Chromoplectic TPM3-ALK rearrangement in a patient with inflammatory myofibroblastic tumor who responded to ceritinib after progression on crizotinib.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas that can occur at any age. Surgical resection is the primary treatment for patients with localized disease; however, these tumors frequently recur. Less commonly, patients with IMTs develop or present with metastatic disease. There is no standard of care for these patients and traditional cytotoxic therapy is largely ineffective. Most IMTs are associated with oncogenic ALK, ROS1 or PDGFRß fusions and may benefit from targeted therapy. PATIENT AND METHODS: We sought to understand the genomic abnormalities of a patient who presented for management of metastatic IMT after progression of disease on crizotinib and a significant and durable partial response to the more potent ALK inhibitor ceritinib. RESULTS: The residual IMT was resected based on the recommendations of a multidisciplinary tumor sarcoma tumor board and analyzed by whole-genome mate pair sequencing. Analysis of the residual, resected tumor identified a chromoplectic TPM3-ALK rearrangement that involved many other known oncogenes and was confirmed by rtPCR. CONCLUSIONS: In our analysis of the treatment-resistant, residual IMT, we identified a complex pattern of genetic rearrangements consistent with chromoplexy. Although it is difficult to know for certain if these chromoplectic rearrangements preceded treatment, their presence suggests that chromoplexy has a role in the oncogenesis of IMTs. Furthermore, this patient's remarkable response suggests that ceritinib should be considered as an option after progression on crizotinib for patients with metastatic or unresectable IMT and ALK mutations.

Activation of TAK1 by MYD88 L265P drives malignant B-cell Growth in non-Hodgkin lymphoma.

Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHLs) including the rare lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia (WM). Using whole-exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88L265P mutation in the tumor genome of 97% of WM patients analyzed (n=39). Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B-cell survival, therapeutic targeting of MYD88 signaling pathways may be clinically useful. However, we are lacking a thorough characterization of the role of intermediary signaling proteins on the biology of MYD88L265P-expressing B cells. We report here that MYD88L265P signaling is constitutively active in both WM and diffuse large B-cell lymphoma cells leading to heightened MYD88L265P, IRAK and TRAF6 oligomerization and NF-κB activation. Furthermore, we have identified the signaling protein, TAK1, to be an essential mediator of MYD88L265P-driven signaling, cellular proliferation and cytokine secretion in malignant B cells. Our studies highlight the biological significance of MYD88L265P in NHL and reveal TAK1 inhibition to be a potential therapeutic strategy for the treatment of WM and other diseases characterized by MYD88L265P.

Selective activation of a parietofrontal circuit during implicitly imagined prehension.

It is generally held that motor imagery is the internal simulation of movements involving one's own body in the absence of overt execution. Consistent with this hypothesis, results from numerous functional neuroimaging studies indicate that motor imagery activates a large variety of motor-related brain regions. However, it is unclear precisely which of these areas are involved in motor imagery per se as opposed to other planning processes that do not involve movement simulation. In an attempt to resolve this issue, we employed event-related fMRI to separate activations related to hand preparation-a task component that does not demand imagining movements-from grip selection-a component previously shown to require the internal simulation of reaching movements. Our results show that in contrast to preparation of overt actions, preparation of either hand for covert movement simulation activates a large network of motor-related areas located primarily within the left cerebral and right cerebellar hemispheres. By contrast, imagined grip selection activates a distinct parietofrontal circuit that includes the bilateral dorsal premotor cortex, contralateral intraparietal sulcus, and right superior parietal lobule. Because these areas are highly consistent with the frontoparietal reach circuit identified in monkeys, we conclude that motor imagery involves action-specific motor representations computed in parietofrontal circuits.

Within grasp but out of reach: evidence for a double dissociation between imagined hand and arm movements in the left cerebral hemisphere.

What roles are played by the cerebral hemispheres in planning object-oriented reaching and grasping movements? In an attempt to address this question, we compared the abilities of the left and right hemispheres of commissurotomy patient J.W. to imagine hand manipulation (i.e., grasp) or arm transportation (i.e., reach) movements. A graphically rendered manipulandum (dowel) was briefly presented to the left (LVF) or right (RVF) visual fields in a variety of different orientations. In the grasp selection task (experiment 1), J.W. was required to determine which side of a dowel his thumb would be on if he were to engage the stimulus in a power grip using either his dominant (right) or non-dominant hand. In the reach selection task (experiment 3), J.W. judged which end his elbow would be on if he treated the dowel as an armrest for his dominant or non-dominant forearm. No actual movements were allowed in either task. Movements selected in the imagery tasks were compared with those chosen during actual motor control under comparable circumstances. These comparisons revealed a left hemisphere advantage for representing grasping movements involving the right hand, and reaching movements involving the left arm. The right hemisphere, by contrast, displayed moderate accuracy when representing grasping movements with the left hand, but appeared incapable of imagining reaching movements with either arm. The double dissociation between imagery for hand and arm movements in the left cerebral hemispere is consistent with the hypothesis that grasping and reaching components of prehension involve dissociable planning mechanisms.

Seeing two sides at once: effects of viewpoint and object structure on recognizing three-dimensional objects.

Five experiments demonstrated that adults can identify certain novel views of 3-dimensional model objects on the basis of knowledge of a single perspective. Geometrically irregular contour (wire) and surface (clay) objects and geometrically regular surface (pipe) objects were accurately recognized when rotated 180 degrees about the vertical (y) axis. However, recognition accuracy was poor for all types of objects when rotated around the y-axis by 90 degrees. Likewise, more subtle rotations in depth (i.e., 30 degrees and 60 degrees) induced decreases in recognition of both contour and surface objects. These results suggest that accurate recognition of objects rotated in depth by 180 degrees may be achieved through use of information in objects' 2-dimensional bounding contours, the shapes of which remain invariant over flips in depth. Consistent with this interpretation, a final study showed that even slight rotations away from 180 degrees cause precipitous drops in recognition accuracy.

Imagining the impossible: intact motor representations in hemiplegics.

Motor imagery is known to involve brain regions vital to the performance of motor skills including primary motor cortex. The present results show that, following cerebral vascular accidents (CVAs) affecting a variety of these regions, many adults with left or right upper-limb paralysis (i.e. hemiparesis/hemiplegia) retain the ability to accurately represent prehensile movements involving the impaired limb. This suggests that during the acute phase of recovery many CVA patients can use motor imagery to activate partially damaged motor networks; a process that may facilitate functional reorganization. This ability was, however, compromised in cases with right posterior parietal or left frontal lesions. This pattern is consistent with the hypothesis that imagined prehension, like actual reaching and grasping, involves a network of highly interconnected areas distributed throughout parietal and frontal cortices.

Use of grade membership analysis to profile the practice styles of individual physicians in the management of acute low back pain.

The objective of this study was to investigate Grade of Membership analysis (GoM) as a means of profiling the practice styles of individual physicians. GoM uses maximum likelihood techniques to estimate occurrences of management items that define unique practice styles. It also provides statistical estimates (grade of membership coefficients) of how well each individual physician's practice fits the identified styles. Data sources were responses to a mailed survey asking 814 physicians to select from predetermined management options in three scenarios depicting patients with acute low back pain. Four distinct types of practice style were identified: watchful waiting; investigative; guideline based; and physiotherapy focused. Most physicians were characterized by high grades of membership in the two profiles that most closely matched existing guidelines for the management of acute low back pain. GoM successfully identified characteristic practice styles, and the GoM coefficients obtained provided descriptions of individual management approaches. GoM is data driven and less subject to judgment than opinion-based measures of performance. It has several potential applications in identifying physicians for whom some form of intervention would be beneficial.

Thinking ahead: the case for motor imagery in prospective judgements of prehension.

How similar are judgements concerning how we expect to perform an action, to how we actually behave? The veracity of such prospective action judgements, and the mechanisms by which they are computed, was explored in a series of tasks that involved either grasping (MC conditions) or thinking about grasping (PJ conditions) a dowel presented in various orientations. PJs concerning limits of comfortable hand supination and pronation when turning a dowel in the picture plane were highly consistent with values obtained during actual hand rotation (Exp. 1). The same was true for judgements regarding the level of awkwardness involved in adopting a prescribed grip (e.g. overhand with right hand) for dowels in various picture plane orientations (Exp. 2). When allowed to select the most natural grip (overhand versus underhand) or hand (left versus right) for engaging dowels in these orientations, subjects preferred virtually identical responses in both PJ and MC conditions. In both instances, they consistently chose the least awkward response options. As would be expected for actual movements, PJs involving awkward hand postures had longer response times (RTs), and were less accurate. Likewise, latencies for both grip and hand judgements tended to increase as a function of the angular distance between the current positions of subjects' hands, and the orientation of the chosen posture. Together, these findings are consistent with a the hypothesis that PJs involve mentally simulated actions, or motor imagery. These results suggest that motor imagery does not depend on the existence of a completed premotor plan (Jeannerod, 1994), but may instead be involved in the planning process itself. A provisional model for the involvement of imagery in motor planning is outlined, as are a set of criteria for evaluating claims of the involvement of motor imagery in problem solving.

Parallel format: making life easier for the reader.

Use parallel style to show the similarity between items in a series. When headings, bullet lists, and sentence phrases that relate to each other are written in a similar style, the reader can understand the information faster than when they are written in different styles.

Coping with census fluctuations.

Census fluctuations are the latest challenge for nurse managers, recruiters, and human resource professionals. How health care facilities deal with this problem affects retention and recruitment.

A preliminary analysis of medical futility decisionmaking: law and professional attitudes.

Judicial decisions reviewed in this article indicate that courts have taken two disparate approaches to disputes over futility of treatment. To explore whether a consensus on medical futility is developing among hospitals, the authors conducted a nationwide survey of health care professionals at hospitals. Respondents assigned importance ratings to factors used in recent futility decisions made at their institutions. The resulting importance ratings showed significant variation by characteristics of the institution (comparing respondents from for-profit, not-for-profit, and government hospitals) and by profession of the respondent (comparing physicians and nurses). The respondents' judgments endorsed three distinct strategies for making futility decisions (i.e., emphasis on the patient's decision preferences, providing for the patient and family, and adhering to objective medical and social norms).

The proofing challenge: finding hidden errors.

Page proofs are deceptive. The beautiful fonts, printout and lay-out of page proofs can be deceptive, because there are usually some errors still lurking. Most nursing journals send page proofs to authors, but most authors are not experienced at proofing final pages for publication, so errors can sneak through. This article provides tips on proofing final pages so that those pesky, final errors can be corrected before printing.

Submitting your manuscript on disk: a steep learning curve for authors and editors.

Many nursing journals are switching to state-of-the-art manuscript production systems. Most of these new systems include computerized typesetting, so some journals are requesting disk submission of manuscripts. However, computer disk submission is not without difficulties. Editors and authors alike are experiencing a fairly steep learning curve before developing a system where the author's disk can work in the publisher's production system. This article describes how authors and editors can collaborate on the disk submission system for nursing publications.

Where are clinical ladders headed?

Now that restructuring projects are under way, revision of the delivery system has expanded to related areas. One system that is being reviewed is the clinical ladder. This article discusses the future directions of clinical ladders within a restructured healthcare system.

Fax etiquette for nurse authors and editors.

Is the facsimile (fax) machine really as great as it seems? Yes, but there is a potential for its misuse. Like all equipment, the fax machine is a tool that needs to be used wisely. This article describes the Do's and Don'ts of using the fax machine to communicate between authors and editors. Tips in this article will help authors and editors to correspond smoothly by fax and use new fax equipment options.

Agenesis of cerebellum associated with arrhinencephaly.

Complete cerebellar agenesis or aplasia is an extremely rare condition with few previously reported cases. We identified a 38-week gestation infant with microcephaly who had complete cerebellar agenesis associated with arrhinecephaly. There was complete lack of the efferent and afferent limbs of the cerebellum, including the nuclei of the basis pontis, the inferior olivary nuclei, ascending spinal and medullary afferents, deep cerebellar nuclei and their afferents, and the red nucleus. Although complete cerebellar agenesis is rare, cerebellar hypoplasia is more common and can be sporadic, asymmetric, or represent clinically, genetically, and pathologically diverse examples of primary cerebellar or vermian hypoplasia.