Safety of systemic anti-cancer treatment in oncology patients with non-severe COVID-19: a cohort study.

BACKGROUND: The viral pandemic coronavirus disease 2019 (COVID-19) has disrupted cancer patient management around the world. Most reported data relate to incidence, risk factors, and outcome of severe COVID-19. The safety of systemic anti-cancer therapy in oncology patients with non-severe COVID-19 is an important matter in daily practice. METHODS: ONCOSARS-1 was a single-center, academic observational study. Adult patients with solid tumors treated in the oncology day unit with systemic anti-cancer therapy during the initial phase of the COVID-19 pandemic in Belgium were prospectively included. All patients (n = 363) underwent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) serological testing after the first peak of the pandemic in Belgium. Additionally, 141 of these patients also had a SARS-CoV-2 RT-PCR test during the pandemic. The main objective was to retrospectively determine the safety of systemic cancer treatment, measured by the rate of adverse events according to the Common Terminology Criteria for Adverse Events, in SARS-CoV-2-positive patients compared with SARS-CoV-2-negative patients. RESULTS: Twenty-two (6%) of the 363 eligible patients were positive for SARS-CoV-2 by RT-PCR and/or serology. Of these, three required transient oxygen supplementation, but none required admission to the intensive care unit. Hematotoxicity was the only adverse event more frequently observed in SARS-CoV-2 -positive patients than in SARS-CoV-2-negative patients: 73% vs 35% (P < 0.001). This association remained significant (odds ratio (OR) 4.1, P = 0.009) even after adjusting for performance status and type of systemic treatment. Hematological adverse events led to more treatment delays for the SARS-CoV-2-positive group: 55% vs 20% (P < 0.001). Median duration of treatment interruption was similar between the two groups: 14 and 11 days, respectively. Febrile neutropenia, infections unrelated to COVID-19, and bleeding events occurred at a low rate in the SARS-CoV-2-positive patients. CONCLUSION: Systemic anti-cancer therapy appeared safe in ambulatory oncology patients treated during the COVID-19 pandemic. There were, however, more treatment delays in the SARS-CoV-2-positive population, mainly due to a higher rate of hematological adverse events.

Pathological responses after angiogenesis or EGFR inhibitors in metastatic colorectal cancer depend on the chemotherapy backbone.

BACKGROUND: Optimal preoperative treatment before colorectal cancer metastases (CRCM) resection remains unclear. This study evaluated pathological responses (pR) in CRCM resected after chemotherapy alone or combined with angiogenesis or epidermal growth factor receptor (EGFR) inhibitors. METHODS: Pathological response was retrospectively evaluated on 264 resected metastases from 99 patients. The proportion of responding metastases after different preoperative treatments was reported and compared. Patient's progression-free survival (PFS) and overall survival (OS) were compared based on pR. RESULTS: The combination of anti-angiogenics with oxaliplatin-based chemotherapy resulted in more pR than when they were combined with irinotecan-based chemotherapy (80% vs 50%; P<0.001). Inversely, the combination of EGFR inhibitors with oxaliplatin-based chemotherapy seemed to induce fewer pR than when they were combined with irinotecan-based treatment (53% vs 72%; P=0.049). Overall survival at 5 years was improved for patients with a pR in all resected metastases compared with those who did not achieve a pR (68.5% vs 32.6%; P=0.023) and this response was the only factor predicting OS in a multivariate analysis. CONCLUSION: The chemotherapy partner combined with angiogenesis or EGFR inhibitors influenced pR in resected CRCM. In our exploratory analysis anti-angiogenic/oxaliplatin-based regimens and anti-EGFR/irinotecan-based regimens were associated with the highest pR. Prospective randomised trials should be performed to validate these observations.

Another case of "European hantavirus pulmonary syndrome" with severe lung, prior to kidney, involvement, and diagnosed by viral inclusions in lung macrophages.

Puumala virus (PUUV) is considered a classic Old World etiologic agent of nephropathia epidemica (NE), or hemorrhagic fever with renal syndrome (HFRS). HFRS is considered to be distinct from hantavirus (cardio-)pulmonary syndrome (HPS or HCPS), described in the New World. Here, we report a severe case, which fulfilled most, if not all, Centers for Disease Control and Prevention (CDC) criteria for HPS, needing non-invasive ventilation and subsequent acute hemodialysis. However, the etiological agent was PUUV, as proved by serological testing, real-time polymerase chain reaction (PCR), and sequencing. Viral antigen was detected by specific anti-PUUV immunostaining, showing, for the first time, greenish intracytoplasmic inclusions in bronchoalveolar lavage (BAL) macrophages. This case definitely confirms that HPS can be encountered during PUUV infections. Interestingly, special findings could render the diagnosis easier, such as greenish homogeneous cytoplasmic inclusions, surrounded by a fine clear halo in BAL macrophages. Therefore, although the diagnosis remains difficult before the onset of renal involvement, the occurrence of severe respiratory failure mimicking community-acquired pneumonia must alert the clinician for possible HPS, especially in endemic areas.

Novel membrane-based targets - Therapeutic potential in gynecological cancers.

Recent advances have been made in the molecular profiling of gynecological tumors. These discoveries have led to the development of targeted therapies that have the potential to disrupt molecular pathways involved in the oncogenesis or tumor progression. In this review, we highlight areas of recent progress in the field of membrane receptor inhibitors in gynecological malignancies and describe the biological rationale underlying the inhibition of these receptors. We will introduce drug immuno-conjugates, and give an update on the biological rationale and the clinical studies involving agents directed against EGFR, HER3, IGFR, MET, FGFR, NOTCH, and TRAIL. We also discuss the challenge facing these new therapies.

The diagnostic value of imaging the patient with dizziness. A Bayesian approach.

BACKGROUND: Imaging studies are routinely used in the evaluation of patients with dizziness. A principal concern of the ordering physician is to rule out a cerebellopontine angle (CPA) mass. The incidence of such masses in patients presenting with dizziness is quite low, however, raising the question of the value of imaging this population. OBJECTIVE: To calculate the probability, using Bayes theorem, that a given patient with dizziness has a CPA mass. DESIGN: Meta-analysis of epidemiological data on CPA masses and of studies reporting the incidence of otologic symptoms in patients with these masses. We also conducted a study of consecutive patients with dizziness to determine the frequency of asymmetric hearing loss in this population. These data were combined in applications of Bayes theorem to calculate disease probabilities. RESULTS: The probability that a patient with dizziness has a CPA mass is 0.0004, indicating that 2500 imaging studies would have to be performed to identify 1 CPA mass. If patients with subjectively normal hearing are investigated (ie, those with isolated dizziness), the probability is 0.000107, indicating that 9307 scans would have to be performed to identify 1 CPA mass. If the search is restricted to those patients with dizziness and asymmetric hearing loss (the patients usually felt to be high risk), the probability is 0.00156, indicating that 638 scans would have to be performed to identify 1 CPA mass. CONCLUSIONS: Even when studying patients with dizziness and asymmetric hearing loss, the probability of identifying a CPA mass is sufficiently low that we do not feel imaging is generally warranted. When faced with a patient with dizziness, we recommend a careful neurologic and otologic examination. If abnormalities are detected on examination that suggest central nervous system disease or invasive otologic disease, imaging should be pursued as appropriate. In cases of acute vertigo, if the patient is at high risk for cerebrovascular disease by virtue of age and additional risk factors, imaging should probably be pursued. For the remainder of patients, if progression of hearing loss is not documented, we do not believe imaging is warranted. Progressive hearing loss with abnormal speech reception thresholds probably warrants a magnetic resonance imaging scan of the internal auditory canals.

Ocular motor function in motor neuron disease.

We studied ocular motor function in 34 patients with motor neuron disease (MND) and in 18 age-matched controls. This included the latency, accuracy, and amplitude-velocity relationships of saccades. We also examined ocular pursuit, the slow phases of optokinetic nystagmus, and the ability to suppress the vestibulo-ocular reflex (VOR) with visual fixation of a head-mounted target. Five of the subjects with MND had pronounced parkinsonian features on neurologic examination. The nonparkinsonian MND subjects had normal ocular motor function for all measures. Most subjects suppressed the VOR completely. The parkinsonian-MND patients had impairment of both saccadic and pursuit eye movements, and one parkinsonian-MND patient with poor pursuit was unable to suppress the VOR. We conclude that ocular motor function is generally spared in MND. The occasional appearance of ocular motor dysfunction probably reflects the incidence of secondary abnormalities such as parkinsonism.

The representation of the spatial vertical in human optokinetic nystagmus.

With our stimulus conditions we were unable to record more than 2-3 beats of OKAN; therefore direct comparison to the data recorded from monkeys is not possible. We did, however, see cross-coupling in OKN. In monkeys, cross-coupling predominates in OKAN, indicating that velocity storage underlies this phenomenon. We consistently saw the axis of response shift towards the spatial vertical. This implies that although OKAN was weak, velocity storage contributed a representation of the spatial vertical to OKN that is dependent on the axis of the head or body with respect to gravity.

Neurosarcoidosis presenting as a tumour of the basal ganglia and brainstem: sequential MRI.

Neurosarcoidosis may spread from the basal leptomeninges via the Virchow-Robin spaces to form intraparenchymal masses. We present a case of sarcoidosis whose first presentation was that of secondary amenorrhoea without other neurological symptoms. Discovery of a mass invading the basal ganglia, hypothalamus, pituitary stalk and midbrain led to a search for systemic involvement. After the diagnosis was proven by mediastinal biopsy, steroids were used effectively to shrink the tumour. Sequential magnetic resonance imaging (MRI) studies demonstrate dramatic reduction in the mass over a six month period. A high index of suspicion for sarcoidosis in intracranial masses, particularly in young adults, is advocated.

Neuro-otologic history.

Throughout medicine, the clinical history is the most important diagnostic tool. This is particularly true in vestibular disease, where pathologic confirmation of the disease process is rare. Many vestibular conditions are more appropriately called syndromes, rather than diseases, because the pathology is either variable or unknown. Knowledge of the anatomy and physiology provides the basis of understanding the control of balance and the symptoms that might occur should something go wrong. History taking should cover the elements of the balance system, including vestibular function, vision, hearing, somatosensation, and motor function.

The familial incidence of benign paroxysmal positional vertigo.

The goal of this investigation was to determine whether there is a familial tendency in the development of benign paroxysmal positional vertigo (BPPV). We hypothesized an increased frequency of BPPV among relatives of patients with the same diagnosis. BPPV is caused by dislodged otoconia from the utricular macula floating in the semicircular canals. At least half of BPPV cases are idiopathic and most pathological associations provide no clue as to the reason otoconia become dislodged. We have noted a number of BPPV patients with family histories of BPPV, suggesting a genetic predisposition to the condition. We surveyed 120 successive BPPV patients and 120 successive dizzy patients without BPPV regarding the frequency of dizziness and BPPV (diagnosed by a physician) among family members. Patients in our group with BPPV were 5 times as likely to have relatives with BPPV compared to the dizzy control group (chi2=5.95, DF=1, p=0.015). We have demonstrated that there is a familial tendency for the occurrence of BPPV. There is nothing in our data that would distinguish between a hereditary or environmental influence in the development of the disease, however.

Suppression of vestibular nystagmus by forced convergence in normal human subjects.

BACKGROUND: It has been suggested that the principal mechanism of nystagmus suppression in the nystagmus blockage syndrome is either adduction of the eye or convergence. We examined this issue using the nystagmus of the vestibulo-ocular reflex (VOR) as a model. METHODS: A motorized, computer-controlled rotary chair was used to produce VOR in darkness, using either sinusoidal or velocity step stimulation. Left eye position was monitored and horizontal slow-phase eye velocity was calculated. Subjects were cued to converge or perform other gaze tasks. RESULTS: Convergence suppressed nystagmus. With sinusoidal stimulation, nystagmus was nearly extinguished in extreme lateroversion, probably due to mechanical tethering of the eye. However, VOR gain suppression of 47% during convergence was observed even when the monitored eye was close to primary position. With velocity step stimulation, nystagmus was nearly extinguished at moderate angles of adduction. CONCLUSIONS: Convergence is sufficient to suppress nystagmus, without vision and without regard to whether the eye is adducted.

Video-oculography as part of the ENG battery.

Recording and quantifying eye movement is the basis of audiologic balance testing. The ability to record and quantify eye movement is a key part of the electronystagmography (ENG) test battery. With computerization, eye movements can be more accurately detected and analysed--testing the limits of the standard recording technique. In response to this, manufacturers are introducing alternative recording protocols. Specifically, infra-red video technology allows an accurate and sophisticated recording and analysis of eye motion in response to balance-related stimuli. The purpose of this technical note is to discuss the limitations of the EOG recording method and discuss the advantages that video-oculography offers.

The effect of lid elevation on the cross-cover test.

OBJECTIVE: To discern the effect of manual lid elevation on muscle balance using the cross-cover test. MATERIALS AND METHODS: One hundred consecutive patients who were orthophoric in all fields of gaze were prospectively studied. A repeat cross-cover test was performed with the eyes looking down and to either side while pulling the lid ipsilateral to the abducting eye up and to either side. The presence and type of any phoria was noted. RESULTS: Eighty-four percent of patients and 76% of eyes developed a phoria with lifting a lid. Vertical phorias developed in 79 patients and 136 eyes, whereas horizontal phorias were seen in 51 patients and 83 eyes. In all but one case, the vertical deviation was a hyperphoria ipsilateral to the elevated lid. Horizontal deviations were esophoric in 63 eyes of 39 subjects. Induced phorias were most commonly symmetric from side to side. CONCLUSIONS: Lifting the lid produces an iatrogenic phoria that mimics a skew or IV nerve paresis. We hypothesize that stretching the lid causes traction on the levator-superior rectus complex, thereby increasing its tone. Although it makes testing more difficult, we recommend that the lids not be manipulated while performing phoria testing.

Management of visual loss after optic nerve sheath decompression in patients with pseudotumor cerebri.

PURPOSE: To determine the appropriate management of patients with pseudotumor cerebri with early, progressive visual loss after optic nerve sheath decompression (ONSD). METHODS: The records of all patients with pseudotumor cerebri who underwent ONSD were reviewed retrospectively. Patients who showed visual loss within 1 month of surgery were studied. RESULTS: Five patients with pseudotumor cerebri, including two with renal failure and hypertension, had visual loss within 1 month of ONSD. The first patient had an abrupt decrease in vision 6 days after ONSD. In this patient, a vessel on the nerve sheath bled into the surgical site. At the time of ONSD, this patient had a visual acuity of 20/20 1 day after surgery. Six days later, visual acuity decreased to 20/200. After high-dose intravenous corticosteroids failed to improve vision, emergency lumboperitoneal shunt resulted in full visual recovery. An apparent infectious optic neuropathy developed in the second patient 3 days after surgery. After 72 hours of intravenous antibiotics, visual acuity improved from 20/600 to 20/15. The other three patients had gradual visual loss after ONSD, which stabilized after lumboperitoneal shunts. CONCLUSIONS: Avoidance of bleeding during ONSD may prevent fibrous occlusion of the surgical site. Patients with no identifiable cause for visual loss after ONSD, who do not respond to intravenous corticosteroids, should be evaluated for emergency lumboperitoneal shunting. Postoperative infectious optic neuropathy should be considered in the differential diagnosis of abrupt visual loss after ONSD.

Orientation of human optokinetic nystagmus to gravity: a model-based approach.

Optokinetic nystagmus (OKN) was induced by having subjects watch a moving display in a binocular, head-fixed apparatus. The display was composed of 3.3 degrees stripes moving at 35 degrees/s for 45 s. It subtended 88 degrees horizontally by 72 degrees vertically of the central visual field and could be oriented to rotate about axes that were upright or tilted 45 degrees or 90 degrees. The head was held upright or was tilted 45 degrees left or right on the body during stimulation. Head-horizontal (yaw axis) and head-vertical (pitch axis) components of OKN were recorded with electro-oculography (EOG). Slow phase velocity vectors were determined and compared with the axis of stimulation and the spatial vertical (gravity axis). With the head upright, the axis of eye rotation during yaw axis OKN was coincident with the stimulus axis and the spatial vertical. With the head tilted, a significant vertical component of eye velocity appeared during yaw axis stimulation. As a result the axis of eye rotation shifted from the stimulus axis toward the spatial vertical. Vertical components developed within 1-2 s of stimulus onset and persisted until the end of stimulation. In the six subjects there was a mean shift of the axis of eye rotation during yaw axis stimulation of approximately 18 degrees with the head tilted 45 degrees on the body. Oblique optokinetic stimulation with the head upright was associated with a mean shift of the axis of eye rotation toward the spatial vertical of 9.2 degrees. When the head was tilted and the same oblique stimulation was given, the axis of eye rotation rotated to the other side of the spatial vertical by 5.4 degrees. This counterrotation of the axis of eye rotation is similar to the "Müller (E) effect," in which the perception of the upright is counterrotated to the opposite side of the spatial vertical when subjects are tilted in darkness. The data were simulated by a model of OKN with a "direct" and "indirect" pathway. It was assumed that the direct visual pathway is oriented in a body, not a spatial frame of reference. Despite the short optokinetic after-nystagmus time constants, strong horizontal to vertical cross-coupling could be produced if the horizontal and vertical time constants were in proper ratio and there were no suppression of nystagmus in directions orthogonal to the stimulus direction. The model demonstrates that the spatial orientation of OKN can be achieved by restructuring the system matrix of velocity storage. We conclude that an important function of velocity storage is to orient slow-phase velocity toward the spatial vertical during movement in a terrestrial environment.

Spatial and temporal analysis by neurons in the representation of the central visual field in the cat's lateral suprasylvian visual cortex.

We studied quantitatively the receptive-field properties of 74 units recorded from the representation of the central visual fields in the cat's lateral suprasylvian (LS) visual cortex. In agreement with previous workers, we found that LS receptive fields tended to be large and to lack discernible spatial structure. They resembled the complex receptive fields of areas 17 and 18 in their general organization. We examined the responses of these neurons to moving optimally oriented sinusoidal gratings that varied in spatial and temporal frequency of drift. Most LS neurons were selective for the spatial frequency of sinusoidal gratings; 7% responded to all spatial frequencies below a cutoff value. In agreement with previous reports, the optimal spatial frequencies for LS neurons covered a wider range than is seen in either area 17 or 18 alone (0.05-1 cycle/deg), but are certainly included in the range covered by both these afferent areas. Individual neurons in LS responded to a range of spatial frequencies broader than is typical for neurons in areas 17 and 18. The effect of varying the drift rate of otherwise optimal gratings was similar in LS to that reported for areas 17 and 18. Most neurons were optimally responsive to drift rates between 0.5 and 4 Hz, and resolved frequencies as high as 10-30 Hz. A few neurons had optima higher than 6 Hz and resolved frequencies in excess of 30 Hz. We conclude that the receptive fields of LS neurons reflect rather closely the properties of their afferents from areas 17 and 18.(ABSTRACT TRUNCATED AT 250 WORDS)

Functions of the nucleus of the optic tract (NOT). II. Control of ocular pursuit.

Ocular pursuit in monkeys, elicited by sinusoidal and triangular (constant velocity) stimuli, was studied before and after lesions of the nucleus of the optic tract (NOT). Before NOT lesions, pursuit gains (eye velocity/target velocity) were close to unity for sinusoidal and constant-velocity stimuli at frequencies up to 1 Hz. In this range, retinal slip was less than 2 degrees. Electrode tracks made to identify the location of NOT caused deficits in ipsilateral pursuit, which later recovered. Small electrolytic lesions of NOT reduced ipsilateral pursuit gains to below 0.5 in all tested conditions. Pursuit was better, however, when the eyes moved from the contralateral side toward the center (centripetal pursuit) than from the center ipsilaterally (centrifugal pursuit), although the eyes remained in close proximity to the target with saccadic tracking. Effects of lesions on ipsilateral pursuit were not permanent, and pursuit gains had generally recovered to 60-80% of baseline after about 2 weeks. One animal had bilateral NOT lesions and lost pursuit for 4 days. Thereafter, it had a centrifugal pursuit deficit that lasted for more than 2 months. Vertical pursuit and visually guided saccades were not affected by the bilateral NOT lesions in this animal. We also compared effects of these and similar NOT lesions on optokinetic nystagmus (OKN) and optokinetic after-nystagmus (OKAN). Correlation of functional deficits with NOT lesions from this and previous studies showed that rostral lesions of NOT in and around the pretectal olivary nucleus, which interrupted cortical input through the brachium of the superior colliculus (BSC), affected both smooth pursuit and OKN. In two animals in which it was tested, NOT lesions that caused a deficit in pursuit also decreased the rapid and slow components of OKN slow-phase velocity and affected OKAN. It was previously shown that slightly more caudal NOT lesions were more effective in altering gain adaptation of the angular vestibulo-ocular reflex (aVOR). The present findings suggest that cortical pathways through rostral NOT play an important role in maintenance of ipsilateral ocular pursuit. Since lesions that affected ocular pursuit had similar effects on ipsilateral OKN, processing for these two functions is probably closely linked in NOT, as it is elsewhere.

Selectivity for orientation and direction of motion of single neurons in cat striate and extrastriate visual cortex.

1. We consider the consequences of the orientation selectivity shown by most cortical neurons for the nature of the signals they can convey about the direction of stimulus movement. On theoretical grounds we distinguish component direction selectivity, in which cells are selective for the direction of movement of oriented components of a complex stimulus, from pattern direction selectivity, or selectivity for the overall direction of movement of a pattern irrespective of the directions of its components. We employed a novel test using grating and plaid targets to distinguish these forms of direction selectivity. 2. We studied the responses of 280 cells from the striate cortex and 107 cells from the lateral suprasylvian cortex (LS) to single sinusoidal gratings to determine their orientation preference and directional selectivity. We tested 73 of these with sinusoidal plaids, composed of two sinusoidal gratings at different orientations, to study the organization of the directional mechanisms within the receptive field. 3. When tested with single gratings, the directional tuning of 277 oriented cells in area 17 had a mean half width of 20.6 degrees, a mode near 13 degrees, and a range of 3.8-58 degrees. Simple cells were slightly more narrowly tuned than complex cells. The selectivity of LS neurons for the direction of moving gratings is not markedly different from that of neurons in area 17. The mean direction half width was 20.7 degrees. 4. We evaluated the directional selectivity of these neurons by comparing responses to stimuli moved in the optimal direction with those elicited by a stimulus moving in the opposite direction. In area 17 about two-thirds of the neurons responded less than half as well to the non-preferred direction as to the preferred direction; two-fifths of the units responded less than one-fifth as well. Complex cells showed a somewhat greater tendency to directional bias than simple cells. LS neurons tended to have stronger directional asymmetries in their response to moving gratings: 83% of LS neurons showed a significant directional asymmetry. 5. Neurons in both areas responded independently to each component of the plaid. Thus cells giving single-lobed directional-tuning curves to gratings showed bilobed plaid tuning curves, with each lobe corresponding to movement in an effective direction by one of the two component gratings within the plaid. The two best directions for the plaids were those at which one or other single grating would have produced an optimal response when presented alone.(ABSTRACT TRUNCATED AT 400 WORDS)