Durable Objective Response to Lurbinectedin in Small Cell Bladder Cancer with TP53 Mutation: A Molecular-Directed Strategy.

Small cell bladder cancer (SCBC) is a rare and aggressive disease, often treated with platinum/etoposide-based chemotherapy. Key molecular drivers include the inactivation of onco-suppressor genes (TP53, RB1) and amplifications in proto-oncogenes (MYC). We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A genomic analysis of a metastatic biopsy prior to lurbinectedin initiation revealed a TP53 mutation and amplification of the cell cycle regulators E2F3 and MYCL. A repeat biopsy following the development of lurbinectedin resistance showed a new actionable ERBB2 alteration without significant change in the tumor mutation burden (six mutations/Mb). The present report suggests that lurbinectedin may be active and should be further explored in SCBC harboring TP53 mutations and amplifications in E2F3 and MYC family complexes.

Tumor-like conditions that mimic liver tumors.

Non-neoplastic tumor-like conditions of the liver can appear similar to hepatic neoplasms. In many cases, a biopsy is required to confirm the pathology. However, several tumor-like conditions can be correctly diagnosed or suggested prospectively, thus saving patients from unnecessary anxiety and expense. In this image-focused review, we present the ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography scan features of eight such entities. Clues that indicate the correct pathology are discussed, and the usual clinical setting is described. Many of these lesions are treated differently from true neoplasms, and the current treatment plan is discussed in many of the cases presented. After reviewing this article, the reader will have a better understanding of these lesions and the situations in which they should be included in the differential diagnosis.

MRI and PSMA PET/CT of Biochemical Recurrence of Prostate Cancer.

Prostate cancer may recur several years after definitive treatment, such as prostatectomy or radiation therapy. A rise in serum prostate-specific antigen (PSA) level is the first sign of disease recurrence, and this is termed biochemical recurrence. Patients with biochemical recurrence have worse survival outcomes. Radiologic localization of recurrent disease helps in directing patient management, which may vary from active surveillance to salvage radiation therapy, androgen-deprivation therapy, or other forms of systemic and local therapy. The likelihood of detecting the site of recurrence increases with higher serum PSA level. MRI provides optimal diagnostic performance for evaluation of the prostatectomy bed. Prostate-specific membrane antigen (PSMA) PET radiotracers currently approved by the U.S. Food and Drug Administration demonstrate physiologic urinary excretion, which can obscure recurrence at the vesicourethral junction. However, MRI and PSMA PET/CT have comparable diagnostic performance for evaluation of local recurrence after external-beam radiation therapy or brachytherapy. PSMA PET/CT outperforms MRI in identifying recurrence involving the lymph nodes and bones. Caveats for use of both PSMA PET/CT and MRI do exist and may cause false-positive or false-negative results. Hence, these techniques have complementary roles and should be interpreted in conjunction with each other, taking the patient history and results of any additional prior imaging studies into account. Novel PSMA agents at various stages of investigation are being developed, and preliminary data show promising results; these agents may revolutionize the landscape of prostate cancer recurrence imaging in the future. ©RSNA, 2023 Quiz questions for this article are available through the Online Learning Center. See the invited commentary by Turkbey in this issue. The slide presentation from the RSNA Annual Meeting is available for this article.

Tyrosine Kinase Inhibitor-related Intestinal Lymphangiectasia.

Online supplemental material is available for this article.

Influences of interpolation error, electrode geometry, and the electrode-tissue interface on models of electric fields produced by deep brain stimulation.

Deep brain stimulation (DBS) is an established therapy for movement disorders, but the fundamental mechanisms by which DBS has its effects remain unknown. Computational models can provide insights into the mechanisms of DBS, but to be useful, the models must have sufficient detail to predict accurately the electric fields produced by DBS. We used a finite-element method model of the Medtronic 3387 electrode array, coupled to cable models of myelinated axons, to quantify how interpolation errors, electrode geometry, and the electrode-tissue interface affect calculation of electrical potentials and stimulation thresholds for populations of model nerve fibers. Convergence of the potentials was not a sufficient criterion for ensuring the same degree of accuracy in subsequent determination of stimulation thresholds, because the accuracy of the stimulation thresholds depended on the order of the elements. Simplifying the 3387 electrode array by ignoring the inactive contacts and extending the terminated end of the shaft had position-dependent effects on the potentials and excitation thresholds, and these simplifications may impact correlations between DBS parameters and clinical outcomes. When the current density in the bulk tissue is uniform, the effect of the electrode-tissue interface impedance could be approximated by filtering the potentials calculated with a static lumped electrical equivalent circuit. Further, for typical DBS parameters during voltage-regulated stimulation, it was valid to approximate the electrode as an ideal polarized electrode with a nonlinear capacitance. Validation of these computational considerations enables accurate modeling of the electric field produced by DBS.

A practical algorithmic approach to the diagnosis and management of solitary pulmonary nodules: part 1: radiologic characteristics and imaging modalities.

The solitary pulmonary nodule (SPN) is frequently encountered on chest imaging and poses an important diagnostic challenge to clinicians. The differential diagnosis is broad, ranging from benign granulomata and infectious processes to malignancy. Important concepts in the evaluation of SPNs include the definition, morphologic characteristics via appropriate imaging modalities, and the calculation of pretest probability of malignancy. Morphologic differentiation of SPN into solid or subsolid types is important in the choice of follow-up and further management. In this first part of a two-part series, we describe the morphologic characteristics and various imaging modalities available to further characterize SPN. In Part 2, we will describe the determination of pretest probability of malignancy and an algorithmic approach to the diagnosis of SPN.

A practical algorithmic approach to the diagnosis and management of solitary pulmonary nodules: part 2: pretest probability and algorithm.

In this second part of a two-part series, we describe an algorithmic approach to the diagnosis of the solitary pulmonary nodule (SPN). An essential aspect of the evaluation of SPN is determining the pretest probability of malignancy, taking into account the significant medical history and social habits of the individual patient, as well as morphologic characteristics of the nodule. Because pretest probability plays an important role in determining the next step in the evaluation, we describe various methods the physician may use to make this determination. Subsequently, we outline a simple yet comprehensive algorithm for diagnosing a SPN, with distinct pathways for the solid and subsolid SPN.

Long-term rehabilitation for chronic stroke arm movements: a randomized controlled trial.

OBJECTIVE: We investigated the effect of long-term practice on motor improvements in chronic stroke patients. DESIGN: Randomized parallel group controlled study. SETTING: Motor Behavior Laboratory, University of Florida. SUBJECTS: Eighteen individuals who experienced a stroke more than nine months prior to enrolling. INTERVENTIONS: The treatment interventions were bilateral arm movements coupled with active neuromuscular stimulation on the impaired arm for both practice duration groups. The short-term group received one treatment protocol, whereas, over 16 months, the long-term practice group completed 10 treatment protocols. All protocol sessions were 6 hours long (90 minutes 1 day/week/4 weeks) and were separated by 22 days. MAIN OUTCOME MEASURES: Repeated data collection on three primary outcome measures (i.e. Box and Block test, fractionated reaction times, and sustained force production) evaluated motor capabilities across rehabilitation times. RESULTS: Mixed design ANOVAs (Group × Retention Test: 2 × 4; Group × Retention Test × Arm Condition: 2 × 4 × 2) revealed improved motor capabilities for the long-term practice duration group on each primary measure. At the 16-month delayed retention test, when compared to the short-term group, the long-term group demonstrated: (a) more blocks moved (43 v 32), (b) faster premotor reaction times (158 v 208 ms), and (c) higher force production (75 v 45 N). CONCLUSION: Sixty hours of rehabilitation over 16 months provided by various bilateral arm movements and coupled active stimulation improved motor capabilities in chronic stroke.

Telaprevir: an NS3/4A protease inhibitor for the treatment of chronic hepatitis C.

OBJECTIVE: To review the use of telaprevir for the treatment of chronic hepatitis C. DATA SOURCES: Clinical studies were identified through MEDLINE (1966-January 2011), bibliographies of articles, clinicaltrials.gov, and fda.gov, using key words VX-950, telaprevir, and chronic hepatitis C. STUDY SELECTION AND DATA EXTRACTION: Phase 1, 2, and 3 human and animal studies describing the pharmacology, pharmacokinetics, efficacy, and safety of telaprevir were identified. Additional articles were identified from the bibliographies of articles retrieved through MEDLINE. DATA SYNTHESIS: Telaprevir is an NS3/4A protease inhibitor under investigation for the treatment of chronic hepatitis C virus (HCV) with pegylated interferon and ribavirin. Telaprevir competes with viral peptide substrates for the active site of NS3 and inhibits NS3-NS4A protease activity. Telaprevir has activity against HCV genotype 1 infection in vitro and in vivo, but monotherapy results in rapid viral resistance. In 3 Phase 2 and 3 Phase 3 randomized placebo-controlled trials, 12 weeks of telaprevir, along with varying durations of ribavirin treatment, induced higher sustained virologic response (SVR) compared with ribavirin alone. SVR was approximately 70% in treatment-naïve patients, 50-60% for patients in whom SVR had not occurred with prior ribavirin treatment, and 40-45% of those who received ribavirin alone. There was a high incidence of maculopapular rash (52% in 1 trial) and anemia (27% in 1 trial) in telaprevir-treated patients. The average dropout rate in Phase 3 trials as a result of adverse effects was 13%. CONCLUSIONS: Twelve weeks of telaprevir with concomitant ribavirin treatment increases SVR for treatment-naïve and non-naïve patients with genotype 1 chronic HCV compared to 48 weeks of ribavirin treatment. Telaprevir may shorten the length of ribavirin therapy for some patients with extended rapid viral response, but viral mutations, adverse effects, and a high dropout rate may reduce the SVR seen in clinical practice.

Force control deficits in chronic stroke: grip formation and release phases.

The aim of the study was to develop a novel approach for quantifying stair-stepping in a trajectory tracking task with the goal of understanding how age and stroke-related differences in motor control contribute to force control deficits. Nine stroke participants, nine age-matched controls, and nine young healthy adults performed an isometric gripping task while squeezing, holding, and releasing a cylindrical device. The visual tracking task involved three different rates of force production (5, 10, and 20% maximal force/s). Four outcome measures determined force control deficits: (a) root mean square error, (b) standard deviation, (c) step number, and (d) mean pause duration. Our findings indicate that step number, and especially mean pause duration, differentiated force control deficits in the three groups more effectively than the traditional root mean square error. Moreover, stroke participants showed the largest force control deficits during the grip release phase compared to age-matched and young healthy controls. Importantly, step number and mean pause duration quantified stair-stepping while measuring different constructs than root mean square error. Distinct step and duration interruptions in force modulation by persons post-stroke during the grip release phase provide new information with implications for motor recovery during rehabilitation.

Children with cerebral palsy: a systematic review and meta-analysis on gait and electrical stimulation.

OBJECTIVE: To conduct a systematic review and meta-analysis using the International Classification of Functioning to determine the summary effect of electrical stimulation on impairment and activity limitations relevant to gait problems of children with cerebral palsy. METHODS: We identified 40 cerebral palsy and electrical stimulation studies, and 17 gait studies qualified for inclusion. Applying enablement classification methods to walking abnormalities created two subgroups: impairment (N = 14) and activity limitations (N = 15). Overall, 238 participants experienced electrical stimulation treatments and 224 served as a no stimulation control group. Calculations followed conventional data extraction and meta-analysis techniques: (a) individual standardized mean differences, (b) summary effect size, (c) I² heterogeneity test, (d) fail-safe N analysis and (e) moderator variable analyses. RESULTS: Common outcome measures associated with impairment (n = 3) and activity limitations (n = 6) were submitted to separate random effects models meta-analyses, and revealed significant cumulative effect sizes: (a) impairment = 0.616 (SE = 0.10) and (b) activity limitations = 0.635 (SE = 0.14). I² indicated low and medium amounts of dispersion, whereas fail-safe analyses revealed high N-values for both disablement categories. Moderator variable analyses further confirmed the positive treatment effects from both functional and neuromuscular stimulation. CONCLUSIONS: The present systematic review and meta-analyses determined medium effect sizes for electrical stimulation on walking impairment and activity limitations of children with cerebral palsy.

Force control and degree of motor impairments in chronic stroke.

OBJECTIVE: This study determined the variability and regularity of force production in impaired upper extremities of chronic stroke survivors. Two hypotheses included: (1) stroke will increase the variability and regularity of force output in comparison to age-matched controls and (2) degree of motor impairments will be positively correlated with the variability and regularity of force output. METHODS: Nine chronic stroke and nine age-matched controls performed unimanual isometric wrist and finger extension movements for 20s to three different target force levels. Force output was indexed by magnitude, accuracy, variability, and regularity. Stroke motor impairment levels were determined by Fugl-Meyer upper extremity assessment. RESULTS: The stroke group demonstrated increased variability and regularity of the force output. Further, motor impairments scaled with increase in variability and regularity of force output. CONCLUSIONS: The variability and regularity of force differentiated isometric contractions performed by chronic stroke survivors from age-matched controls. Moreover, in clinical settings an objective assessment of force control on variability and regularity appears to be most meaningful at 25% of MVC. SIGNIFICANCE: Increased variability contributes to reduced steadiness in force output. Increased regularity characterizes the adaptability losses in motor capabilities following stroke. This knowledge may facilitate planning and evaluating rehabilitation protocols.

Motor coordination in autism spectrum disorders: a synthesis and meta-analysis.

Are motor coordination deficits an underlying cardinal feature of Autism Spectrum Disorders (ASD)? Database searches identified 83 ASD studies focused on motor coordination, arm movements, gait, or postural stability deficits. Data extraction involved between-group comparisons for ASD and typically developing controls (N = 51). Rigorous meta-analysis techniques including random effects models, forest and funnel plots, I (2), publication bias, fail-safe analysis, and moderator variable analyses determined a significant standardized mean difference effect equal to 1.20 (SE = 0.144; p <0.0001; Z = 10.49). This large effect indicated substantial motor coordination deficits in the ASD groups across a wide range of behaviors. The current overall findings portray motor coordination deficits as pervasive across diagnoses, thus, a cardinal feature of ASD.

Bilateral balance impairments after lateral ankle trauma: a systematic review and meta-analysis.

Research indicates that balance is impaired in the involved limb following an ankle injury. However, bilateral balance impairments are a viable reason for previous non-significant findings between involved and uninvolved limbs. The purpose of this investigation was to conduct a meta-analysis on studies reporting the effects of lateral ankle trauma on balance of the involved and uninvolved limb after acute ankle injury and chronic ankle instability. Twelve studies qualified for inclusion and assessed static balance for both the involved and uninvolved limbs post-injury and a control group. Meta-analyses calculated standardized mean difference effects and explored moderating variables for the involved and uninvolved limbs relative to controls. A significant cumulative effect size (ES=0.448, p<0.00001) indicated that balance of the involved limb is impaired after a history of ankle injury. Moderator variable analysis revealed that both acute (ES=0.529, p<0.0002) and chronic (ES=0.338, p<0.001) lateral ankle trauma negatively affected balance. Analysis of the uninvolved limb also revealed postural stability impairments (ES=0.275, p<0.003). Additional, moderator analysis showed a significant acute effect (ES=0.564, p<0.0001), but failed to find significance for individuals with chronic ankle instability (ES=0.070, p=0.552). These findings provide strong evidence that balance is bilaterally impaired after an acute lateral ankle sprain. However, these findings suggest that bilateral balance deficits are not present in patients with chronic ankle instability. Based on these findings, the uninvolved limb should not be used as a reference for "normal balance" following an acute lateral ankle sprain. Further, patients with acute lateral ankle sprains should undergo balance training on both limbs.

Bilateral movement training and stroke motor recovery progress: a structured review and meta-analysis.

The purpose was to conduct a structured review and meta-analysis to determine the cumulative effect of bilateral arm training on motor capabilities post stroke. Forty-eight stroke studies were selected from three databases with 25 comparisons qualifying for inclusion in our meta-analysis. We identified and coded four types of bilateral arm interventions with 366 stroke patients. A random effects model using the standardized mean difference technique determined a large and significant effect size (0.734; SE=0.125), high fail-safe N (532), and medium variability in the studies (I(2)=63%). Moderator variable analysis on the type of bilateral training revealed two large and significant effects: (a) BATRAC (0.842; SE=0.155) and (b) coupled bilateral and EMG-triggered neuromuscular stimulation (1.142; SE=0.176). These novel findings provide strong evidence supporting bilateral arm training with the caveat that two coupled protocols, rhythmic alternating movements and active stimulation, are most effective.

Clavicular tuberculosis following trivial trauma.

Tuberculosis of the clavicular bone is a very rare clinical entity, with limited cases reported in the United States. Furthermore, sparing of the sternoclavicular joint is exceedingly unusual. A literature review of the prevalence of clavicular tuberculosis identified fewer than 80 cases reported since the discovery of the tubercular bacillus, over a century ago. To our knowledge, there have been no cases reported over the last decade in the United States. A rare case of tuberculous osteomyelitis of the clavicle in an immunocompetent patient who presented with swelling of the upper chest is reported.

Balance capabilities after lateral ankle trauma and intervention: a meta-analysis.

UNLABELLED: Despite the high incidence of lateral ankle sprains, the issue about whether postural control is impaired after acute or chronic injury is still unresolved. In addition, the literature is unclear if balance training, a commonly prescribed intervention, improves postural control after a history of lateral ankle trauma. PURPOSE: To conduct a meta-analysis on studies reporting the effects of lateral ankle trauma on postural control and how balance training affects postural control after acute and chronic lateral ankle trauma cumulatively and separately as moderating variables. METHODS: Thirty-seven postural control studies qualified for inclusion in the meta-analysis. Twenty-five studies investigated postural control independent of an intervention, and 15 studies administered balance-training interventions. Separate analyses on the two types of studies calculated Hedges' g individual effect sizes (ES). Further, we explored moderating variables for both the postural stability and the intervention studies. RESULTS: A significant cumulative effect size (ES) indicated that postural stability is impaired after a history of ankle injury (ES = 0.492, P < 0.0001). Moderator analysis revealed that both acute and chronic lateral ankle trauma negatively affected balance: a) acute: ES = 0.419, P < 0.0001, and b chronic, ES = 0.570, P < 0.0001. A third meta-analysis showed that balance training improves postural control (ES = -0.857, P < 0.0001). In addition, moderator variables indicated large ES for both types of ankle trauma. CONCLUSIONS: Postural control impairments are present in patients with a history of lateral ankle trauma. However, clinicians should exercise caution when using the uninjured contralateral limb as a reference of normal postural control. In addition, balance training improves postural control scores after both acute and lateral ankle trauma. However, further research should determine the optimal dosage, intensity, type of training, and a risk reduction/preventative effect associated with balance training after both acute and chronic ankle trauma.

Upper extremity improvements in chronic stroke: coupled bilateral load training.

BACKGROUND: The current treatment intervention study determined the effect of coupled bilateral training (i.e., bilateral movements and EMG-triggered neuromuscular stimulation) and resistive load (mass) on upper extremity motor recovery in chronic stroke. METHODS: Thirty chronic stroke subjects were randomly assigned to one of three behavioral treatment groups and completed 6 hours of rehabilitation in 4 days: (1) coupled bilateral training with a load on the unimpaired hand, (2) coupled bilateral training with no load on the unimpaired hand, and (3) control (no stimulation assistance or load). RESULTS: Separate mixed design ANOVAs revealed improved motor capabilities by the coupled bilateral groups. From the pretest to the posttest, both the coupled bilateral no load and load groups moved a higher number of blocks and demonstrated more regularity in the sustained contraction task. Faster motor reaction times across test sessions for the coupled bilateral load group provided additional evidence for improved motor capabilities. CONCLUSIONS: Together these behavioral findings lend support to the contribution of coupled bilateral training with a load on the unimpaired arm to improved motor capabilities on the impaired arm. This evidence supports a neural explanation in that simultaneously moving both limbs during stroke rehabilitation training appears to activate balanced interhemispheric interactions while an extra load on the unimpaired limb provides stability to the system.