scholarly journals Neoplastic Meningitis: How MRI and CSF Cytology Are Influenced by CSF Cell Count and Tumor Type

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
P. Prömmel ◽  
S. Pilgram-Pastor ◽  
H. Sitter ◽  
J.-H. Buhk ◽  
H. Strik
Keyword(s):  
Cell Count ◽  
Solid Tumors ◽  
Neoplastic Meningitis ◽  
Leptomeningeal Disease ◽  
Neoplastic Disease ◽  
Tumor Type ◽  
Csf Cytology ◽  
Hematological Neoplasms ◽  
Cell Counts ◽  
Solid Malignancies

Background. Although CSF cytology and MRI are standard methods to diagnose neoplastic meningitis (NM), this complication of neoplastic disease remains difficult to detect. We therefore reevaluated the sensitivity of gadolinium (GD)-enhanced MRI and cerebrospinal-fluid (CSF)-cytology and the relevance of tumor type and CSF cell count.Methods. We retrospectively identified 111 cases of NM diagnosed in our CSF laboratory since 1990 with complete documentation of both MRI and CSF cytology. 37 had haematological and 74 solid neoplasms. CSF cell counts were increased in 74 and normal in 37 patients.Results. In hematological neoplasms, MRI was positive in 49% and CSF cytology in 97%. In solid tumors, the sensitivity of MRI was 80% and of cytology 78%. With normal CSF cell counts, MRI was positive in 59% (50% hematological, 72% solid malignancies) and CSF cytology in 76% (92% in hematological, 68% in solid neoplasms). In cases of elevated cell counts, the sensitivity of MRI was 72% (50% for hematological, 83% for solid malignancies) and of CSF cytology 91% (100% for haematological and 85% for solid neoplasms). 91% of cytologically positive cases were diagnosed at first and another 7% at second lumbar puncture. Routine protein analyses had a low sensitivity in detecting NM.Conclusions. The high overall sensitivity of MRI was only confirmed for NM from solid tumors and for elevated CSF cell counts. With normal cell counts and haematological neoplasms, CSF-cytology was superior to MRI. None of the analysed routine CSF proteins had an acceptable sensitivity and specificity in detecting leptomeningeal disease.

Neoplastic meningitis—Is MRI as sensitive as CSF cytology?

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9566-9566
Author(s):  
H. M. Strik ◽  
P. Proemmel ◽  
S. Pilgram-Pastor ◽  
J. H. Buhk
Keyword(s):  
High Sensitivity ◽  
Neoplastic Meningitis ◽  
Solid Tumours ◽  
Lower Sensitivity ◽  
Neoplastic Disease ◽  
Haematological Malignancies ◽  
Csf Cytology ◽  
Cell Counts ◽  
Solid Malignancies ◽  
Haematological Neoplasms

9566 Background: Although CSF cytology and MRI are standard methods for the diagnosis of neoplastic meningitis (NM), this complication of neoplastic disease still remains to be difficult to detect in some cases. We therefore re-evaluated the sensitivity of gadolinium(GD)-enhanced MRI and cerebrospinal-fluid (CSF)-cytology for the diagnosis of LM differentially for solid and haematological malignancies and for normal or elevated cell counts. Methods: We identified retrospectively 101 cases of NM diagnosed in our CSF laboratory since 1990 with complete data of both MRI and CSF-cytology. 34 had haematological, 67 solid neoplasms. CSF-cell counts were increased in 63 and normal in 35 patients. Results: For haematological neoplasms, MRI was positive in 53%. CSF cytology was positive in 97%. In solid tumours, we found MRI-sensitivity of 0.81 and cytological sensitivity of 0.76. With normal CSF-cell-counts, MRI was positive in 63%, (0.57 haematological, 0.75 solid malignancies), CSF-cytology in 78%, (0.9 in haematological, 0,64 in solid neoplasms). In cases of increased cell-counts, MRI-sensitivity was 0.75 (0.52 for haematological, 0.87 for solid malignancies), and sensitivity of CSF-cytology was 0.89 (1.0 for haematological and 0.82 for solid neoplasms). 23 patients were treated with intrathecal MTX or Ara-C, 16 patients with liposomal Ara-C. 62 patients were not treated intrathecally. Conclusions: We confirmed here the high overall sensitivity of MRI for the diagnosis of neoplastic meningitis. The best sensitivity, however, was seen in solid tumours and elevated cell counts. In haematological malignancies, a markedly lower sensitivity of MRI was seen. Of note, we consider the very high sensitivity of cytology in haematological malignancies to be artificial due to methodological reasons of this retrospective study. We conclude that MRI is a very sensitive method to detect NM especially in solid tumours and elevated cell counts. With normal cell counts and haematological neoplasms, CSF-cytology remains to be superior to radiological methods. [Table: see text]

The predictive value of protein, glucose, and lactate for a diagnosis of neoplastic meningitis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e12005-e12005
Author(s):  
Jonathan McClain ◽  
Michael J. Glantz
Keyword(s):  
Solid Tumors ◽  
Roc Curves ◽  
Neoplastic Meningitis ◽  
Screening Tools ◽  
Csf Cytology ◽  
Likelihood Ratios ◽  
Positive Cytology ◽  
At Risk Populations ◽  
Cancer Types ◽  
Sensitivity Specificity

e12005 Background: Neoplastic Meningitis (NM) is a complication of many common cancers that occurs with an incidence as high as 15% in some cancer types. Diagnosis remains elusive with poor screening tools and insensitive diagnostic options. Methods: A retrospective analysis of 341 consecutive patients with suspected NM was undertaken. Clinical presentation, demographic, cytologic and MRI data were recorded. Using cytology as the diagnostic gold standard, sensitivity, specificity, ROC curves and likelihood ratios were calculated. Results: 210 patients met inclusion criteria, 87 with primary brain tumors (PBT), 72 with non-CNS solid tumors, and 44 with lymphomas. 111 patients were male; 123 (58.6%) ultimately had a positive cytology. Only 59% of patients with positive cytology presented with symptoms concerning for NM. 32.9% of patients with PBTs and positive CSF cytology exhibited neurologic symptoms suggestive of NM. Patients with non-CNS solid tumors and positive CSF cytology presented with symptoms concerning for NM 80% of the time. Patients with cytology-positive, MRI-positive and symptom-positive NM had very different survivals. Potentially informative CSF values are in table below. Conclusions: A definitive diagnosis for patients with suspected NM remains elusive without a positive cytology, but some clinical, radiographic, and CSF findings are useful for raising diagnostic concern, and for screening in at-risk populations. Symptom-positive or MRI-positive NM may represent different diseases than cytology-positive NM. [Table: see text]

Intravenous administration of ALKS 4230 as monotherapy and in combination with pembrolizumab in a phase I study of patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2649-TPS2649
Author(s):  
Ulka N. Vaishampayan ◽  
Mayer N. Fishman ◽  
Daniel C. Cho ◽  
Christopher J. Hoimes ◽  
Vamsidhar Velcheti ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Solid Tumors ◽  
High Dose ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Part C ◽  
Cell Counts ◽  
Liver And Kidney ◽  
Ecog Ps

TPS2649 Background: ALKS 4230 is a fusion protein of circularly permuted IL-2 and IL-2 Receptor (IL-2R) α designed to selectively bind the intermediate-affinity (ia) IL-2R, comprised of IL-2Rβ and γc, for activation of CD8+ T cells and NK cells, which drive antitumor immune responses. In contrast, unmodified IL-2 activates high-affinity (ha) IL-2R, driving the expansion of immunosuppressive CD4+ regulatory T cells (Tregs) at concentrations below those that activate iaIL-2R expressing cells. Binding of IL-2 to haIL-2R on endothelial cells may contribute to capillary leak syndrome seen with high-dose IL-2. Thus, selective activation of the iaIL-2R by ALKS 4230 has the potential to enhance tumor killing and improve tolerability. ALKS 4230 has previously been shown to improve antitumor activity relative to IL-2 in murine models. In this clinical study, ALKS 4230 will be assessed as monotherapy and in combination with anti-PD-1 therapy. Methods: ALKS 4230 is being studied in adults with advanced solid tumors in a phase I first-in-human trial designed primarily to assess the safety of ALKS 4230 alone and with pembrolizumab. The study will also determine a monotherapy recommended phase 2 dose (RP2D) and characterize pharmacokinetics, pharmacodynamics (PD), immunogenicity, and evidence of anti-tumor activity. It will be conducted in 3 parts: monotherapy dose escalation (Part A), monotherapy dose expansion at the RP2D (Part B), and combination therapy with pembrolizumab (Part C). ALKS 4230 is administered as a 30 minute IV infusion once daily for five days in each 14 or 21 day cycle. Part A is inpatient. Eligibility requires ECOG PS 0-1 and adequate bone marrow, liver and kidney function. Part B will enroll 21 patients each in renal cell carcinoma and melanoma cohorts. Part C will enroll up to 79 patients total into 3 cohorts based on tumor type and prior anti-PD-1 therapy; a 4th cohort will enroll patients from Part A or B who received at least 4 cycles of ALKS 4230 or experienced disease progression on monotherapy. The primary PD endpoint is change from baseline in CD8+ T, NK, and Treg cell counts. Inflammatory cytokine levels will also be measured. Parts A and C are currently enrolling. Clinical trial information: NCT02799095.

scholarly journals 2568 Pembrolizumab for patients with leptomeningeal disease from advanced solid tumors

2018 ◽  
Vol 2 (S1) ◽  
pp. 44-45
Author(s):  
Jarushka Naidoo ◽  
Chen Hu ◽  
Karisa Schrek ◽  
Roisin Connolly ◽  
Cesar Santa-Maria ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Solid Tumors ◽  
Progression Free Survival ◽  
Small Cell ◽  
Leptomeningeal Disease ◽  
Advanced Solid Tumors ◽  
Csf Cytology ◽  
Small Cell Lung ◽  
Free Survival ◽  
Enhanced Mri

OBJECTIVES/SPECIFIC AIMS: Pembrolizumab is an anti-PD-1 immune checkpoint antibody that has demonstrated promising anti-tumor activity in patients with solid tumor malignancies, including patients with brain metastases from malignant melanoma and non-small cell lung cancer. Leptomeningeal disease (LMD) is a rare form of malignant spread to the central nervous system (CNS), that occurs in 2%–10% of patients with solid tumors, most commonly in breast cancer and non-small cell lung cancer. We propose an open-label phase II study of pembrolizumab in patients with LMD from advanced solid tumors (NCT03091478). This study aims to determine if pembrolizumab therapy can lead to a radiologic, cytologic or clinical response in the CNS, in patients with LMD. METHODS/STUDY POPULATION: Patients with pathologically confirmed advanced solid tumors, and either radiologic or cytologic evidence of LMD, will be identified at a single institution. Radiologic LMD will be defined as a >4 mm area of measurable LMD on gadolinium-enhanced MRI brain/total-spine; and cytologic LMD will be defined as the presence of malignant cells on CSF cytology. Patients will be excluded if they have: active autoimmune conditions that require immunosuppression, received radiation therapy to the only area of measurable LMD within 3 months of study enrollment, have an ECOG performance status <1. Once enrolled, patients will receive pembrolizumab 200 mg intravenously every 3-weeks, until disease progression or unacceptable toxicity. Patients will have CSF sample sampling, blood draws, radiologic imaging of the body (CT), brain/total-spine (gadolinium-enhanced MRI) pre-treatment, after 2 and after 4 cycles of therapy, for response assessment and correlative studies. The primary endpoint of the study is CNS response assessed at 12 weeks/after 4 cycles of pembrolizumab, defined either as radiologic response (reduction in size of LMD on gadolinium-enhanced MRI) and/or cytologic response (conversion of positive to negative CSF cytology on 2 consecutive samples) and/or clinical response. Secondary endpoints will include progression-free survival, overall survival, and safety. To explore the mechanisms by which pembrolizumab may affect LMD, we will assess dynamic changes in genomic and immunologic markers in the CSF and serum pre and post pembrolizumab using next-generation sequencing and multi-color flow cytometry, respectively. RESULTS/ANTICIPATED RESULTS: We will aim to accrue a total of 20 patients, allowing for a 10% drop-out rate, the final sample size will include 18 patients who have received at least 1 dose of pembrolizumab. CNS-response at 12 weeks will be assessed radiologically +/− cytologically, and the proportion of patients with CNS response and associated 95% confidence interval with be reported. CNS-progression-free survival and overall survival will be assessed using the Kaplan-Meier method. Cause of death will be recorded. Safety will be assessed as detailed above, and monitored as per an institutional Data Safety and Monitoring Plan. Exploratory endpoints will include genomic testing of tumor cells and cell-free DNA in CSF and serum, and immunologic studies of immune cells in CSF and serum at pre-defined timepoints. These data will be presented descriptively. We conservatively estimate that we will accrue 1 patient per month at our institution. Study duration will be approximately 24 months, allowing 18 months for accrual and 6 months for follow-up and data analysis. DISCUSSION/SIGNIFICANCE OF IMPACT: There are no currently FDA-approved therapies for patients with LMD from solid tumors. Anti-PD-1 immunotherapy is a promising class of agents, with known efficacy in patients with CNS metastatic disease, across tumor types. This study seeks to identify whether pembrolizumab may lead to CNS responses in patients with LMD. Additionally, genomic and immunologic analyses in CSF and blood pre and post-pembrolizumab may identify mechanisms by which immunotherapy affects the CNS in patients with LMD.

A quantitative evaluation of some factors affecting the non-fatty solids of cow's milk

1960 ◽  
Vol 27 (1) ◽  
pp. 19-32 ◽  
Author(s):  
W. H. Alexander ◽  
F. B. Leech
Keyword(s):  
Cell Count ◽  
Residual Effect ◽  
Clinical Mastitis ◽  
High Cell ◽  
Factors Affecting ◽  
Stage Of Lactation ◽  
Cell Counts ◽  
Satisfactory Analysis ◽  
The Difference ◽  
Image Position

SummaryTen farms in the county of Durham took part in a field study of the effects of feeding and of udder disease on the level of non-fatty solids (s.n.f.) in milk. Statistical analysis of the resulting data showed that age, pregnancy, season of the year, and total cell count affected the percentage of s.n.f. and that these effects were additive and independent of each other. No effect associated with nutritional changes could be demonstrated.The principal effects of the factors, each one freed from effects of other factors, were as follows:Herds in which s.n.f. had been consistently low over a period of years were compared with herds in which s.n.f. had been satisfactory. Analysis of the data showed that about 70% of the difference in s.n.f. between these groups could be accounted for by differences in age of cow, stage of lactation, cell count and breed.There was some evidence of a residual effect following clinical mastitis that could not be accounted for by residual high cell counts.The within-cow regression of s.n.f. on log cell count calculated from the Durham data and from van Rensburg's data was on both occasions negative.The implications of these findings are discussed, particularly in relation to advisory work.

scholarly journals CAR-NK Cells in the Treatment of Solid Tumors

2021 ◽  
Vol 22 (11) ◽  
pp. 5899
Author(s):  
Ewa Wrona ◽  
Maciej Borowiec ◽  
Piotr Potemski
Keyword(s):  
Nk Cells ◽  
Solid Tumors ◽  
Hematological Malignancies ◽  
Toxicity Profile ◽  
Multiple Sources ◽  
Eligibility Criteria ◽  
Hematological Neoplasms ◽  
Current State ◽  
Car T ◽  
The Cost

CAR-T (chimeric antigen receptor T) cells have emerged as a milestone in the treatment of patients with refractory B-cell neoplasms. However, despite having unprecedented efficacy against hematological malignancies, the treatment is far from flawless. Its greatest drawbacks arise from a challenging and expensive production process, strict patient eligibility criteria and serious toxicity profile. One possible solution, supported by robust research, is the replacement of T lymphocytes with NK cells for CAR expression. NK cells seem to be an attractive vehicle for CAR expression as they can be derived from multiple sources and safely infused regardless of donor–patient matching, which greatly reduces the cost of the treatment. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have activity against non-hematological neoplasms. Here, we present a thorough overview of the current state of knowledge regarding the use of CAR-NK cells in treating various solid tumors.

scholarly journals Extrapolation of pharmacokinetics and pharmacodynamics of sunitinib in children with gastrointestinal stromal tumors

2021 ◽  
Author(s):  
Reza Khosravan ◽  
Steven G. DuBois ◽  
Katherine Janeway ◽  
Erjian Wang
Keyword(s):  
Body Size ◽  
Solid Tumors ◽  
Gastrointestinal Stromal Tumors ◽  
Drug Exposure ◽  
Tumor Type ◽  
Plasma Drug ◽  
Safety And Efficacy ◽  
Stromal Tumors ◽  
Mixed Effects Modeling ◽  
Starting Dose

Abstract Purpose The starting dose of sunitinib in children with gastrointestinal stromal tumors (GIST) was extrapolated based on data in adults with GIST or solid tumors and children with solid tumors. Methods Integrated population pharmacokinetics (PK), PK/pharmacodynamics (PD), and exposure–response analyses using nonlinear mixed-effects modeling approaches were performed to extrapolate PK and PD of sunitinib in children with GIST at projected dose(s) with plasma drug exposures comparable to 50-mg/day in adults with GIST. The analysis datasets included PK/PD data in adults with GIST and adults and children with solid tumors. The effect of covariates on PK and safety/efficacy endpoints were explored. Results Two-compartment models with lag time were successfully used to describe the PK of sunitinib and its active metabolite SU012662. PK/PD models were successfully built to describe key continuous safety and efficacy endpoints. The effect of age on sunitinib apparent clearance (CL/F) and body surface area on SU012662 CL/F was statistically significant (P ≤ 0.001): children who were younger or of smaller body size had lower CL/F; however, age and body size did not appear to negatively affect safety or efficacy response to plasma drug exposure. Conclusion Based on PK, safety, and efficacy trial simulations, a sunitinib starting dose of ~ 25 mg/m2/day was predicted to provide comparable plasma drug exposures in children with GIST as in adults with GIST treated with 50 mg/day. However, in the absence of a tumor type effect of sunitinib on CL/F in children, the projected equivalent dose for this population would be ~ 20 mg/m2/day.

scholarly journals Frequency of Cytomegalovirus Viral Load in Iranian Human Immunodeficiency Virus-1-Infected Patients with CD4+ Counts <100 Cells/mm3

Intervirology ◽  
2021 ◽  
pp. 1-5
Author(s):  
Mohammad Reza Jabbari ◽  
Hoorieh Soleimanjahi ◽  
Somayeh Shatizadeh Malekshahi ◽  
Mohammad Gholami ◽  
Leila Sadeghi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Cell Count ◽  
Previous History ◽  
Cd4 Count ◽  
Cd4 Cell Count ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Cd4 Cell ◽  
Hiv 1

<b><i>Objectives:</i></b> The aim of present work was to assess cytomegalovirus (CMV) viremia in Iranian human immunodeficiency virus (HIV)-1-infected patients with a CD4+ count &#x3c;100 cells/mm<sup>3</sup> and to explore whether CMV DNA loads correlate with CD4+ cell counts or associated retinitis. <b><i>Methods:</i></b> This study was conducted at the AIDS research center in Iran on HIV-1-infected patients with CD4+ count &#x3c;100 cells/mm<sup>3</sup>, antiretroviral therapy-naive, aged ≥18 years with no previous history of CMV end-organ disease (CMV-EOD). <b><i>Results:</i></b> Thirty-nine of 82 patients (47.56%) had detectable CMV viral load ranging from 66 to 485,500 IU/mL. CMV viral load in patients with retinitis ranges from 352 to 2,720 IU/mL, and it was undetectable in 2 patients. No significant associations between CMV viremia and CD4+ cell count was found (<i>p</i> value = 0.31), whereas significant association of CMV viremia in HIV-infected patients with retinitis was found (<i>p</i> &#x3c; 0.02). <b><i>Conclusions:</i></b> We estimated the frequency of CMV viral load infection in Iranian HIV-1-infected patients with a CD4+ cell count &#x3c;100 mm<sup>3</sup>/mL in the largest national referral center for HIV-1 infection in Iran. Further research is required on the relevance of CMV viral load in diagnostic and prognostic value of CMV-EOD.

scholarly journals CD19 Cell Count at Baseline Predicts B Cell Repopulation at 6 and 12 Months in Multiple Sclerosis Patients Treated with Ocrelizumab

2021 ◽  
Vol 18 (15) ◽  
pp. 8163
Author(s):  
Gianmarco Abbadessa ◽  
Giuseppina Miele ◽  
Paola Cavalla ◽  
Paola Valentino ◽  
Girolama Alessandra Marfia ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Count ◽  
Considerable Proportion ◽  
Cell Counts ◽  
Time Scheduling ◽  
Magnetic Resonance Imaging Mri ◽  
Multiple Sclerosis Patients ◽  
Kinetics Of ◽  
Cell Repopulation

Background: The kinetics of B cell repopulation in MS patients treated with Ocrelizumab is highly variable, suggesting that a fixed dosage and time scheduling might be not optimal. We aimed to investigate whether B cell repopulation kinetics influences clinical and radiological outcomes and whether circulating immune asset at baseline affects B cell repopulation kinetics. Methods: 218 MS patients treated with Ocrelizumab were included. Every six months we collected data on clinical and magnetic resonance imaging (MRI) activity and lymphocyte subsets at baseline. According to B cell counts at six and twelve months, we identified two groups of patients, those with fast repopulation rate (FR) and those with slow repopulation rate (SR). Results: A significant reduction in clinical and radiological activity was found. One hundred fifty-five patients had complete data and received at least three treatment cycles (twelve-month follow-up). After six months, the FR patients were 41/155 (26.45%) and 10/41 (29.27%) remained non-depleted after twelve months. FR patients showed a significantly higher percentage of active MRI scan at twelve months (17.39% vs. 2.53%; p = 0,008). Furthermore, FR patients had a higher baseline B cell count compared to patients with an SR (p = 0.02 and p = 0.002, at the six- and twelve-month follow-ups, respectively). Conclusion: A considerable proportion of MS patients did not achieve a complete CD19 cell depletion and these patients had a higher baseline CD19 cell count. These findings, together with the higher MRI activity found in FR patients, suggest that the Ocrelizumab dosage could be tailored depending on CD19 cell counts at baseline in order to achieve complete disease control in all patients.

scholarly journals Lymphocyte subset analysis to evaluate the prognosis of HIV-negative patients with pneumocystis pneumonia

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fan Jin ◽  
Jing Xie ◽  
Huan-ling Wang
Keyword(s):  
T Cell ◽  
Cell Count ◽  
Lymphocyte Subsets ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Pneumocystis Pneumonia ◽  
Lymphocyte Subset ◽  
Cd4 T Cell ◽  
Cell Counts ◽  
Hiv Negative

Abstract Objectives We analysed the peripheral blood lymphocyte subsets of human immunodeficiency virus (HIV)-negative patients infected with pneumocystis pneumonia (PCP) to determine the relationships between the levels of different types of lymphocytes and the prognosis of patients. Methods We retrospectively reviewed HIV-negative patients with PCP diagnosed in our department. All the eligible patients underwent lymphocyte subset analysis on admission. Results A total of 88 HIV-negative PCP patients were enrolled in the study. In univariate analyses, low CD4+ T cell count, low CD8+ T cell count, and low natural killer cell (NK cell) count were associated with higher in-hospital mortality. CD8+ T cell count ≤300/μL was found to be an independent risk factor for poor prognosis in multivariate logistical regression analysis (p = 0.015, OR = 11.526, 95% CI = 1.597–83.158). Although low CD4+ T cell and NK cell counts were not independent risk factors, the mortality rates of PCP patients decreased as the CD4+ T cell and NK cell counts increased. Conclusion The immune process of Pneumocystis jirovecii infection is complex but important. We propose that lymphocyte subsets could give clinicians a better understanding of patient immune status, helping with the early identification of potentially lethal infections and treatment decision making, such as adjusting the immunosuppressive regimen and choosing an appropriate patient monitoring level.

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