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Dermatoglyphic patterns were recorded using standard ink method. The result showed in SCC, there was an increase in frequency of arch and ulnar loop patterns on fingertips, decrease in frequency of simple whorl patterns on fingertips, decrease in frequency of palmar accessory triradii on right and left hands. Significant findings in OSF included an increase in frequency of arch and ulnar loop pattern, decrease in frequency of simple whorl patterns on fingertips, decrease in ATD angle on right hand decrease in frequency of palmar accessory triradii on right hand. The results revealed that the field of dermatoglyphics holds promising results for determining the genetic susceptibility of individuals to develop SCC and OSF. Keywords: Dermatoglyphics, Sponge rubber.

Hyperbaric oxygen therapy refers to inhalation of pure oxygen in a closed chamber. Hyperbaric oxygen has a therapeutic effect in numerous pathological conditions, such as decompression sickness, arterial gas embolism, carbon monoxide poisoning and smoke inhalation, osteomylitis, osteoradionecrosis and wound healing. Hyperbaric oxygen therapy is used for treating underlying hypoxia. This review indicates the action of hyperbaric oxygen on biochemical and various physiological changes in cellular level. Narrative review covers the current indications and contraindications of hyperbaric oxygen therapy. The review also focuses on the therapeutic effects of hyperbaric oxygen pretreatment and precondition in different pathological conditions. The complications and side effects of hyperbaric oxygen therapy are discussed.

Cenesthopathy is characterized by abnormal sensations at various parts of the body. When it occurs in the oral cavity it is termed as oral cenesthopathy. These patients complain of unusual sensations without corresponding abnormal findings, such as excessive mucus secretion, a slimy sensation, or a feeling of coils or wires being present within the oral cavity. They usually visit multiple dentists rather than psychiatrists and repeatedly pursue unnecessary surgical procedures to remove their ‘foreign body’ which sometimes creates a dilemma for the dentists. This review focuses on the various aspects of oral cenesthopathy. Keywords: Oral cenesthopathy, Oral dysesthesia, Delusional disorder somatic type, Antidepressants, Antipsychotics.

Postmenopause is a phase of life which leads physical and emotional instability from multiple health related issues. Oral health in this stage of life is also compromised. Oral health has an impact on general wellbeing of the individual as oral cavity is commonly act as a mirror to general health. Menopause is phase in a woman’s life when menstrual cycles cease by reduced secretion of the ovarian hormones, such as estrogen and progesterone. This review article has emphasized on the diverse oral presentations of peri- and postmenopausal phase of women’s life. Practicing dental surgeons and general physician should be aware of the possible association of postmenopause and its various oral signs and symptoms in this midlife phase of women. It also focuses on its symptomatic management of various oral health issues. This article explains diverse oral conditions in detailed and their management. Stress causing anxiety and depression among this midlife phase of women can lead to alteration in immunity which can again lead to various oral conditions, like lichen planus, apthous ulcer that can cause burning sensation in oral mucosa and alter the food habit. By dealing with all this diverse condition, practicing oral physician can help to reduce and manage oral manifestation of postmenopausal phase of life.

Application of ozone in oral care comes as new and alternative treatment modality in dentistry. The impact of biological and digital information leads to use of ozone application by various means for numerous treatment options in oral cavity. Ozone is a form of oxygen, which has an effective role in management of oral diseases. This review mainly emphasizes on utility of ozone in oral health care management. Its therapeutic potential and its clinical application in oral pathologies, periodontology, endodontics, oral surgery, prosthodontics, orthodontics, restorative dentistry, wound healing, tooth mineralization as treatment choice are reviewed.

Ultrasonography is used to view internal body structures and organs. Ultrasonic images, also known as sonograms that are produced by sending pulses of ultrasound into tissue through the use of a probe, which carries a transducer containing material that produces a piezoelectric effect. The lower the frequency, the higher the penetration of tissues but the lower the potential image resolution. Intraoral USG makes it possible to visualize oral cavity organs, such as the sublingual gland and the submandibular duct, tongue, lips, tonsils, and soft palate, which are virtually impossible to image via conventional USG. Keywords: Ultrasound, Sound waves, Hyperthermia, Acoustic cavitation.

Parasites have always been a point of interest for the medical fraternity. They cause numerous amount of diseases around the globe and are of prime importance of studies of major health organisations like WHO and CDC. Hydatid cyst are one of the commonest occurring cysts affecting the world population. However the oral complications has been less studied because of its rare occurrence in that region. This review article deals with the life cycle, intra oral complications along with diagnosis and treatment of such cysts. Keywords: Parasites, WHO, CDC, Rare.

Parkinson's disease (PD) traditionally is characterized by tremor, rigidity, and bradykinesia, although cognitive impairment also is a common symptom. The clinical presentation of PD is heterogeneous and associated with different risk factors for developing cognitive impairment. PD patients with primary akinetic/rigidity (PDAR) are more likely to develop cognitive deficits compared to those with tremor-predominant symptoms (PDT). Because cognitive impairment in PD appears to be related to changes in the default mode network (DMN), this study tested the hypothesis that DMN integrity is different between PDAR and PDT subtypes.Resting state fMRI (rs-fMRI) and whole brain volumetric data were obtained from 17 PDAR, 15 PDT and 24 healthy controls (HCs) using a 3T scanner. PD patients were matched closely to HCs for demographic and cognitive variables, and showed no symptoms of dementia. Voxel-based morphometry (VBM) was used to examine brain gray matter (GM) volume changes between groups. Independent component analysis (ICA) interrogated differences in the DMN among PDAR, PDT, and HC.There was decreased activity in the left inferior parietal cortex (IPC) and the left posterior cingulate cortex (PCC) within the DMN between PDAR and both HC and PDT subjects, even after controlling for multiple comparisons, but not between PDT and HC. GM volume differences between groups were detected at a lower threshold (p 0.001, uncorrected). Resting state activity in IPC and PCC were correlated with some measures of cognitive performance in PD but not in HC.This is the first study to demonstrate DMN differences between cognitively comparable PDAR and PDT subtypes. The DMN differences between PD and HC appear to be driven by the PDAR subtype. Further studies are warranted to understand the underlying neural mechanisms and their relevance to clinical and cognitive outcomes in PDAR and PDT subtypes.

TPS146 Background: KRAS is the most frequently mutated oncogene in cancer and a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS G12C tumor mutations occur in approximately 14% of patients with lung adenocarcinoma and 3-4% of colorectal adenocarinoma. SHP2 is a phosphatase that acts as a key mediator of signaling from receptor tyrosine kinases (RTKs) to downstream RAS/MAPK pathways. Adagrasib (MRTX849) is a specific small-molecule investigational inhibitor of KRAS G12C that covalently binds to and locks mutant KRAS in its GDP-bound inactive form. Adagrasib has been optimized for a long half-life and extensive tissue distribution to enable inhibition throughout the entire dosing interval. Preliminary results from a Phase 1/2 study of adagrasib demonstrated promising antitumor activity and tolerability across multiple KRAS G12C tumor types. TNO155 is a selective inhibitor of SHP2 with demonstrated inhibition of RTK signaling and significant antitumor activity in preclinical models. Preclinical studies have shown that resistance to KRAS G12C inhibition may be mediated by SHP2-dependent feedback loops. Because KRAS G12C retains some level of cycling between GTP- and GDP-bound states, KRAS G12C that is not bound by inhibitor can activate downstream signaling. Active SHP2 functions to increase the active state of RAS proteins (including mutant KRAS) and also increases ERK pathway activation. Therefore, the addition of TNO155 to adagrasib may augment antitumor activity and overcome resistance by inhibiting cycling to GTP-bound KRAS and/or through inhibition of feedback activation and more comprehensively inhibiting downstream ERK signaling. In KRAS G12C human tumor models, adagrasib combined with a SHP2 inhibitor demonstrated greater activity compared to each agent alone. These data provide support for clinical evaluation of this combination in KRAS G12C tumors. Methods: KRYSTAL-2 is a multicenter Phase 1/2 study evaluating adagrasib and TNO155 in patients with advanced solid tumors harboring a KRAS G12C mutation. Overall objectives of the trial include evaluating safety, tolerability, and PK. The Phase 1 portion will evaluate adagrasib and TNO155 utilizing a modified Toxicity Probability Interval dose escalation design to identify maximum tolerated dose and recommended Phase 2 dose. The Phase 2 portion utilizes a Simon's optimal two-stage design to evaluate the clinical activity of adagrasib with TNO155 in 2 cohorts of up to 108 patients—CRC (54 patients) and NSCLC (54 patients). Efficacy endpoints include Objective Response Rate (RECIST 1.1), Duration of Response (DOR), Progression-free Survival (PFS), and Overall Survival (OS). The study is currently enrolling and patients will receive study treatment until disease progression, unacceptable adverse events, patient withdrawal, or death. Clinical trial information: NCT04330664.

Background Parkinson's disease (PD) is a neurodegenerative disorder that generally begins with asymmetric motor symptoms that persist over time. This suggests that the dysfunction in the nigrostriatal motor circuit may be lateralized. The present study examined whether the asymmetric motor presentation is associated with hemisphere-specific cognitive decline and lateralized gray matter volume loss. Methods Data from comprehensive cognitive tests that measured visuospatial and verbal functions and high-resolution T1-weighted magnetic resonance images of the brain were acquired in 23 PD subjects with left-side motor symptom onset (PDL), 23 PD subjects with right-side onset (PDR), and 23 matched Controls. GM volume differences were assessed using voxel-based morphometry (VBM). Cognitive results and VBM were compared among the three groups, and correlation analyses were performed between those cognitive domains and brain areas that showed significant differences. Results PDL subjects had lower performance on visuospatial memory tasks compared to PDR. Furthermore, PDL subjects experienced lateralized GM loss, which was localized predominantly in the right hemisphere contralateral to the side of motor symptom onset. Visuospatial memory performance in PDL was correlated with GM loss in the right middle frontal gyrus and precuneus. Conclusion These data suggest that the onset of asymmetric motor symptoms in PD may be associated with hemisphere-specific memory decline and lateralized GM loss, particularly in PDL. This study underscores the importance of classifying PD subgroups based on the side of motor symptom onset for clinical care and research to optimize cognitive outcomes.

Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.

Purpose LCL161 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby promoting cancer cell death. This first-in-human dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of LCL161 in patients with advanced solid tumors. A second part of the study assessed the relative bioavailability of a tablet versus solution formulation. Patients and Methods LCL161 was administered orally, once weekly, on a 21-day cycle to adult patients with advanced solid tumors by using an adaptive Bayesian logistic regression model with overdose control–guided dose escalation. Results Fifty-three patients received at least one dose of LCL161 (dose range, 10 to 3,000 mg). LCL161 was well tolerated at doses up to 1,800 mg. Cytokine release syndrome (CRS) was the only dose-limiting toxicity (in three [6%] of 53 patients) and was the most common grades 3 to 4 event (in five [9%] of 53 patients). Vomiting, nausea, asthenia/fatigue, and anorexia were common but not severe. Although the MTD was not formally determined, an 1,800-mg dose was selected in compliance with the protocol for additional study, given the dose-limiting CRS at higher doses and pharmacodynamic activity at lower doses. LCL161 was rapidly absorbed, and exposure was generally increased with dose. The tablet formulation of LCL161 was better tolerated than the solution; tablet and solution formulations had similar exposures, and the solution was discontinued. No patient had an objective response. LCL161 induced degradation of cellular IAP1 protein in the blood, skin, and tumor and increased circulating cytokine levels. Conclusion The 1,800-mg dose of LCL161, administered as a single agent once weekly, in tablet formulation is the recommended dose for additional study. This combined dose and formulation was well tolerated and had significant pharmacodynamic activity, which warrants additional investigation.

Summary Dickkopf-1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti-DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose-limiting toxicity (DLT) of escalating doses in combination with anti-myeloma therapy and zoledronic acid. Twenty-eight patients were enrolled and received BHQ880 at doses of 3–40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal-related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.

Background: Whereas the motor dysfunction in Parkinson’s disease (PD) has been related to deficits in basal ganglia (BG) structures, neural correlates of cognitive changes remain to be fully defined. This study tested the hypothesis that cognitive changes in non-demented PD may be related to cortical gray matter (GM) loss. Methods: High-resolution T1-weighted magnetic resonance images of the brain and comprehensive cognitive function tests were acquired in 40 right-handed, non-demented PD subjects and 40 matched controls. GM changes were assessed using voxel-based morphometry (VBM) in FSL. VBM and cognitive results were compared between PD and controls, and correlation analyses were performed between those brain areas and cognitive domains that showed significant group differences. Results: PD patients demonstrated significant GM reduction localized predominantly in frontal and parieto-occipital regions. Patients also showed reduced performance in fine motor speed and set-shifting compared to controls. Fine motor speed and set-shifting were associated with GM volume in the frontal cortex in controls, whereas these domains were associated primarily with occipital GM regions in PD patients. Conclusions: Non-demented PD subjects demonstrate cortical structural changes in frontal and parietooccipital regions compared to controls. The association between typically recognized “frontal lobe” function and occipital lobe volume suggested a compensatory role of occipital lobe to primary frontostriatal pathology in PD. Further longitudinal study of these changing structureefunction relationships is needed to understand the neural bases of symptom progression in PD.

The pattern of dopamine cell loss in Parkinson's disease (PD) is known to be prominent in the ventrolateral and caudal substantia nigra (SN), but less severe in the dorsal and rostral region. Both diffusion tensor imaging (DTI) and R2* relaxometry of the SN have been reported as potential markers for PD, but their relative ability to mark disease progression and differences in pathophysiological bases remains unclear. High-resolution T2-weighted, R2*, and DTI were obtained from 28 controls and 40 PD subjects [15 early stage [disease duration ≤1 year], 14 mid stage [duration 2-5 years], and 11 late stage [duration >5 years]). Fractional anisotropy and R2* values in both rostral and caudal SN were obtained for all subjects, and clinical measures (e.g., disease duration, levodopa-equivalent daily dosage, and "off"-drug UPDRS motor score) were obtained for Parkinson's subjects. There was no correlation between fractional anisotropy and clinical measures, whereas R2* was strongly associated with disease progression. Compared to controls, fractional anisotropy in caudal SN was significantly decreased in PD patients of all stages, whereas in rostral SN, it was decreased significantly only in the late-stage group. R2* in both SN regions was significantly increased in the mid- and late-stage, but not early-stage, of PD subjects. These findings suggest that fractional anisotropy changes may mark early pathological changes in caudal SN, whereas the changes in R2* may more closely track PD's clinical progression after symptom onset.

Recent magnetic resonance imaging studies suggest an increased transverse relaxation rate and reduced diffusion tensor imaging fractional anisotropy values in the substantia nigra in Parkinson's disease. The transverse relaxation rate and fractional anisotropy changes may reflect different aspects of Parkinson's disease-related pathological processes (ie, tissue iron deposition and microstructure disorganization). This study investigated the combined changes of transverse relaxation rate and fractional anisotropy in the substantia nigra in Parkinson's disease. High-resolution magnetic resonance imaging (T2-weighted, T2*, and diffusion tensor imaging) were obtained from 16 Parkinson's disease patients and 16 controls. Bilateral substantia nigras were delineated manually on T2-weighted images and coregistered to transverse relaxation rate and fractional anisotropy maps. The mean transverse relaxation rate and fractional anisotropy values in each substantia nigra were then calculated and compared between Parkinson's disease subjects and controls. Logistic regression, followed by receiver operating characteristic curve analysis, was employed to investigate the sensitivity and specificity of the combined measures for differentiating Parkinson's disease subjects from controls. Compared with controls, Parkinson's disease subjects demonstrated increased transverse relaxation rate (P

Parkinson's disease (PD) presents clinically with varying degrees of resting tremor, rigidity, and bradykinesia. For decades, striatal-thalamo-cortical (STC) dysfunction has been implied in bradykinesia and rigidity, but does not explain resting tremor in PD. To understand the roles of cerebello-thalamo-cortical (CTC) and STC circuits in the pathophysiology of the heterogeneous clinical presentation of PD, we collected functional magnetic resonance imaging (fMRI) data from 17 right-handed PD patients [nine tremor predominant (PDT) and eight akinetic-rigidity predominant (PDAR)] and 14 right-handed controls while they performed internally-guided (IG) sequential finger tapping tasks. The percentage of voxels activated in regions constituting the STC and CTC [divided as cerebellar hemisphere-thalamo-cortical (CHTC) and vermis-thalamo-cortical (CVTC)] circuits was calculated. Multivariate analysis of variance compared the activation patterns of these circuits between study groups. Compared to controls, both PDAR and PDT subjects displayed an overall increase in the percentage of voxels activated in both STC and CTC circuits. These increases reached statistical significance in contralateral STC and CTC circuits for PDT subjects, and in contralateral CTC pathways for PDAR subjects. Comparison of PDAR and PDT subjects revealed significant differences in ipsilateral STC (P=0.005) and CTC (P=0.043 for CHTC and P=0.003 for CVTC) circuits. These data support the differential involvement of STC and CTC circuits in PD subtypes, and help explain the heterogeneous presentation of PD symptoms. These findings underscore the importance of integrating CTC circuits in understanding PD and other disorders of the basal ganglia.

Background/Aim: The aim of this pilot study was to perform morphometric analysis of the foramen magnum (FM) using cone-beam computed tomography (CBCT). Materials and Methods: This study included CBCT images of 120 individuals (60 males and 60 females). The sagittal and transverse diameters and circumference of the FM were measured. The data were statistically analyzed with Chi-square and t-tests to assess the level of significance for sex and age. Results: The means of its sagittal and transverse diameters and also circumference were higher in males than in females. Statistically significant differences were found between transverse and circumference in case of males and females for all variables (P < 0.05). No statistically significant difference (P > 0.05) was found in sagittal diameter and age groups for all variables. Conclusion: CBCT images can provide valuable information regarding FM and the measurements of its sagittal and transvers diameters and also its circumference may be reliably used for sexual dimorphism in anthropometric analysis and forensic medicine.

Both the basal ganglia and cerebellum are known to influence cortical motor and motor-associated areas via the thalamus. Whereas striato-thalamo-cortical (STC) motor circuit dysfunction has been implicated clearly in Parkinson’s disease (PD), the role of the cerebello-thalamo-cortical (CTC) motor circuit has not been well defined. Functional magnetic resonance imaging (fMRI) is a convenient tool for studying the role of the CTC in vivo in PD patients, but large inter-individual differences in fMRI activation patterns require very large numbers of subjects in order to interpret data from cross-sectional, case control studies. To understand the role of the CTC during PD progression, we obtained longitudinal fMRI two years apart from five PD (57 ± 8 yr) and five Controls (57 ± 9 yr) performing either externally- (EG) or internally-guided (IG) sequential finger movements. All PD subjects had unilateral motor symptoms at baseline, but developed bilateral symptoms at follow-up. Within-group analyses were performed by comparing fMRI activation patterns between baseline and follow-up scans. Between-group comparisons were made by contrasting fMRI activation patterns generated by the more-affected and less-affected hands of PD subjects with the dominant and non-dominant hands of Controls, respectively. Compared to baseline, Controls showed changes in CTC circuits, but PD subjects had increased recruitment of both cortical motor-associated and cerebellar areas. Compared to Controls, PD subjects demonstrated augmented recruitment of CTC circuits over time that was statistically significant when the IG task was performed by the hand that transitioned from non-symptomatic to symptomatic. This longitudinal fMRI study demonstrates increased recruitment of the CTC motor circuit concomitant with PD progression, suggesting a role of the CTC circuit in accommodation to, or pathophysiology of, PD.

The CD22 extracellular domain regulates B lymphocyte function by interacting with α2,6-linked sialic acid-bearing ligands. To understand how CD22 ligand interactions affect B cell function in vivo, mouse anti-mouse CD22 mAbs were generated that inhibit CD22 ligand binding to varying degrees. Remarkably, mAbs which blocked CD22 ligand binding accelerated mature B cell turnover by 2- to 4-fold in blood, spleen, and lymph nodes. CD22 ligand-blocking mAbs also inhibited the survival of adoptively transferred normal (73–88%) and malignant (90%) B cells in vivo. Moreover, mAbs that bound CD22 ligand binding domains induced significant CD22 internalization, depleted marginal zone B cells (82–99%), and reduced mature recirculating B cell numbers by 75–85%. The CD22 mAb effects were independent of complement and FcRs, and the CD22 mAbs had minimal effects in CD22AA mice that express mutated CD22 that is not capable of ligand binding. These data demonstrate that inhibition of CD22 ligand binding can disrupt normal and malignant B cell survival in vivo and suggest a novel mechanism of action for therapeutics targeting CD22 ligand binding domains.

8034 Background: Identifying molecular drivers in lung squamous cell carcinoma (SCC) is a major medical need since no targeted therapy is available yet for this subtype. Fibroblast growth factor receptors (FGFRs) are physiologically involved in cell proliferation and survival. Genetic alteration of FGFR genes leads to deregulated activation in various cancers, and FGFR1 amplification has been detected in lung SCC. Here, we report on patients (pts) with FGFR1-amplified lung SCC treated in a phase 1 study of BGJ398, a potent, selective pan-FGFR inhibitor. Methods: While this phase 1 dose-escalation study enrolled pts ≥ 18 years of age with any FGFR genetically altered tumor, we report here on the subgroup of pts with FGFR1-amplified advanced or metastatic lung SCC treated with 100 or 125 mg BGJ398 once daily in 28-day cycles. Pts who had progressed following at least 1 line of therapy, including platinum, were eligible for enrollment. FGFR1-amplified tumors were identified by fluorescent/chromogenic in situ...

Welding-generated metallic fumes contain a substantial amount of manganese (Mn), making welders susceptible to Mn toxicity. Although overt Mn toxicity manifests as a type of parkinsonism, the consequences of chronic, low-level Mn exposure are unknown. To explore region-specific Mn accumulation and its potential functional consequences at subclinical levels of Mn exposure, we studied seven welders without obvious neurological deficits and seven age- and gender-matched controls. Mn exposure for welders was estimated by an occupational questionnaire. High-resolution brain magnetic resonance imaging (MRI), Grooved Pegboard performance of both hands, Trail making, and olfactory function tests were obtained from all subjects. Compared with controls, the welders had a significantly higher T1 relaxation rate (R1) in the olfactory bulb (OB, p = 0.02), mean T1-weighted intensity at frontal white matter (FWM; p = 0.01), bilateral globus pallidus (GP; p = 0.03), and putamen (p = 0.03). The welders scored worse than the controls on the Grooved Pegboard test for both dominant (p = 0.06) and nondominant hand (p = 0.03). The dominant hand Grooved Pegboard scores correlated best with mean MRI intensity of FWM (R² = 0.51, p = 0.004), GP (R² = 0.51, p = 0.004), putamen (R² = 0.49, p= 0.006), and frontal gray matter (R² = 0.42, p = 0.01), whereas the nondominant hand scores correlated best with intensity of FWM (R² = 0.37, p = 0.02) and GP (R² = 0.28, p = 0.05). No statistical differences were observed in either the Trail-making test or the olfactory test between the two groups. This study suggests that Mn accumulates in OB and multiple other brain regions in "asymptomatic" welders and that MRI abnormalities correlate with fine motor but not cognitive deficits. Further investigations of subclinical Mn exposure are warranted.

335 Background: CCA is a hepatobiliary malignancy with poor prognosis and few treatment options following cytotoxic therapy in the first-line metastatic setting. The fibroblast growth factor receptor (FGFR) axis may promote CCA tumorigenesis. FGFR2 fusions (in up to 17% of intrahepatic CCAs) may predict FGFR inhibitor sensitivity. A prior phase 1 trial of the selective pan-FGFR inhibitor BGJ398 showed antitumor activity in a pt with CCA harboring an FGFR2 fusion. Methods: This ongoing phase 2, open-label study is evaluating oral BGJ398 125 mg once daily on a 3-week-on/1-week-off schedule (28-day cycle) in pts with advanced or metastatic CCA with FGFR2 fusions (n ≈ 40) or other FGFR genetic alterations (n ≤ 15) who progressed after cisplatin/gemcitabine or are cisplatin intolerant (NCT02150967). The primary endpoint is investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints include progression-free survival, best overall response (BOR), disease control rate (DCR), overall survival, safety, and pharmacokinetics. Results: As of 10 July 2015, 26 pts with CCA harboring FGFR2 fusions (n = 22) or other FGFR alterations (n = 4), pretreated with 1 to ≥ 4 prior regimens, were enrolled. Common adverse events (AEs; ≥ 20% of pts), were hyperphosphatemia (50%), fatigue (42%), constipation (38%), cough (23%), and nausea (23%). Grade 3/4 AEs occurring in ≥ 2 pts were hyper/hypophosphatemia, lipase increase, and hyponatremia. AEs were manageable, reversible, and rarely led to treatment discontinuation. Among 22 pts evaluable for BOR, 3 achieved partial response and 15 had stable disease, including 10 with tumor reductions (-41%, n = 1; -2% to -29%, n = 9). Overall DCR was 82%. As of the cutoff date, 18 pts remained on therapy, of which 13 were on for > 120 days. Kaplan-Meier estimated lower limit (95% CI) of median time on study was 143 days. Conclusions: BGJ398 shows impressive anti-tumor activity and a manageable safety profile in pts with advanced FGFR-altered CCA, an indication of high unmet medical need. Updated data including additional responses post data cutoff will be presented. Clinical trial information: NCT02150967.

Background: Fibroblast growth factor receptors (FGFRs) play a role in cell proliferation and survival. Genetic alterations of FGFRs can lead to deregulated activation in various cancers, including squamous cell carcinoma (SCC) of the lung and urothelial bladder cancer. Here, we report on a phase I study of BGJ398 a potent, selective pan-FGFR inhibitor. Methods: Eligible patients (pts; ≥ 18 years of age) had tumors with any FGFR genetic alteration identified by central or local prescreening. Pts received BGJ398 once or twice daily (qd or bid) in 28-day cycles in escalating cohorts. Dose-limiting toxicities (DLTs) were predefined and included both severe events and those resulting in significant dosing delays. Upon determination of maximum tolerated dose (MTD), 3 expansion arms were treated: arm 1 included FGFR1-amplified SCC of the lung (continuous qd dosing); arms 2 and 3 included FGFR-altered solid tumors given qd continuous doses (arm 2) or qd doses on a 3-weeks-on/1-week-off schedule (arm 3). Results: As of September 24, 2013, 94 pts were enrolled (median age 57.5 years). Pts were treated in qd dose cohorts (5-150 mg; n = 90) or a bid dose cohort (50 mg; n = 4). Arms 1 and 3 are ongoing. Of the 82 pts who discontinued, the most common reasons were disease progression (n = 56), consent withdrawal (n = 12), and adverse events (AEs; n = 10). DLTs during dose escalation were grade 3 aminotransferase increases (1 each at 100 and 125 mg), hyperphosphatemia (125 mg), and grade 1 corneal toxicity (150 mg). The 125-mg qd dose was identified as the MTD. Common treatment-emergent AEs (any grade, suspected to be related) at 125 mg qd (n = 41) include hyperphosphatemia (78%), stomatitis (37%), alopecia (32%), decreased appetite (32%), and fatigue (22%) and were generally mild, with stomatitis (7%) the only grade 3/4 AE occurring ≥ 5%. Elevated serum phosphate levels, a pharmacodynamic marker of FGFR pathway inhibition, could be managed through diet, phosphate lowering therapy, and drug interruptions. Preliminary analysis of efficacy data indicates tumor regressions in pts with various FGFR genetic alterations, including 4 of 5 pts with urothelial cell carcinomas (4 of which originated in the bladder) with FGFR3-activating mutations (with tumor reductions ranging from 27% to 48%). Additionally, 1 pt with FGFR1-amplified SCC lung cancer achieved confirmed partial response (PR) while another pt achieved a PR confirmed after 27 days. Tumor reductions were also observed in cholangiocarcinoma with an FGFR2 gene fusion, and FGFR1-amplified breast cancer. Conclusions: BGJ398 had a tolerable safety profile and demonstrated single-agent activity in pts with FGFR-genetically altered solid tumors. The 3-weeks-on/1-week-off schedule has been chosen for future studies based on its improved safety profile. Clinical activity was observed in multiple tumor types, and pts with FGFR3-mutated bladder cancer may be especially sensitive to BGJ398. Citation Format: Lecia V. Sequist, Phillippe Cassier, Andrea Varga, Josep Tabernero, Jan HM Schellens, Jean-Pierre Delord, Patricia LoRusso, D. Ross Camidge, Manuel Hidalgo Medina, Martin Schuler, Mario Campone, G. Gary Tian, Steven Wong, Jesus Corral, Randi Isaacs, Suman K. Sen, Diana Graus Porta, Swarupa G. Kulkarni, Caroline Lefebvre, Jürgen Wolf. Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT326. doi:10.1158/1538-7445.AM2014-CT326

Objective: To investigate the clinical implications of MRI R2* relaxation rate and DTI fractional anisotropy (FA) in different areas of the SN in PD. Background R2* and FA values may reflect different pathophysiologies in the SN of Parkinson9s disease (PD) patients. The majority (>80%) of PD-related cell death is known to occur prior to the diagnosis and affect more ventral than dorsal parts of SN. Design/Methods: High resolution MRI (T2*, DTI) were obtained from 28 Controls and 40 PD subjects with 15 early (disease duration≤1 year), 14 medium (disease duration 2-5 years), and 11 later (disease duration>5 years) stage disease. FA and R2* in dorsal and ventral SN of all and each stage of PD subjects were compared to those of Controls, and correlated with clinical measures (UPDRS-III, akinetic/rigidity, and tremor scores “off” drug, disease duration, and levodopa equivalent dosage), after controlling for age and gender. Results: Compared to Controls, PD subjects demonstrated significantly increased R2* and reduced FA in the SN overall. R2* changes presented a similar pattern in both ventral and dorsal SN and correlated with all clinical measures except tremor scores. FA changes in ventral and dorsal SN were not correlated with clinical measurements, except for tremor score in dorsal SN. The pattern of change in the two regions, however, was different. Ventral SN changes occurred early and persisted through later stages of PD, whereas FA changes in dorsal SN seemed not to be present early in disease but became significant in later stages. Conclusions: The differential clinical correlation of R2* and FA measures in the SN supports the notion that FA changes in ventral SN at earlier stages may reflect existing PD-related cell death, but R2* may be gauging the changes of progression that are either pathoetiological or compensative related. Further studies are warranted. Supported by: NS060722 (GD, MML, QXY, and XH), and the HMC GCRC (NIH M01RR10732) and GCRC Construction Grant (C06RR016499). Disclosure: Dr. Du has nothing to disclose. Dr. Lewis has nothing to disclose. Dr. Sen has nothing to disclose. Dr. Shaffer has nothing to disclose. Dr. Styner has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Yang has nothing to disclose. Dr. Huang has nothing to disclose.

Introduction: LCL161 is a potent small molecule mimetic of the Smac mitochondrial protein. Like Smac, it binds to inhibitor of apoptosis proteins (IAPs) and prevents their interaction with active caspases. In addition, LCL161's binding to cIAP1 and cIAP2 leads to their proteasomal degradation, with subsequent NFκB activation and induction of IL-8 and MCP-1. LCL161 has single agent activity in tumor models with high basal TNF-α levels and broad synergistic anti-tumor activity in combination with taxanes. This first-in-human study of single agent LCL161 assesses its safety, pharmacokinetics (PK), pharmacodynamics (PD) and evidence of anti-tumor activity. Methods: Patients with advanced treatment-refractory solid tumors receive LCL161 as an oral solution once weekly. The dose of LCL161 is increased in successive cohorts of patients, with dose escalation guided by a Bayesian logistic regression model. PK and PD are assessed primarily during the first cycle (3 weeks) of treatment and disease status is assessed after the completion of every 2 cycles. Therapy continues until disease progression or unacceptable toxicity occurs. PK parameters are derived from non-compartmental analysis of plasma concentration versus time profiles. cIAP1 is detected in tissue by immunohistochemistry (IHC) and in peripheral blood mononuclear cells (PMBCs) by western blot. Circulating markers of cell death (e.g., M65) and a panel of cytokines are measured in plasma by ELISA. Results: As of November 1, 2009, 27 patients with an ECOG PS 0-1 have been enrolled and treated with LCL161 doses ranging from 10-1800 mg/week. In patients receiving doses ≤ 900 mg the median number of cycles is 2 (range 1-5). There have been no dose-limiting toxicities, although grade 1/2 nausea and vomiting have occurred at the 1800 mg dose. LCL161 exhibits dose-proportional PK through 1800 mg, demonstrates rapid absorption with a median Tmax of 1 h (range 0.5-2 h), and has a median half-life of 7 h (range 3-11 h). Doses >500 mg achieve an AUC0–24 equal to or greater than those needed for either single agent or combination activity in preclinical models. At LCL161 doses ≥ 320 mg cIAP1 levels are reduced consistently in skin punch biopsies 8 h after the first dose, and in a tumor biopsy at 24 h. cIAP1 levels in PMBCs are decreased 2 h post-dose and recover by the following week. Circulating markers of cell death peak on day 2 following doses ≥ 320 mg, and circulating cytokines, including MCP-1 and IL-8, increase 4 h post-doses ≥ 900 mg. No objective responses have been observed. At the 900 mg dose one patient (with rectal cancer) remains on study with stable disease for > 5 cycles. Conclusions: Oral LCL161 is well tolerated, has dose-proportional PK, and demonstrates target inhibition in patients, as demonstrated by cIAP degradation and cytokine induction. A solid oral formulation of LCL161 is being evaluated in this study, with plans to continue dose escalation and evaluate consecutive days of treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2775.