions is typically accomplished using x-ray fluoroscopy. There are many potential advantages to developing magnetic resonance imaging-based approaches that will allow three-dimensional imaging of the tissue/vasculature interface while monitoring other physiologically-relevant criteria, without exposing the patient or clinician team to ionizing radiation. Here we introduce a proof-of-concept development of a magnetic resonance imaging-guided catheter tracking method that utilizes hyperpolarized silicon particles. The increased signal of the silicon particles is generated via low-temperature, solid-state dynamic nuclear polarization, and the particles retain their enhanced signal for ≥40 minutes—allowing imaging experiments over extended time durations. The particles are affixed to the tip of standard medical-grade catheters and are used to track passage under set distal and temporal points in phantoms and live mouse models. With continued development, this method has the potential to supplement x-ray fluoroscopy and other MRI-guided catheter tracking methods as a zero-background, positive contrast agent that does not require ionizing radiation.

Abstract 944: Development of predictive and pharmacodynamic biomarker strategies for GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine

Abstract GDC-0425 is a potent and selective small molecule inhibitor of checkpoint kinase 1 (Chk1) recently evaluated in the DPM4957g phase I study in combination with the nucleoside analog gemcitabine. The cytotoxic effect of gemcitabine, elicited through the induction of genotoxic stress, is limited by Chk1 activation, which leads to cell cycle arrest and allows time for repair of damaged DNA. Chk1 inhibition by GDC-0425 can convert a genotoxic insult into a cytotoxic event by overriding cell cycle arrest and thereby driving cancer cells into mitotic catastrophe. A panel of nearly 200 cancer cell lines was screened to evaluate potential benefit of combining GDC-0425 and gemcitabine. Elastic net modeling was applied to cell line data including exome-seq, RNA-seq, DNA copy number, and loss of heterozygosity to perform a broad and unbiased search for predictors of drug activity and synergy. In the model for GDC-0425 and gemcitabine synergy, TP53 mutations were found to be the highest-ranking features, followed by mRNA expression of SLFN11, a gene encoding a putative helicase implicated in sensitizing cells to DNA-damaging agents. Expression levels of several p53-regulated transcripts were also found to be high-ranking features in this model, underscoring the value of p53 pathway functionality as a predictor of synergy between GDC-0425 and gemcitabine. In consideration of pharmacodynamic (PD) biomarkers, phosphorylated CDK2 (pCDK2) and phosphorylated H2AX (pH2AX), located at proximal and distal points in the Chk1 pathway, respectively, were found to be modulated by GDC-0425 and gemcitabine in cell line and xenograft models in a dose-dependent fashion. The GDC-0425 dose response for these biomarkers correlated with anti-tumor activity. Finally, to understand why GDC-0425 and gemcitabine synergy is more pronounced in some TP53 mutant cell lines than in others, a screen was performed to evaluate engagement of the Chk1 and p53 pathways in response to gemcitabine in a representative panel of cell lines. Chk1 activation was evaluated using pCDK2, whereas p53 activation was evaluated using expression of known p53 transcriptional targets. Higher synergy was generally observed when gemcitabine activated Chk1 and not p53, regardless of TP53 mutational status. These studies provide a foundation for predictive and PD biomarker strategies to support the evaluation of GDC-0425 with gemcitabine in early stage clinical trials that are based on markers of p53 pathway functionality and Chk1 pathway modulation. Citation Format: Sami Mahrus, Kelly DuPree, Kaska Kowanetz, Jenille Tan, Jarrod Tremayne, Diana Jakubiak, Peter Haverty, Yuda Zhu, Franklin Peale, Elizabeth Blackwood, Richard Bourgon, Robert Yauch, Mark Lackner, Marie Evangelista. Development of predictive and pharmacodynamic biomarker strategies for GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 944. doi:10.1158/1538-7445.AM2015-944