Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits.

A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10(-5), OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.

Effects of postural changes and removal of vestibular inputs on blood flow to and from the hindlimb of conscious felines.

Considerable data show that the vestibular system contributes to blood pressure regulation. Prior studies reported that lesions that eliminate inputs from the inner ears attenuate the vasoconstriction that ordinarily occurs in the hindlimbs of conscious cats during head-up rotations. These data led to the hypothesis that labyrinthine-deficient animals would experience considerable lower body blood pooling during head-up postural alterations. The present study tested this hypothesis by comparing blood flow though the femoral artery and vein of conscious cats during 20-60 degrees head-up tilts from the prone position before and after removal of vestibular inputs. In vestibular-intact animals, venous return from the hindlimb dropped considerably at the onset of head-up tilts and, at 5 s after the initiation of 60 degrees rotations, was 66% lower than when the animals were prone. However, after the animals were maintained in the head-up position for another 15 s, venous return was just 33% lower than before the tilt commenced. At the same time point, arterial inflow to the limb had decreased 32% from baseline, such that the decrease in blood flow out of the limb due to the force of gravity was precisely matched by a reduction in blood reaching the limb. After vestibular lesions, the decline in femoral artery blood flow that ordinarily occurs during head-up tilts was attenuated, such that more blood flowed into the leg. Contrary to expectations, in most animals, venous return was facilitated, such that no more blood accumulated in the hindlimb than when labyrinthine signals were present. These data show that peripheral blood pooling is unlikely to account for the fluctuations in blood pressure that can occur during postural changes of animals lacking inputs from the inner ear. Instead, alterations in total peripheral resistance following vestibular dysfunction could affect the regulation of blood pressure.

Responses of caudal vestibular nucleus neurons of conscious cats to rotations in vertical planes, before and after a bilateral vestibular neurectomy.

Although many previous experiments have considered the responses of vestibular nucleus neurons to rotations and translations of the head, little data are available regarding cells in the caudalmost portions of the vestibular nuclei (CVN), which mediate vestibulo-autonomic responses among other functions. This study examined the responses of CVN neurons of conscious cats to rotations in vertical planes, both before and after a bilateral vestibular neurectomy. None of the units included in the data sample had eye movement-related activity. In labyrinth-intact animals, some CVN neurons (22%) exhibited graviceptive responses consistent with inputs from otolith organs, but most (55%) had dynamic responses with phases synchronized with stimulus velocity. Furthermore, the large majority of CVN neurons had response vector orientations that were aligned either near the roll or vertical canal planes, and only 18% of cells were preferentially activated by pitch rotations. Sustained head-up rotations of the body provide challenges to the cardiovascular system and breathing, and thus the response dynamics of the large majority of CVN neurons were dissimilar to those of posturally-related autonomic reflexes. These data suggest that vestibular influences on autonomic control mediated by the CVN are more complex than previously envisioned, and likely involve considerable processing and integration of signals by brainstem regions involved in cardiovascular and respiratory regulation. Following a bilateral vestibular neurectomy, CVN neurons regained spontaneous activity within 24 h, and a very few neurons (<10%) responded to vertical tilts <15 degrees in amplitude. These findings indicate that nonlabyrinthine inputs are likely important in sustaining the activity of CVN neurons; thus, these inputs may play a role in functional recovery following peripheral vestibular lesions.

Consequences of postural changes and removal of vestibular inputs on the movement of air in and out of the lungs of conscious felines.

A variety of experimental approaches in human subjects and animal models established that the vestibular system contributes to regulation of respiration. In cats, the surgical elimination of labyrinthine signals produced changes in the spontaneous activity and posturally related responses of a number of respiratory muscles. However, these effects were complex and sometimes varied between muscle compartments, such that the physiological role of vestibulo-respiratory responses is unclear. The present study determined the functional significance of vestibulo-respiratory influences by examining the consequences of a bilateral labyrinthectomy on breathing rate and the pressure, volume, and flow rate of air exchanged during inspiration and expiration as body orientation with respect to gravity was altered. Data were collected from conscious adult cats acclimated to breathing through a facemask connected to a pneuomotach during 60 degrees head-up pitch and ear-down roll body rotations. Removal of vestibular inputs resulted in a 15% reduction in breathing rate, a 13% decrease in minute ventilation, a 16% decrease in maximal inspiratory airflow rate, and a 14% decrease in the maximal expiratory airflow rate measured when the animals were in the prone position. However, the lesions did not appreciably affect phasic changes in airflow parameters related to alterations in posture. These results suggest that the role of the vestibular system in the control of breathing is to modify baseline respiratory parameters in proportion to the general intensity of ongoing movements, and not to rapidly alter ventilation in accordance with body position.

Effects of postural changes and removal of vestibular inputs on blood flow to the head of conscious felines.

Prior studies have shown that removal of vestibular inputs produces lability in blood pressure during orthostatic challenges (Holmes MJ, Cotter LA, Arendt HE, Cass SP, and Yates BJ. Brain Res 938: 62-72, 2002; Jian BJ, Cotter LA, Emanuel BA, Cass SP, and Yates BJ. J Appl Physiol 86: 1552-1560, 1999). Furthermore, these studies led to the prediction that the blood pressure instability results in susceptibility for orthostatic intolerance. The present experiments tested this hypothesis by recording common carotid blood flow (CCBF) in conscious cats during head-up tilts of 20, 40, and 60 degrees amplitudes, before and after the surgical elimination of labyrinthine inputs through a bilateral vestibular neurectomy. Before vestibular lesions in most animals, CCBF remained stable during head-up rotations. Unexpectedly, in five of six animals, the vestibular neurectomy resulted in a significant increase in baseline CCBF, particularly when the laboratory was illuminated; on average, basal blood flow measured when the animals were in the prone position was 41 +/- 17 (SE) % higher after the first week after the lesions. As a result, even when posturally related lability in CCBF occurred after removal of vestibular inputs, blood supply to the head was not lower than when labyrinthine inputs were present. These data suggest that vestibular influences on cardiovascular regulation are more complex than previously appreciated, because labyrinthine signals appear to participate in setting basal rates of blood flow to the head in addition to triggering dynamic changes in the circulation to compensate for orthostatic challenges.

Selective down-regulation of D1 dopamine mediated rotational behavior in supersensitive mice.

The effects of continuous exposure to selective D1 and D2 agonists on rotational behavior were examined in mice with unilateral 6-hydroxydopamine-induced lesions of the corpus striatum. Continuously exposing mice to the D1 agonist SKF 38393 produced an initial rotational behavioral response which decreased dramatically within 4 hours. At the time these rotations ceased, the mice were totally unresponsive to an acute challenge injection of SKF 38393 but responded normally to an acute injection of the D2 agonist quinpirole. Mice chronically implanted with quinpirole also showed marked rotational behavior, but in contrast to the results with SKF 38393, essentially no diminution of these rotations was seen during a one week period of exposure. The results suggest that there are different mechanisms involved in the long term regulation of D1 and D2 dopamine systems in supersensitive animals.

Effects of bilateral vestibular lesions on orthostatic tolerance in awake cats.

Previous experiments in anesthetized or decerebrate cats showed that the vestibular system participates in adjusting blood pressure during postural changes. The present experiments tested the hypothesis that removal of vestibular inputs in awake cats would affect orthostatic tolerance. Before the lesion, blood pressure typically remained within 10 mmHg of baseline values during nose-up-pitch body rotations of up to 60 degrees in amplitude. In contrast, bilateral peripheral vestibular lesions altered the pattern of orthostatic responses in all animals, and blood pressure fluctuated >10 mmHg from baseline values during most 60 degrees nose-up tilts in five of six animals. The deficit in correcting blood pressure was particularly large when the animal also was deprived of visual cues indicating position in space. During this testing condition, either a decrease or increase in blood pressure >10 mmHg in magnitude occurred in >80% of tilts. The deficit in adjusting blood pressure after vestibular lesions persisted for only 1 wk, after which time blood pressure remained stable during tilt. These data show that removal of vestibular inputs alters orthostatic responses and are consistent with the hypothesis that vestibular signals are one of several inputs that are integrated to elicit compensatory changes in blood pressure during movement.

Effects of postural changes and vestibular lesions on genioglossal muscle activity in conscious cats.

Previous studies in humans showed that genioglossal muscle activity is higher when individuals are supine than when they are upright, and prior experiments in anesthetized or decerebrate animals suggested that vestibular inputs might participate in triggering these alterations in muscle firing. The present study determined the effects of whole body tilts in the pitch (nose-up) plane on genioglossal activity in a conscious feline model and compared these responses with those generated by roll (ear-down) tilts. We also ascertained the effects of a bilateral vestibular neurectomy on the alterations in genioglossal activity elicited by changes in body position. Both pitch and roll body tilts produced modifications in muscle firing that were dependent on the amplitude of the rotation; however, the relative effects of ear-down and nose-up tilts on genioglossal activity were variable from animal to animal. The response variability observed might reflect the fact that genioglossus has a complex organization and participates in a variety of tongue movements; in each animal, electromyographic recordings presumably sampled the firing of different proportions of fibers in the various compartments and subcompartments of the muscle. Furthermore, removal of labyrinthine inputs resulted in alterations in genioglossal responses to postural changes that persisted until recordings were discontinued approximately 1 mo later, demonstrating that the vestibular system participates in regulating the muscle's activity. Peripheral vestibular lesions were subsequently demonstrated to be complete through the postmortem inspection of temporal bone sections or by observing that vestibular nucleus neurons did not respond to rotations in vertical planes.

Effects of postural changes and vestibular lesions on diaphragm and rectus abdominis activity in awake cats.

Changes in posture can affect the resting length of the diaphragm, requiring alterations in the activity of both the abdominal muscles and the diaphragm to maintain stable ventilation. To determine the role of the vestibular system in regulating respiratory muscle discharges during postural changes, spontaneous diaphragm and rectus abdominis activity and modulation of the firing of these muscles during nose-up and ear-down tilt were compared before and after removal of labyrinthine inputs in awake cats. In vestibular-intact animals, nose-up and ear-down tilts from the prone position altered rectus abdominis firing, whereas the effects of body rotation on diaphragm activity were not statistically significant. After peripheral vestibular lesions, spontaneous diaphragm and rectus abdominis discharges increased significantly (by approximately 170%), and augmentation of rectus abdominis activity during nose-up body rotation was diminished. However, spontaneous muscle activity and responses to tilt began to recover after a few days after the lesions, presumably because of plasticity in the central vestibular system. These data suggest that the vestibular system provides tonic inhibitory influences on rectus abdominis and the diaphragm and in addition contributes to eliciting increases in abdominal muscle activity during some changes in body orientation.

Effects of lesions of the caudal cerebellar vermis on cardiovascular regulation in awake cats.

The vestibular system is known to participate in cardiovascular regulation during movement and postural alterations. The present study considered whether lesions of two regions of the posterior cerebellar vermis (the nodulus and uvula) that provide inputs to vestibular nucleus regions that affect control of blood pressure would alter cardiovascular responses during changes in posture. Blood pressure and heart rate were monitored in awake cats during nose-up tilts up to 60 degrees in amplitude before and following aspiration lesions of the nodulus or uvula; in most animals, cardiovascular responses were also recorded following the subsequent removal of vestibular inputs. Lesions of the nodulus or uvula did not affect baseline blood pressure or heart rate, although cardiovascular responses during nose-up tilts were altered. Increases in heart rate that typically occurred during 60 degrees nose-up tilt were attenuated in all three animals with lesions affecting both dorsal and ventral portions of the uvula; in contrast, the heart rate responses were augmented in the two animals with lesions mainly confined to the nodulus. Furthermore, following subsequent removal of vestibular inputs, uvulectomized animals, but not those with nodulus lesions, experienced more severe orthostatic hypotension than has previously been reported in cerebellum-intact animals with bilateral labyrinthectomies. These data suggest that the cerebellar nodulus and uvula modulate vestibulo-cardiovascular responses, although the two regions play different roles in cardiovascular regulation.

Combined approaches for resection of extensive glomus jugulare tumors. A review of 12 cases.

Complete resection with conservation of cranial nerves is the primary goal of contemporary surgery for glomus jugulare tumors. This publication reports the value of combined surgical approaches in achieving this goal in 12 patients with extensive tumors. Eleven of these tumors were classified as Fisch Class C and/or D, while eight were categorized as Jackson-Glasscock Grade III or IV. Intracranial (intradural) extension was present in 10 patients; four patients had tumor extension into the clivus and two into the cavernous sinus. The petrous internal carotid artery (ICA) was involved in eight and the vertebral artery (VA) in one. Subtemporal-infratemporal, retrosigmoid, and/or extreme lateral transcondylar approaches were added to the usual transtemporal-infratemporal approach. This improved the exposure, provided early control of the petrous ICA, and facilitated tumor removal from the clivus, cavernous sinus, posterior fossa, and foramen magnum, allowing a single-stage resection in eight patients. Ten patients had a complete microscopic resection with no mortality. The facial nerve was preserved in nine cases, with tumor involvement requiring nerve resection followed by grafting in the remaining three. Mobilization of the facial nerve was avoided in five cases; of these, three had intact function and two had House-Brackmann Grade III function on follow-up review. Only one patient had a mild persistent swallowing difficulty. The ICA was preserved in 10 patients and resected in two, while the VA required reconstruction in one case. There were no instances of stroke, and blood transfusions were required in five patients who had tumors with nonembolizable ICA or VA feeders. While complete resection provides the best possibility for cure, the important role of adjuvant radiation therapy in cases with residual tumor is discussed. The importance of degrees of brain-stem compression and vascular encasement is emphasized in classifying the more extensive tumors.

Clinical assessment of postural stability following vestibular nerve section.

Little is known about the recovery of postural control in patients following acute vestibular loss. This paper reports on the results of moving-platform posturography to assess the recovery of postural stability in 24 patients following vestibular nerve section. Posturography was abnormal prior to surgery in 17% of the patients. Seven days following surgery, 44% of the patients demonstrated vestibular deficit patterns, while 56% of the patients had normal posturography. Posturography was normal in all patients 1 month following surgery. Abnormal posturography was subsequently noted in 21% of the patients between 3 and 20 months following surgery. Each of the patients with abnormal preoperative posturography subsequently demonstrated abnormal late postoperative posturography. These results suggest that perioperative posturography may be useful in the evaluation and counseling of patients considering ablative vestibular surgery.

Patterns of vestibular function following vestibular nerve section.

Bithermal caloric irrigations, low-frequency rotational chair stimulation, and posturography were performed on 20 patients before and after vestibular nerve section. Twelve patients demonstrated acute postoperative spontaneous nystagmus and rotational vestibulo-ocular reflex (VOR) asymmetry. Eight patients demonstrated minimal acute postoperative spontaneous nystagmus and VOR asymmetry. Four patients had suppression of all vestibular function characterized by an absent contralateral caloric response, low VOR gain, and falls on posturography when required to rely solely on vestibular input to maintain posture. Four patients had a severe preoperative vestibular loss and no acute change in vestibular function following surgery. Over time, 5 patients continued to manifest elevated spontaneous nystagmus, 2 patients manifested a persistent rotational VOR asymmetry, and 5 patients exhibited a return of caloric function in the operated ear. It is suggested that multiple clinical factors contributed to the variable vestibular responses demonstrated in this study.

Galvanic-induced postural movements as a test of vestibular function in humans.

Galvanic stimulation produces a postural sway and eye movements in humans. Since galvanic currents are thought to exert their effect at the trigger zone of the vestibular nerve, an intact vestibular nerve should be necessary to produce a response. We have used galvanic stimulation in humans to test the hypothesis that intact vestibular nerve fibers are required to obtain a postural away response. Experimental subjects included normal subjects, patients who had undergone resection of an acoustic neuroma, and patients who had undergone vestibular neurectomy and surgical labyrinthectomy. Our results support the hypothesis that an intact vestibular nerve is necessary to produce a response. Moreover, two patients with recurrent vertigo following vestibular neurectomy and labyrinthectomy, who had absent ice-water caloric test responses in the operated ears, were found to have a positive galvanic response. This result suggested that their recurrent vertigo was based on intact residual vestibular nerve fibers. Although previous research has not yielded a routine clinical use for galvanic stimulation, our results suggest that galvanic stimulation of the vestibular system can provide unique and valuable diagnostic information.

Vestibular compensation after labyrinthectomy and vestibular neurectomy in cats.

Labyrinthectomy and vestibular neurectomy are two ablative procedures used for definitive control of disabling vertigo. It is not known if vestibular compensation after labyrinthectomy and vestibular neurectomy differs. We have addressed this question by examining the pattern of recovery of the vestibular ocular reflex in cats after either labyrinthectomy or vestibular neurectomy. Temporal bone histologic examination confirmed the surgical lesion. Our results demonstrate a reduction of the long time constant of the vestibular ocular reflex in both groups of animals. Although gain of the vestibular ocular reflex recovered substantially, it never returned to control levels in either group. In general, animals that had undergone vestibular neurectomy demonstrated greater vestibular ocular reflex asymmetries than did labyrinthectomized animals. The recovery pattern of the vestibular ocular reflex indicates vestibular compensation is more rapid after labyrinthectomy than after vestibular neurectomy. We believe this result is related to survival of the vestibular nerve after labyrinthectomy, but not after vestibular neurectomy, suggesting that the vestibular nerve can contribute to the adaptive response after labyrinthectomy.

Neurotologic manifestations of Chiari 1 malformation.

It is important for otolaryngologists to recognize Chiari malformations as part of the differential diagnosis of balance disorders because patients may initially be seen with symptoms referable to the vestibular system, including ataxia, nystagmus, or vertigo. The objective of this paper is to review the signs, symptoms, and vestibular test findings of a series of patients with Chiari 1 malformation. Six patients were identified by retrospective chart review with a diagnosis of Chiari malformation. Each patient had a complete otoneurologic examination and vestibular function testing. The results indicated that patients fell into two different vestibular test result profiles. First, patients with advanced symptoms demonstrated oculomotor dysfunction, central vestibular nystagmus, abnormal vestibular visual interaction, and abnormal tilt suppression of postrotatory nystagmus. On the other hand, a number of patients were identified with incidentally noted Chiari malformation on magnetic resonance imaging scan who had a vestibular test profile consistent with peripheral vestibulopathy without signs and symptoms of central nervous system dysfunction. Guidelines are provided to help determine the extent of the group of symptoms attributable to an incidentally discovered Chiari malformation.

Survival of the vestibular nerve after labyrinthectomy in the cat.

Temporal bone studies in cat, monkey, and man demonstrate that the cell bodies of the primary vestibular neurons located in Scarpa's ganglion persist after labyrinthectomy. However, it is not known whether the centrally directed axon process of deafferented vestibular neurons survive or degenerate after labyrinthectomy. If the central axon were to persist, then the primary vestibular neuron could influence vestibular compensation or produce symptoms of vestibular dysfunction. In the present study the temporal bones and brain stem of four cats were prepared for light microscopic examination with hematoxylin-eosin, silver, and trichrome connective tissue stains. Cell counts within Scarpa's ganglion were performed. After labyrinthectomy, many intact axons were demonstrated in the brain stem, a finding that correlated with survival of neurons in Scarpa's ganglion. This study provides anatomic evidence that primary vestibular neurons that survive labyrinthectomy may retain their central axon processes. The persistence of this neural pathway and data from behavioral studies in the cat suggest that vestibular neurons may affect vestibular compensation after labyrinthectomy. Deafferented vestibular neurons may play a role in human vestibular compensation and dysfunction.

An anatomic variant of the anterior inferior cerebellar artery in a patient with Ménière's disease.

OBJECTIVE: To describe an anatomic variant of the anterior inferior cerebellar artery in a patient with Ménière's disease. STUDY DESIGN: Retrospective case review and review of the literature. SETTING: Tertiary referral clinic. INTERVENTION: Vestibular nerve section and microvascular decompression. MAIN OUTCOME MEASURES: Audiometric testing and control of vertigo. RESULTS: The eighth nerve was identified via a retromastoid approach. The anterior inferior cerebellar artery was observed bisecting the eighth nerve. The vestibular nerve was sectioned, and microvascular decompression was performed on the cochlear division. At last follow-up, the patient had not experienced any vertiginous attacks but was observed to have progressive hearing loss. CONCLUSIONS: The course of the anterior inferior cerebellar artery is highly variable and difficult to predict. Knowing the potential paths is a necessity in performing posterior fossa surgery. Although the patient's vertigo was controlled by the vestibular nerve section, microvascular decompression of the cochlear nerve did not result in hearing improvement or stabilization. This case report does not support a benefit of microvascular decompression in Méniére's disease. Vestibular nerve section remains the authors' treatment of choice for controlling disabling vertigo caused by Ménière's disease.

Short- and long-term outcomes of canalith repositioning for benign paroxysmal positional vertigo.

This is a prospective, nonrandomized study of the canalith repositioning procedure (CRP) for treatment of benign paroxysmal positional vertigo (BPPV). CRP was used to treat 168 patients with BPPV. Patient data were gathered by yearly telephone interviews to determine whether symptoms of position-induced vertigo had returned. After 1 or 2 treatment sessions 91.3% of patients reported complete symptom resolution. Average follow-up for the study population after the initial treatment was 26 months. A recurrence rate of 26.8% was found among those patients who initially reported resolution of symptoms after CRP. Application of recurrence data to a Kaplan-Meier estimation suggests a 15% recurrence rate per year of BPPV, with a 50% recurrence rate of BPPV at 40 months after treatment. There was no significant association between cure or recurrence rate and sex, age, duration of symptoms, presumed cause, or treating physician.