Intervertebral Disc Protrusion Research Articles

Fibrocartilaginous Embolism Associated with the Extrusion of the Intervertebral Disc in a Dog

Background: Intervertebral disc disease is a usual neurological disorder in dogs, which the spinal cord is compressed by intervertebral disc extrusion or protrusion. Fibrocartilaginous embolic myelopathy isan acute infarction disease of spinal cord caused by fibrocartilaginous emboli histologically identical to the nucleus pulposus of intervertebral discs. The aim of this report is present two cases of fibrocartilaginous embolic myelopathy in dogs with intervertebral disc disease.Cases: Two dogs - dachshund breed - were referred to the Veterinary Medical Teaching Hospital of the UFSM. In the first case, the dog was three years old and the owner described complete inability to move the pelvic limbs. The neurological examination revealed paraplegia, postural reactions deficits, normal spinal reflexes and muscle tonus in the hind limbs, pain on palpation in T12-T11 region and loss of deep pain in hind limbs. In the other case, the dog was seven years old and the owner described partial inability to move four limbs. The neurological examination revealed non-ambulatory tetraparesis, postural reactions deficit, normal spinal reflexes in four limbs and pain on palpation in cervical spine. In both cases, the presumptive diagnosis was intervertebral disc disease and surgical treatment was indicated. The dog with thoracolumbar injury died during the anesthesia and the dog with cervical injury was euthanized, after decision of owner. During the necropsy was observed intervertebral disc extrusion between L1-L2 vertebrae in a dog and between C3-C4 vertebrae in the other case with cartilaginous fragments in the spinal canal. Histopathology revealed marked diffuse necrosis with multifocal hemorrhage and cartilaginous emboli.Discussion: Fibrocartilaginous embolic myelopathy is commonly reported in large and giant breed dogs, though also occur in small and medium-sized breeds of dogs. One hypothesis is the pulpous nucleus remains soft for a longer period in large breed dogs, empowering to infiltration in the spinal cord vessels. The intervertebral disc extrusion occurs predominantly in dogs with age between three and six years old, in the cervical, thoracolumbar (T11-L3) and lumbar regions. Chondroid or fibroid degeneration of the intervertebral disc is the most common cause of spinal cord compression in small animals. In chondrodistrophic breed dogs is frequently chondroid degeneration, which the nucleus pulposus moves into the spinal canal through rupture of the annulus fibrosus (extrusion or Hansen type I), causing acute spinal cord compression. The prevalence of fibrocartilaginous embolism in adult and old dogs increase the possibility of predisposing factors, facilitating the injection intravascular of nucleus pulposus material. One of the most accepted theories about the mechanism of fibrocartilaginous emboli into the vessels is due to increase of inside discal pressure and liberation of fibrocartilaginous emboli from nucleus pulposus into the vertebral artery for retrograde flow, reaching the spinal cord by blood flow. The simultaneous occurrence of intervertebral disc disease and the infarction of spinal cord in the proximate region accentuate the hypothesis that the etiology of fibrocartilaginous embolic myelopathy is mechanical into the vessels of the spinal cord.Keywords: neurology, spinal cord, intervertebral disc disease, dogs.

Diagnosis of lumbosacral intervertebral disc disease and protrusion in a horse using ultrasonographic evaluation and computed tomography

SummaryThis case report describes the clinical presentation, diagnostic imaging modalities, treatment and post mortem evaluation of lumbosacral intervertebral disc protrusion in a mature Quarter Horse gelding 10 days after initial signs were noted. Grade 3 hindlimb ataxia, conscious proprioceptive deficits, urinary and faecal incontinence were present, which did not improve with anti‐inflammatories, antimicrobial therapy, corticosteroids, antioxidant therapy, cold‐laser therapy or electroacupuncture. Imaging modalities utilised ante mortem were computed radiography, transcutaneous and transrectal ultrasonography. Transrectal ultrasonography yielded findings highly suggestive of lumbosacral intervertebral disc protrusion and due to the lack of improvement and a poor prognosis, the horse was humanely subjected to euthanasia. Post mortem computed tomography, necropsy and histopathological evaluation confirmed lumbosacral intervertebral disc disease and protrusion into the spinal canal with subsequent impingement of the spinal nerve roots. Lumbosacral intervertebral disc protrusion as a clinical disease in the horse has not been previously described and should be included as a differential diagnosis in cases with acute hindlimb ataxia, proprioceptive deficits, and urinary and faecal incontinence.

DISTRIBUTION AND SHORT- AND LONG-TERM EFFECTS OF INJECTED GELIFIED ETHANOL INTO THE LUMBOSACRAL INTERVERTEBRAL DISC IN HEALTHY DOGS.

Radiopaque gelified ethanol preparation has been described as a useful agent for treatment of humans with intervertebral disc protrusion. The material is injected into the nucleus pulposus under image guidance with intention to cause the protruded disc material to recede. Because treatment options for dogs with chronic protrusions are limited, new and minimally invasive treatments are desirable. The aim of this experimental, descriptive, prospective study was to assess the feasibility and safety of percutaneous injection of gelified ethanol into the lumbosacral intervertebral disc of dogs. Lumbosacral intervertebral discs of normal dogs (n = 9) were imaged with magnetic resonance imaging and then injected with gelified ethanol using image guidance. The accuracy of gelified ethanol placement in the nucleus pulposus and presence of leakage of the injected material were documented. Postinjection computed tomography (CT) findings (n = 9), short-term (n = 9) and long-term (n = 4) follow-up magnetic resonance imaging and CT findings were compared to document the distribution of the injected preparation and identify effects on adjacent tissues. Percutaneous injection of the intervertebral disc was successful in delivering radiopaque gelified ethanol to the nucleus pulposus in all dogs. Leakage of the injected material into the vertebral canal was present in three dogs immediately following injection and in another additional dog at 1 year following injection. All dogs tolerated the injection well and had no clinical adverse reactions within the study period. Findings indicated that injection of the nucleus pulposus of healthy dogs was well tolerated, even in the presence of mild leakage of material from the intervertebral disc.

Thoracic intervertebral disc calcification and herniation in adults: a report of two cases

Acute paraplegia due to thoracic intervertebral disc protrusion and calcification is rare. The purpose of this study was to report two cases with acute paraplegia due to a calcified thoracic disc prolapse, and discuss its clinical diagnosis and surgical treatment with literature reviews. These two cases were verified by patient history, physical examination, laboratory examination, CT and MRI studies, and pathological findings. CT scan revealed disc calcification and protrusion at the T11-12 level in case 1 and at the T10-11 level in case 2, respectively. MRI images revealed severe spinal cord compression with a hyperintense central core and surrounding hypointense area in two cases, which were directly connected to the calcified intervertebral nucleus pulposus. Pathological examination revealed calcium deposition. Patients underwent discectomy followed by interbody fusion, and satisfactory therapeutic outcomes were obtained. We suggest that decompression surgery should be carried out as early as possible for patients with early spinal myelopathy or paraplegia caused by a calcified protruded disc.

Clinical reasoning in canine spinal disease: what combination of clinical information is useful?

Spinal disease in dogs is commonly encountered in veterinary practice. Numerous diseases may cause similar clinical signs and presenting histories. The study objective was to use statistical models to identify...

Nucleoplasty for the Treatment of Low Back Pain Caused by Degenerative Disc Disease

Introduction Puncture methods—Nucleoplasty by coblation and radio frequency denervation—have recently been widely used for the treatment of pain syndrome caused by intervertebral disc protrusion. The purpose of this study was to assess the effectiveness of nucleoplasty and radio frequency denervation of intervertebral joints as advanced minimally invasive surgical techniques for alleviating pain in the case of intervertebral disc disease, spondylarthrosis, and other vertebroneurologic diseases accompanying degenerative disc disease. Methods Since 2010, 70 patients with lumbar disc protrusion and signs disc-radicular conflict underwent nucleoplasty by cold plasma. All patients had a history of back pain or/and leg pain for not less than 3 months and were followed up after undergoing minimally invasive procedures for a year. Visual Analog Scale, Oswestry Disability Index (ODI), and Treatment Satisfaction Scale were used for evaluation. A total of 50 patients of control group also with protrusion of intervertebral disc were treated therapeutically. Results No complications were noted. At 12-month follow-up, all the operated patients showed the decrease of pain syndrome intensity according to the Visual Analogue Scale ( p < 0.0001), and decrease ODI compared with patients treated therapeutically ( p < 0.001). Treatment Satisfaction scores were higher as compared with the patients of the control group. Conclusions Nucleoplasty allowed us to successfully treat patients affected by lumbar disc protrusion who treated therapeutically not less than 6 weeks without effect. Minimally invasive electrosurgical techniques appeared to be safe and effective in the treatment of carefully selected patients suffering from low back and leg pains caused by a degenerative-dystrophic process. Nucleoplasty technique is more effective in younger patients. Procedures performed at several levels also result in marked clinical improvement. the primary advantages of these techniques were their safety and efficacy, minimal invasiveness, and the absence of a peridural scar. They do not complicate further microsurgical intervention.

Neurological signs and pre- and post-traction low-field MRI findings in Dobermanns with disc-associated cervical spondylomyelopathy.

To investigate whether the presence of neurological signs and magnetic resonance imaging findings could predict the presence of a traction-responsive lesion in Dobermanns affected by disc-associated cervical spondylomyelopathy. Retrospective review of neurological signs and low-field pre- and post-traction magnetic resonance imaging abnormalities of the cervical spine (abnormal vertebral body shape and vertebral tipping, intervertebral disc degeneration, protrusion and ligamentum flavum hypertrophy) in Dobermanns with disc-associated cervical spondylomyelopathy. The main outcome of interest was response to linear traction (dynamic versus static) at C6-C7 intervertebral disc space. The association between investigated variables and response to linear traction was assessed. The study included 25 dogs. No association was identified between neurological status grading and the presence of a static or traction-responsive lesion. Of the investigated magnetic resonance findings, C7-T1 intervertebral disc degeneration was significantly (P = 0 · 03) associated with the presence of a traction-responsive lesion at C6-C7 intervertebral disc space. The presence of C7-T1 intervertebral disc degeneration might help in predicting the presence of traction-responsive C6-C7 intervertebral disc lesions.

A new pathological classification of lumbar disc protrusion and its clinical significance.

Lumbar disc protrusion is common. Its clinical manifestations and treatments are closely related to the pathological changes; however, the pathological classification of lumbar disc protrusion is controversial. This article introduces a new pathological classification comprising four types of lumbar disc protrusion according to intraoperative findings. The damage-herniation type is probably caused by injury and is characterized by soft herniation, the capsule can easily be cut and the broken disc tissue blocks overflow or is easily removed. The broken disc substances should be completely removed; satisfactory results can be achieved by minimally invasive endoscopic surgery. The degeneration-protrusion type is characterized by hard and tough protrusions and the pathological process by degeneration and proliferative reaction. The nerve should be decompressed and relaxed with minimally invasive removal of the posterior wall; the bulged or protruded disc often need not be excised. The posterior vertebral osteochondrosis with disc protrusion type is characterized by deformity of the posterior vertebral body, osteochondral nodules and intervertebral disc protrusion. The herniated and fragmented disc tissue should be removed with partially protruding osteochondral nodules. Intervertebral disc cyst is of uncertain pathogenesis and is characterized by a cyst that communicates with the disc. Resection of the cyst under microscopic or endoscopic control can achieve good results; and whether the affected disc needs to be simultaneously resected is controversial. The new pathological classification proposed here is will aid better understanding of pathological changes and pathogenesis of lumbar disc protrusion and provides a reference for diagnosis and treatment.

Effect of high-expression HOXB4 on human cartilage endplate stem cells and its significance

Objective To observe the effect and significance of high-expression HOXB4 in controlling proliferation and cycle of human cartilage endplate stem cells (CESCs).Methods CESCs were divided into adenovirus-mediated HOXB4 delivery group (Group A),empty virus delivery group (Group B) and blank control group.Gene and protein expressions of HOXB4 in Group A were detected by PCR and Western blot respectively; cell proliferation among those groups were determined using cell counting kit 8 (CCK8) technique; cell cycle among those groups was measured by propidium iodide (PI) assay and flow cytometry.Results (1) Over-expressed HOXB4 virus was transferred to CESCs successfully; (2) Real-time quantitative PCR results showed 3.6 times higher expression of HOXB4 in Group A than in blank control group.Western blotting indicated HOXB4 protein in Group A was 3 times the level in control group; (3) HOXB4 promoted CESCs proliferation (P ＜ 0.05) and blocked the cells at phase S.Cells at phase S in Group A was increased from 29.27 to 30.28 (P ＜ 0.05).Conclusion Over-expressed HOXB4 accelerates proliferation of CESCs and increases cell population at phase S,indicating that HOXB4 hindering CESCs degeneration may be an approach to treat lumbar intervertebral disc protrusion. Key words: Intervertebral disc; Cartilage; Stem cells

Treatment of Refractory Low Back Pain Caused by Degenerative Spine Disease with Minimally Invasive Techniques

Introduction Puncture techniques—nucleoplasty and radio frequency denervation—have recently been widely used for the treatment of pain syndrome caused by intervertebral disc protrusion. The purpose of the study was to assess the effectiveness of nucleoplasty and radio frequency denervation of intervertebral joints as advanced minimally invasive surgical techniques for alleviating pain in the case of intervertebral disc disease, spondylarthrosis, and other vertebroneurologic diseases accompanying degenerative disc disease. Materials and Methods All patients had a history of pain syndrome for not less than 3 months and were followed up after undergoing minimally invasive procedures for 1 year. To assess the effectiveness, the visual analogue scale and treatment satisfaction scale were used. A total of 81 patients, aged between 30 and 57 years, underwent nucleoplasty and radio frequency denervation. Of the 81 patients, 70 patients of control group were treated therapeutically. Results No complications were noted. At 12-month follow-up all operated patients showed the decrease of pain syndrome intensity according to the visual analogue scale ( p < 0.0001), and treatment satisfaction scores were higher compared with patients treated therapeutically ( p < 0.001). Conclusion Minimally invasive electrosurgical techniques appeared to be safe and effective in the treatment of carefully selected patients suffering from low back pain and leg pain caused by a degenerative-dystrophic process. Nucleoplasty technique is more effective in younger patients. Procedures performed at several levels also result in marked clinical improvement. Primary advantages of these techniques were their safety and efficacy, minimal invasiveness, and the absence of a peridural scar. They do not complicate further microsurgical intervention. Disclosure of Interest None declared

Moderately Degenerative Disc with Annular Rupture is a Source of Low Back Pain

Introduction Difficulty remains in identification of the sources of low back pain (LBP) due to spinal degenerative disorders. Degenerative intervertebral disc (IVD) may contribute to pain generation. However, the relationship of disc degeneration and occurrence of LBP is still unclear, which makes it difficult to locate a surgical target for a discectomy and predict the clinical outcome. The purpose of the present study was to explore the characteristic changes of a painful disc in MRI and attempt to clarify the underlying role of inflammatory mediators and AF tears in disc degeneration and LBP occurrence. Materials and Methods Human disc specimens and MRI from 57 single segment IVD protrusion patients with radiculopathy were collected by discectomy. VAS of low back pain were recorded before and postsurgery for all patients. All patients were grouped according to the LBP occurrence or the disc degeneration Pfirrmann grades. Degenerated disc inflammatory mediators (IL-1β, TNF-α, iNOS, and substance P) expression were compared with immunohistochemical analysis and real-time polymerase chain reaction (RT-PCR) among different groups. The relationship of IVD degeneration severity, incidence of HIZ, and occurrence of LBP was investigated via MRI. Results RT-PCR and immunohistochemical analysis showed no significant differences in inflammatory mediators expression between the disc samples with and without LBP. Moderately degenerative IVD according to Pfirrmann grade demonstrated the highest inflammatory mediators expression compared with mildly and severely degenerative IVD. For LBP patients, the postoperative VAS of LBP was significantly decreased. The LBP occurrence in moderately degenerated patients was the highest (70.8%). The HIZ incidence was 75% in moderately degenerated patients, while 61.9% in severely degenerated patients. The patients who demonstrated both moderate disc degeneration and HIZ had 83.3% LBP occurrence, higher than the rest of the patient population. Conclusion Moderately degenerative disc with AF tear is a source of LBP. MRI showing moderately degenerative disc with HIZ could be an indication of discectomy and may predict good prognosis. Disclosure of Interest None declared

Focal Myositis of Lower Extremity Responsive to Botulinum A Toxin

Focal myositis is a rare, mostly benign disease (pseudotumor) of skeletal muscle, histopathologically characterized by interstitial myositis and tumorous enlargement of a single muscle. The etiology of focal myositis remains unknown; however, localized myopathy has been postulated to be caused by denervation lesions. This case report describes a patient that presented with clinical, laboratory, electromyoneurography, and magnetic resonance imaging features of focal myositis complicated with intervertebral disk protrusion in the lumbosacral spine affected with radicular distress. In most cases, focal myositic lesions show spontaneous regression, relapses are rare, and long-term prognosis is good. There is a wide spectrum of therapeutic options, from no therapy at all through nonsteroidal antirheumatics and glucocorticoids to radiotherapy, surgical excision, and immunosuppressants. In the patient presented, treatment with glucocorticoids, methotrexate, and surgical excision failed to produce satisfactory results. Clinical improvement, pain relief, and reduction in lower leg volume were only achieved by local infiltration of botulinum A toxin.

ANTEMORTEM DIAGNOSIS AND SUCCESSFUL MANAGEMENT OF NONCOMPRESSIVE SEGMENTAL MYELOPATHY IN A SIBERIAN-BENGAL MIXED BREED TIGER

A 10-yr-old female spayed mixed breed tiger presented for a 9-day history of acute and nonprogressive paralysis of the pelvic limbs. Magnetic resonance imaging revealed a lesion suggestive of fibrocartilaginous embolic myelopathy with regional spinal cord edema, decreased disk signal intensity at L2-L3, and mild intervertebral disk protrusion at L1-L2 and L2-L3. Cerebral spinal fluid analysis showed no overt evidence of infection or neoplasia. Medical therapy was instituted, including corticosteroids and gastroprotectants as well as nursing care and physical therapy. The tiger began showing clinical improvement 2 wk after initiating treatment, progressing to the point where the animal was standing and intermittently walking. Three months after diagnosis, the tiger had regained muscle strength of its hind limbs and walked regularly with improving coordination. This case is the first report of antemortem diagnosis and successful medical management of suspected fibrocartilaginous embolic myelopathy in a large exotic felid.

Meta-analysis of lumbar disc herniation in Chinese adolescents

To provide evidence-based medicine rationales for the diagnosis and treatment of lumbar disc herniation (LDH) in Chinese adolescents. The related medical literature of pediatric LDH between January 1990 and December 2012 was collected by retrospective searches of WANGFANG and CNKI databases. The data concerning mechanism, clinical manifestations, diagnosis and treatment were recorded and analyzed. A total of 1208 cases of LDH in adolescents were retrieved from 45 articles. Most of them were males (74.2%). And the primary cause was trauma (65.9%). Their clinical presentations were characterized by mild symptoms and serious physical signs. And 87.0% of them had a positive straight-leg raising test. Single-level intervertebral disk protrusion accounted for 92%. And the levels were at L4-L5 (54.7%) and L5-S1 (37.6%). There was a higher incidence of lumbar scoliosis deformity (38.2%), lumbar spine physiological curvature change (41.4%) and loss of vertebral height (33.6%) in adolescents than adults. There were many different treatments for pediatric LDH. Each method had its own advantages and disadvantages. The success rates of micro endoscopic discectomy (MED) and open discectomy were more than 90%. Trauma is a common cause of pediatric LDH. Males are more frequently affected. The single-level protrusion of L4/5 or L5/S1 has a much higher incidence. Positive straight-leg raising test and imaging findings of lumbar scoliosis deformity, lumbar spine physiological curvature change and a loss of vertebral height may aid the diagnosis. Normally conservative treatment is offered. And chemonucleolysis, MED and open discectomy are alternative options.

Scanning pattern of diffusion tensor tractography and an analysis of the morphology and function of spinal nerve roots.

Radiculopathy, commonly induced by intervertebral disk bulging or protrusion, is presently diagnosed in accordance with clinical symptoms because there is no objective quantitative diagnostic criterion. Diffusion tensor magnetic resonance imaging and diffusion tensor tractography revealed the characterization of anisotropic diffusion and displayed the anatomic form of nerve root fibers. This study included 18 cases with intervertebral disc degeneration-induced unilateral radiculopathy. Magnetic resonance diffusion tensor imaging was creatively used to reveal the scanning pattern of fiber tracking of the spinal nerve root. A scoring system of nerve root morphology was used to quantitatively assess nerve root morphology and functional alteration after intervertebral disc degeneration. Results showed that after fiber tracking, compared with unaffected nerve root, fiber bundles gathered together and interrupted at the affected side. No significant alteration was detected in the number of fiber bundles, but the cross-sectional area of nerve root fibers was reduced. These results suggest that diffusion tensor magnetic resonance imaging-based tractography can be used to quantitatively evaluate nerve root function according to the area and morphology of fiber bundles of nerve roots.

Synergistic effects of elevated homocysteine level and abnormal blood lipids on the onset of stroke.

Hyperhomocysteinemia and abnormal blood lipids are independent risk factors for stroke. However, whether both factors exert a synergistic effect in the onset of stroke remains unclear. The present study is a retrospective analysis of 2 089 cases of stroke and 2 089 control cases of simple intervertebral disk protrusion using a paired multivariate logistic regression method. Adjusting for known confounding variables including the patients' age, gender, smoking status, alcohol consumption status, patient and family medical history, and clinical biochemical indices, elevated homocysteine level was related to the onset of stroke. Patients with elevated homocysteine levels and abnormal blood lipids showed a 40.9 % increase in the risk for stroke compared to patients with normal homocysteine levels and blood lipids (odds ratio 1.409; 95% confidence interval 1.127-1.761). These results indicate that elevated homocysteine and abnormal blood lipids exert synergistic effects in the onset of stroke. Patients with elevated homocysteine levels and abnormal blood lipids are predisposed to stroke.

Observation on clinical therapeutic effect of Liyao granule in the treatment of damp-heat syndrome type lumber intervertebral disc protrusion

Objective To observe the clinical curative effect of Liyao granule for treatment of damp-heat syndrome type lumber intervertebral disc protrusion.Methods Totally 60 patients with dampheat syndrome type lumber intervertebral disc protrusion were randomly divided into two groups:treatment group (Liyao granule plus foundation therapy,n=30) and control group (Fenbid plus foundation therapy,n=30).After two courses of treatment,VAS score and general clinical efficacy were observed.Result Compared with the treatment before,after 2 courses of treatment,VAS score of two groups were decreased (P＜0.01); the general efficacy of treatment group and control group were 86.7％ and 90％ respectively; however,there was no significant statistical difference between two groups in VAS score and general efficacy (P＞0.05).Conclusion Liyao granule has short-term analgesic effect on damp-heat syndrome type lumber intervertebral disc protrusion,the same as Fenbid. Key words: Liyao granule; Damp-heat syndrome type; Lumber intervertebral disc Protrusion

Intervertebral Disc Protrusion in a Ferret with Triple Thoracic Block Vertebrae

Hind limb paresis or plegia in ferrets is a common sign of illness, which can be produced by intervertebral disc (IVD) extrusion or protrusion along with many other systemic diseases. This case report describes a ferret (Mustela putorius furo) with chronic onset paraplegia in which T7-T8, T8-T9, and T10-T11 IVD herniations and T9-T10 block vertebrae were diagnosed with the assistance of myelography. It is believed that the excessive stress on the adjacent annulus fibrosus and vertebral endplates resulting from block vertebrae could have been the cause of IVD disease in the atypical location described in this case.

The expression of interleukin-10 in intervertebral disc and its correlation with clinical features

Objective The expression of anti-inflammatory cytokine interleukin(IL)-10 in protrusion and extrusion tissue of intervertebral disc and its correlation with clinical features.Methods The specimens were from 30 cases of disc herniation in single level.The patients were enquired about the medical histories and evaluated by JOA index preoperation before operation,which were all completed by one trained doctor.The contents of IL-10 in the inter=43vertebral disc were detected by enzyme-linked immunosorbent assay after operation.Results The level of IL-10 had no statistical significance between protrusion and extrusion tissue of intervertebral disc (t =0.032,P =0.725).Patient's JOA index has negative correlation with IL-10(r =-0.377,P =0.040),and positive correlation with Patient's history (r =0.449,P =0.013).Conclusion Protrusion and extrusion tissue of intervertebral disc have abilities of excreting anti-inflammatory cytokine IL-10.The level of cytokine has correlation with patient's clinical features. Key words: Intervertebral disc displacement; Cytokines

Phase I dose finding study of AZD8931, an inhibitor of EGFR, HER2, and HER3 signaling, alone or in combination with paclitaxel in Japanese patients.

e13501 Background: AZD8931 is an equipotent, reversible inhibitor of signaling by EGFR, HER2 and HER3. Methods: This open-label, multiple-dose cohort study (NCT01003158) was conducted in Japan to evaluate the safety, tolerability and PK of ascending doses of AZD8931 alone (starting dose 40 mg bd) in patients (pts) with advanced solid malignancies and AZD8931 in combination with paclitaxel (P; 90 mg/m2on days 1, 8 and 15 of a 28-day cycle) in pts with advanced breast cancer. Results: Between Jan 2010 and Apr 2012,17 pts were treated; 11 with AZD8931 monotherapy (40/60/80 mg bd [n=3/4/4]) and 6 with AZD8931 40 mg bd plus P. Median (range) duration of exposure to AZD8931 was 42.5 (22–238) and 79.5 (53–244) days for monotherapy and combination therapy, respectively. No DLTs were observed (in the DLT evaluation period) and therefore the MTD was not confirmed for AZD8931 alone or with P. The most frequent AEs (all grades) with AZD8931 monotherapy were diarrhea, paronychia, rash pustule and dry skin (each n=8) and with combination therapy were diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n=4). Throughout the study grade ≥3 AEs were reported for 1, 2 and 4 pts in the 40 mg, 60 mg and combination groups, respectively. One serious AE was reported each in the 40 mg (grade 3 intervertebral disc protrusion) and combination (grade 2 infectious pneumonia) groups; neither was considered related to study treatment. One pt in the combination therapy part discontinued due to an AE of grade 1 pneumonia. AZD8931 was rapidly absorbed (median tmax 1–2 hours), well distributed, had moderate clearance (31–39 L/h) and a t½ of 12 hours. There was no suggestion of a PK interaction between AZD8931 and P. One pt on AZD8931 80 mg bd (primary stomach cancer) and another receiving AZD8931 plus P (advanced breast cancer) had an unconfirmed and confirmed PR, respectively (duration of responses 42 and 172 days, respectively) demonstrating preliminary efficacy. Conclusions: Although a MTD was not confirmed for AZD8931, based on overall incidence of AEs of rash and diarrhea in the 80 mg group, doses up to 60 mg bd as monotherapy and 40 mg bd combined with P are the recommended doses for evaluation in Japanese pts. Clinical trial information: NCT01003158.