Rocuronium bromide: clinical application of single-dose pharmacokinetic models to continuous infusion

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Pharmacokinetic and pharmacodynamics of intravenous dexmedetomidine in morbidly obese patients undergoing laparoscopic surgery

Abstract

Background

This study was designed to investigate the pharmacokinetics and pharmacodynamics of dexmedetomidine in morbidly obese patients undergoing laparoscopic surgery.

Methods

Morbidly obese (body mass index ≥40 kg/m²) and normal weight patients scheduled for elective laparoscopic surgery were included (n = 8, each group). After baseline hemodynamic measurement, dexmedetomidine 1 μg/kg was administered over 10 min. General anesthesia was induced with propofol 1.5 mg/kg and fentanyl 4 μg/kg 20 min after completion of dexmedetomidine infusion; the lungs were mechanically ventilated after tracheal intubation. The pharmacokinetics of dexmedetomidine was analyzed by a noncompartment model. Hemodynamic data and peripheral oxygen saturation (SpO₂) were measured up to 30 min after starting dexmedetomidine infusion. Sedation level was measured with the Observer's Assessment of Alertness/Sedation (OAA/S) scale.

Results

Peak plasma concentration, area under the curve to infinity, elimination half-life, and apparent volume of distribution were significantly larger in morbidly obese than in normal weight patients (3.75 ± 0.56 vs. 2.54 ± 0.32 µg/l, P < 0.001; 2174 ± 335 vs. 1594 ± 251 ng h/l, P < 0.001; 225 ± 55 vs. 158 ± 53 min, P = 0.02; 310 ± 63 vs. 164 ± 41 l, P < 0.001, respectively). Although clearance was also higher in obese patients than in normal body weight patients (58.6 ± 10.7 vs. 44.9 ± 9.0 l/h, P = 0.02), it was lower in obese patients than in normal body weight patients after normalization to total body weight (0.47 ± 0.07 vs. 0.64 ± 0.09 l/h/kg, P < 0.001). There were no differences in systolic or diastolic blood pressure or heart rate between the two groups within the 30 min. Sedation level was deeper and SpO₂ was lower in morbidly obese than in normal weight patients. More patients in the morbidly obese patient group experienced deeper sedation after the start of the dexmedetomidine infusion (P < 0.05).

Conclusion

The pharmacokinetics and pharmacodynamics of dexmedetomidine are significantly different in morbidly obese patients compared with normal weight patients. Level of sedation was significantly deeper, and oxygen saturation was significantly lower, in morbidly obese than in normal weight patients, probably resulting from higher plasma concentration after infusion of 1.0 µg/kg.

Clinical trial number, registry URL

ClinicalTrials.gov (NCT01864187), http://ift.tt/2vWvn43.

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Der moderne Dreiklang der Onkologie

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Adoptiver Immuntransfer und CAR-T-Zellen bei malignen Erkrankungen

Zusammenfassung

Hintergrund

Die adoptive Zelltherapie (ACT) mit tumorinfiltrierenden Lymphozyten (TIL) ist eine wirkungsvolle Form der Krebsimmuntherapie. Ein alternativer hochwirksamer Ansatz ist die ACT mit gentechnisch veränderten T‑Zellen, die mit tumorspezifischen T‑Zell-Rezeptoren (TCR) oder chimären Antigenrezeptoren (CAR) ausgestattet sind. Im Gegensatz zu TCR erkennen CAR MHC-unabhängig ein breites Spektrum an extrazellulären Tumorantigenen.

Ziel

Dieser Übersichtsartikel stellt die aktuelle klinische Studienlage zur ACT mit einem besonderen Fokus auf die CAR-T-Zell-Therapie dar.

Ergebnisse

Die ACT mit TIL zeigt in klinischen Studien objektive Ansprechraten von bis zu 50 % bei Patienten mit einem fortgeschrittenen metastasierten malignen Melanom (mmM). 10–22 % dieser Patienten erreichen eine anhaltende komplette Remission. Trotz vielversprechender klinischer Daten ist die Herstellung einer therapeutischen Anzahl von tumorreaktiven TIL bis heute eine herausfordernde Hürde dieser Therapiestrategie. Die ACT mit TCR-modifizierten T‑Zellen führt bei Patienten mit mmM, Synovialsarkom und multiplem Myelom zu signifikanten klinischen Ansprechraten. Sie ist allerdings mit schweren Nebenwirkungen aufgrund von Kreuz- oder On-target-off-tumor-Reaktivitäten assoziiert. Die ACT mit CAR-modifizierten T‑Zellen zeigt in klinischen Studien beeindruckende Remissionsraten von bis zu 90 %, die hauptsächlich bei B‑Zell-Neoplasien erzielt werden. Bei soliden Tumoren ist dieser Ansatz bislang weniger erfolgreich. Auch die CAR-T-Zell-Therapie kann mit schweren Nebenwirkungen wie dem Zytokinfreisetzungssyndrom oder Neurotoxizität einhergehen. Die Verbesserung der Sicherheit und Effektivität von CAR-T-Zellen ist eine wesentliche wissenschaftliche Zielsetzung in der Weiterentwicklung dieser Therapieform.

http://ift.tt/2ijjiCN

Adjuvant chemoradiation does not improve survival in elderly patients with high-risk resected head and neck cancer

Objectives/Hypothesis

Randomized trials have demonstrated that adjuvant chemoradiotherapy (CRT) confers an overall survival (OS) benefit over adjuvant radiation therapy (RT) alone in patients with resected head and neck squamous cell carcinoma (HNSCC) with adverse pathologic features (positive surgical margins [SM+] and/or extracapsular extension [ECE]). Whether this OS benefit exists in an elderly population remains unknown.

Study Design

Retrospective database study.

Methods

Using the National Cancer Database, we identified 1,686 elderly patients (age ≥70 years) with resected HNSCC with SM+ and/or ECE, who received adjuvant CRT (491 patients, 29%) or adjuvant RT alone (1,195 patients, 71%) between 1998 and 2011. Three-year survival rates were estimated using the Kaplan-Meier method both before and after propensity score matching (PSM). Crude and adjusted hazard ratios (HR) with 95% confidence intervals (CI) were computed using Cox regression modeling.

Results

Median follow-up was 23.5 and 42.8 months for all and surviving patients, respectively. Three-year OS was 50.7% and 44.4% among patients receiving adjuvant CRT and RT alone, respectively (P = .002). On multivariate analysis, there was no significant improvement in OS with adjuvant CRT relative to adjuvant RT alone (HR: 0.88, 95% CI: 0.73-1.06). Similarly, a PSM cohort showed no significant difference in the 3-year OS for patients receiving adjuvant CRT versus adjuvant RT alone (48.8% and 50.9%, respectively; P = .839).

Conclusions

Although the addition of chemotherapy to adjuvant RT has been proven effective in randomized trials of patients with resected HNSCC with SM+ or ECE, it may be less efficacious in an elderly patient population treated outside of a controlled trial setting.

Level of Evidence

2c Laryngoscope, 2017

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Benefits of initial CT staging before sentinel lymph node biopsy in patients with head and neck cutaneous melanoma

Abstract

Background

The value of CT at the time of diagnosis for patients with cutaneous head and neck melanoma clinically asymptomatic for metastatic disease is unclear.

Methods

A retrospective medical chart review was performed on 198 consecutive patients identified with primary T1b-T4b head and neck melanoma clinically asymptomatic for metastatic disease referred for sentinel lymph node biopsy procedures between 2004 and 2014.

Results

Initial CTs identified clinically occult melanoma metastases in 8.1% and advanced second primary tumors in 3.5% of patients. CT findings were false-negative in 1% and false-positive in 6% of patients. Overall survival (OS) for patients with true-positive CT findings was lower than for the other patients (P < .001).

Conclusion

CT imaging when staging patients with head and neck melanoma seems to identify more metastases than has been reported for melanoma at other sites. Preoperative CTs decreased the number of sentinel lymph node biopsy (SLNBs), thus avoiding the stress and cost of this surgical procedure in 12% of patients.

http://ift.tt/2wvaqPY

Long-term outcome of 18F-fluorodeoxyglucose-positron emission tomography-guided dose painting for head and neck cancer: Matched case-control study

Abstract

Background

The purpose of this study was to report the long-term outcome of ¹⁸F-fluorodeoxyglucose-positron emission tomography (¹⁸F-FDG-PET)-guided dose painting for head and neck cancer in comparison to conventional intensity-modulated radiotherapy (IMRT) in a matched case-control study.

Methods

Seventy-two patients with nonmetastatic head and neck cancer treated with dose painting were compared with 72 control patients matched on tumor site and T classification. Either ¹⁸F-FDG-PET-guided dose painting by contour (DPBC) or voxel intensity-based dose painting by number (DPBN) was performed; control patients underwent standard IMRT. A total median dose to the dose-painted target was 70.2-85.9 Gy/30-32 fractions versus 69.1 Gy/32 fractions with conventional IMRT. In 31 patients, dose painting was adapted to per-treatment changes in the tumor and organs-at-risk (OAR).

Results

Median follow-up in living dose-painting and control patients was 87.7 months (range 56.1-119.3) and 64.8 months (range 46.3-83.4), respectively. Five-year local control rates in the dose-painting patients were 82.3% against 73.6% in the control (P = .36); in patients treated to normalized isoeffective doses >91 Gy (NID2Gy) local control reached 85.7% at 5 years against 73.6% in the control group (P =.39). There was no difference in regional (P = .82) and distant control (P = .78). Five-year overall and disease-specific survival rates were 36.3% versus 38.1% (P = .50) and 56.5% versus 51.7% (P = .72), respectively. A half of the dose-painting patients developed acute grade ≥3 dysphagia (P = .004). Late grade 4 mucosal ulcers at the site of dose escalation in 9 of 72 patients was the most common severe toxicity with dose painting versus 3 of 72 patients with conventional IMRT (P = .11). Patients in the dose-painting group had increased rates of acute and late dysphagia (P = .004 and P = .005).

Conclusion

Dose-painting strategies can be used to increase dose to specific tumor subvolumes. Five-year local, regional, and distant control rates are comparable with patients treated with conventional IMRT. Volume and intensity of dose escalation should be further tailored, given the possible increase in severe acute and chronic toxicity. Adapting treatment and decreasing dose to the swallowing structures might contribute to lower toxicity rates when applied in smaller tumor volumes. Whether adaptive DPBN can significantly improve outcomes is currently being investigated in a novel clinical trial.

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