Second primary malignancies in multiple myeloma: an overview and IMWG consensus.

Background: Therapeutic advancements following the introduction of autologous stem cell transplantation and 'novel' agents have significantly improved clinical outcomes for patients with multiple myeloma (MM). Increased life expectancy, however, has led to renewed concerns about the long-term risk of second primary malignancies (SPMs). This review outlines the most up-to-date knowledge of possible host-, disease-, and treatment-related risk factors for the development of SPMs in patients with MM, and provides practical recommendations to assist physicians. Design: A Panel of International Myeloma Working Group members reviewed the most relevant data published in the literature as full papers, or presented at meetings of the American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, or International Myeloma Workshops, up to June 2016. Here, we present the recommendations of the Panel, based on this literature review. Results: Overall, the risk of SPMs in MM is low, multifactorial, and partially related to the length of patients' survival and MM intrinsic susceptibility. Studies suggest a significantly increased incidence of SPMs when lenalidomide is administered either following, or concurrently with, oral melphalan. Increased SPM incidence has also been reported with lenalidomide maintenance following high-dose melphalan, albeit to a lesser degree. In both cases, the risk of death from MM was significantly higher than the risk of death from SPMs, with lenalidomide possibly providing a survival benefit. No increase in SPM incidence was reported with lenalidomide plus dexamethasone (without melphalan), or with bortezomib plus oral melphalan, dexamethasone, or thalidomide. Conclusion: In general, the risk of SPMs should not alter the current therapeutic decision-making process in MM. However, regimens such as lenalidomide plus dexamethasone should be preferred to prolonged exposure to lenalidomide plus oral melphalan. SPM risk should be carefully discussed with the patient in the context of benefits and risks of different treatment options.

Age and sex affect quantitative genetic parameters for dominance rank and aggression in free-living greylag geese.

Knowledge of the genetic and environmental influences on a character is pivotal for understanding evolutionary changes in quantitative traits in natural populations. Dominance and aggression are ubiquitous traits that are selectively advantageous in many animal societies and have the potential to impact the evolutionary trajectory of animal populations. Here we provide age- and sex-specific estimates of additive genetic and environmental components of variance for dominance rank and aggression rate in a free-living, human-habituated bird population subject to natural selection. We use a long-term data set on individually marked greylag geese (Anser anser) and show that phenotypic variation in dominance-related behaviours contains significant additive genetic variance, parental effects and permanent environment effects. The relative importance of these variance components varied between age and sex classes, whereby the most pronounced differences concerned nongenetic components. In particular, parental effects were larger in juveniles of both sexes than in adults. In paired adults, the partner's identity had a larger influence on male dominance rank and aggression rate than in females. In sex- and age-specific estimates, heritabilities did not differ significantly between age and sex classes. Adult dominance rank was only weakly genetically correlated between the sexes, leading to considerably higher heritabilities in sex-specific estimates than across sexes. We discuss these patterns in relation to selection acting on dominance rank and aggression in different life history stages and sexes and suggest that different adaptive optima could be a mechanism for maintaining genetic variation in dominance-related traits in free-living animal populations.

Female androgen patterns and within-pair testosterone compatibility in domestic geese (Anser domesticus).

For successfully raising offspring, long-term monogamous pair partners need to be behaviorally and hormonally coordinated. In the monogamous, biparental greylag geese (Anser anser) a dyadic pairbond-specific measure, 'within-pair testosterone compatibility' (TC) indicated how closely synchronized are seasonal androgen levels, which co-varied with reproductive output. Males, in particular, were assumed to respond to their females' hormonal and fecundity phases. We now present experiments with biparental domestic geese (Anser domesticus) kept as pairs to ask whether TC occurs also in these generally polygynous animals. We further ask how different conditions of mate choice affect TC and whether established TC is maintained during a polygynous flock situation. We measured androgen metabolites (AM) non-invasively from individual droppings. In females, AM was related with gonadal activity as it increased after GnRH but not ACTH challenge. Females with preferred partners had higher maximum AM during egg laying and higher rates of initiating incubation than randomly paired females. Domestic ganders had seasonal AM patterns typical for polygynous males. Within-pair TC ranged from almost perfectly positive to non-correlated in domestic geese but mate choice did not explain TC variation. TC of previous pairs was generally reduced in the flock situation, probably confounded by factors of the social environment, i.e. mating opportunity and availability of multiple partners. On top of the underlying reproductive physiology our results suggest two episodic components of TC: a female androgen responsiveness to the preferred partner at least during egg formation, and the male's facultative potential to respond to her readiness to breed.

Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996.

OBJECTIVES: Published reports were reviewed to evaluate the characteristics of peripartal management and the late pregnancy outcome in women with pulmonary vascular disease (PVD). BACKGROUND: Pulmonary hypertension poses one of the highest risks for maternal mortality, but actual data on the maternal and neonatal prognosis in this group are lacking. METHODS: Reports published from 1978 through 1996 of Eisenmenger's syndrome (n = 73), primary pulmonary hypertension (PPH) (n = 27) and secondary vascular pulmonary hypertension (SVPH) (n = 25) complicating late pregnancy were included and analyzed using logistic regression analysis. RESULTS: Maternal mortality was 36% in Eisenmenger's syndrome, 30% in PPH and 56% (p < 0.08 vs. other two groups) in SVPH. Except for three prepartal deaths due to Eisenmenger's syndrome, all fatalities occurred within 35 days after delivery. Neonatal survival ranging from 87% to 89% was similar in the three groups. Previous pregnancies, timing of the diagnosis and hospital admission, operative delivery and diastolic pulmonary artery pressure were significant univariate (p < 0.05) maternal risk factors. Late diagnosis (p = 0.002, odds ratio 5.4) and late hospital admission (p = 0.01, odds ratio 1.1 per week of pregnancy) were independent predictive risk factors of maternal mortality. CONCLUSIONS: In the last two decades maternal mortality was comparable in patients with Eisenmenger's syndrome and PPH; however, it was relevantly higher in SVPH. Maternal prognosis depends on the early diagnosis of PVD, early hospital admission, individually tailored treatment during pregnancy and medical therapy and care focused on the postpartal period.

Reduction and elimination of systemic heparinization during cardiopulmonary bypass.

After extensive experimental evaluation, heparin-coated perfusion equipment was clinically evaluated with low or no systemic heparinization in three different groups of patients (n = 47). In group 1, resection of descending thoracic aortic aneurysms (n = 24) was performed with heparin-coated equipment used for left heart bypass (n = 12) or partial cardiopulmonary bypass (n = 12) for proximal unloading and distal protection (heparin 5000 IU, autotransfusion). All devices remained functional throughout the procedures and no systemic emboli were detected. The sole death (1 of 24, 4%) occurred in a patient with ruptured thoracoabdominal aortic aneurysm requiring operation in extremis. Paraparesis with spontaneous recovery occurred in one patient (1 of 24, 4%). In group 2, coronary artery revascularization randomized for low (activated clotting time greater than 180 seconds) versus full (activated clotting time greater than 480 seconds) systemic heparinization was prospectively analyzed in 22 patients. All patients recovered without sequelae, and no myocardial infarction was diagnosed. Low dose of heparin (8041 +/- 1270 IU versus 52,500 +/- 17,100 IU; p less than 0.0005) resulted in reduced protamine requirements (7875 +/- 1918 IU versus 31,400 +/- 14,000 IU; p less than 0.0005), reduced blood loss (831 +/- 373 ml versus 2345 +/- 1815 ml; p less than 0.01), reduced transfusion requirements of homologous blood products (281 +/- 415 ml versus 2731 +/- 2258 ml; p less than 0.001), and less patients transfused (5 of 12 versus 10 of 10; p less than 0.05). Lower D-dimer levels in the group perfused with low systemic heparinization (0.50 +/- 0.43 mg/L versus 1.08 +/- 0.59 mg/L; p less than 0.05) were attributed to the absence of cardiotomy suction in this group. In group 3, rewarming in accidental hypothermia by cardiopulmonary bypass was successfully performed without systemic heparinization in a patient with hypothermic cardiac arrest (23.3 degrees C) and intracranial trauma. We conclude that systemic heparinization for clinical cardiopulmonary bypass can be reduced and eliminated in selected patients if perfusion equipment with improved biocompatibility is used. Bypass-induced morbidity can be reduced.

Complications during and following radial artery cannulation: a prospective study.

One hundred and eighteen 20-g radial artery catheters were prospectively evaluated in 109 cardiovascular surgical patients. 0.024% papaverine in saline was used as a continuous flushing solution. Using the Doppler method, obstruction of the radial artery with the catheter in situ was found in 11 (9.8%) patients. Decannulation was performed at the end of the monitoring in 93 (78.9%) cases while 25 (21.1%) catheters had to be removed earlier. According to Allen's radial flush and Doppler evaluation after decannulation, three (2.5%) radial artery occlusions and one stenosis persisted. However, no vascular insufficiency occurred during the study period. Female patients developed more complications with the catheter in situ but not after catheter removal. Wrist size did not predict the complications. Age, concomitant diseases, traumatic cannulation, type of the surgery, longer cannulation time and perioperative complications did not influence the incidence of abnormal radial blood flow after decannulation. Our results confirm the low incidence of significant complications following radial artery cannulation.

Risk and benefit of low systemic heparinization during open heart operations.

Heparin surface-coated perfusion equipment with improved thromboresistance was evaluated in 104 consecutive patients undergoing open heart operation in a prospective, randomized trial with low versus full systemic heparinization. Surgical procedures included coronary artery revascularization in 47 of 54 (87%) for low versus 44 of 50 patients (88%; not significant [NS]) for full, valve repair/replacement in 8 of 54 (15%) for low versus 5 of 50 patients (10%; NS) for full, left ventricular aneurysm repair in 1 of 54 (2%) for low versus 2 of 50 patients (4%; NS) for full, and other in 3 of 54 (6%) for low versus 3 of 50 patients (6%; NS) for full. Cross-clamp time was 39.2 +/- 10.7 minutes for low versus 39.5 +/- 10.5 minutes for full (NS). Cardiopulmonary bypass time was 68.6 +/- 20.1 minutes for low versus 69.3 +/- 16.6 minutes for full (NS). Lowest activated coagulation time during perfusion was 255 +/- 75 seconds for low versus 537 +/- 205 seconds for full (p < 0.0005). In the low group, the target activated coagulation time of more than 180 seconds was not reached during perfusion in 4 of 54 patients (7%), the lowest value being 164 seconds. No oxygenator failure occurred. Hospital mortality was 0 of 54 (0%) for low versus 1 of 50 patients (2%) for full (NS). Bleeding required surgical revision in 0 of 54 (0%) for low versus 4 of 50 patients (8%) for full (p = 0.05). Drainage (24 hours) was 790 +/- 393 mL for low versus 1,039 +/- 732 mL for full (p < 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Perfusion with low systemic heparinization during resection of descending thoracic aortic aneurysms.

Two series of 20 consecutive patients with aneurysms of the descending thoracic aorta (TAA) and thoraco-abdominal aorta (TAAA) underwent multisegmental aortic repair using either simple normothermic crossclamping and rapid reanastomosis (historic) or partial cardiopulmonary bypass (CPB) with heparin coated perfusion equipment and low systemic heparinization (actual). Chronic lesions were present in 14/20 patients (70%) for simple versus 13/20 (65%) for CPB (NS). Acute lesions (symptomatic less than 24 h) were present in 6/20 patients (30%) for simple versus 7/20 (35%) for CPB (NS). Dissecting lesions were observed in 4/20 patients (20%) for simple versus 8/20 (40%) for CPB (NS). Aneurysmal lesions were found in 16/20 patients (80%) for simple versus 12/20 (60%) for CPB (NS). Mean number of aortic segments (n = 8) resected was 3.2 +/- 1.1 for simple versus 4.0 +/- 1.2 for CPB (P less than 0.01). Replacement of the transdiaphragmatic aorta was performed in 10/20 patients (50%) for simple and 13/20 patients (65%) for CPB (NS). A heparin loading dose of 5000 IU for simple versus 100 IU/kg bodyweight for CPB was used. In the latter group, the activated clotting time was kept above 180 s during a mean perfusion time of 46 +/- 28 min at a mean pump flow of 2.2 +/- 0.7 l/min. Thirty-day survival for all (transdiaphragmatic) was 12/20 (5/10) patients for simple versus 20/20 (13/13) for CPB (P less than 0.002, P less than 0.01). One-year survival (all) was 11/20 patients (55%) for simple versus 19/20 (95%) for CPB (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced blood loss and transfusion requirements with low systemic heparinization: preliminary clinical results in coronary artery revascularization.

In coronary artery revascularization, low systemic heparinization was compared to full systemic heparinization during perfusion with heparin surface-coated cardiopulmonary bypass equipment. Twelve patients were randomly assigned to two groups and perfused with low [activated clotting time (ACT) greater than 180 s] or full (ACT greater than 480 s) systemic heparinization. A standard battery of blood samples was taken before the procedure, after heparinization, and at regular intervals during and after cardiopulmonary bypass. No differences were seen between the two groups in regard to age, body surface area, preoperative hematocrit, duration of bypass, bypass hypothermia, cross-clamp time, and number of bypasses per patient. However, there were more internal thoracic artery (ITA) grafts in the group with low systemic heparinization (1.5 +/- 0.8 ITA grafts per patient versus 0.8 +/- 0.4 ITA grafts per patient with full heparinization; p less than 0.05). The oxygenator gradient at the end of perfusion (before weaning) was 107 +/- 40 mmHg for low versus 110 +/- 10 mmHg for full heparinization (difference not significant). The total amount of heparin used was 7200 +/- 1030 IU for low versus 51400 +/- 9700 IU for full (p less than 0.05). Postoperative hematocrit was 35.0 +/- 2.0% for low versus 24.7 +/- 2.7% for full (p less than 0.05). Total chest tube drainage was 428 +/- 153 ml/m2 for low versus 935 +/- 414 ml/m2 for full (p less than 0.05). Homologous transfusions of blood products were necessary in 3/6 patients for low versus 6/6 patients for full (p less than 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)

Superior hemodynamics in left heart bypass without systemic heparinization.

Open-chest left heart bypass was performed in 10 canine experiments (30 +/- 9 kg) by a servo controlled roller pump for 6 h at a pump flow of 50 ml/min per kg bodyweight. The surfaces of the tubing sets were either standard (with systemic heparinization) or with end-point attached heparin (no systemic heparin). Besides continuous monitoring of hemodynamics, a standard battery of blood samples was taken before bypass, after 10 min and every hour thereafter. There is no evidence of increased fibrin production in the group with end-point attached heparin surfaces perfused without systemic heparinization. Superior hemodynamics in left heart bypass performed without systemic heparinization appear to be due to improved hemostasis, reduced blood loss and therefore reduced transfusion requirements. Left heart bypass with heparin-coated equipment has been successfully used for resection of a thoracoabdominal aneurysm in six patients.

Heparin-coated left heart bypass: renal function and hormonal response.

The effect of partial (50 ml/min/kg) left heart bypass (LHBP) on renal function, plasma renin activity (PRA), aldosterone, arginine vasopressin and atrial natriuretic peptide (ANP) response was studied in ten anesthetized, open-chested mongrel dogs (weight 23-50 kg) over a period of 6 h. Standard equipment with systemic heparinization (control), initially 300 IU/kg, was employed in five dogs, and heparin-coated equipment without additional heparin in the other five (heparin coated). Urine was continuously collected through a transurethral catheter. Urine samples and pulmonary artery blood samples for hormonal assays were taken at preset intervals before and during LHBP. The results in each group were summarized as median (25th-75th) and compared using the Mann-Whitney U test. In the control group higher blood loss required higher volume substitution. Urine output was maintained in heparin coated and slightly decreased at 3-4 h in control LHBP. Creatinine clearance at 3-5 h and free-water clearance at 3-6 h were significantly higher with heparin-coated LHBP. PRA, aldosterone and vasopressin peaked at 1-2 h of LHBP similarly in both groups, not exceeding the values before perfusion. PRA and aldosterone response was sustained during 6 h and the percentage changes corrected for hemodilution indicated a stronger response with standard equipment. Vasopressin concentrations were slightly but significantly higher in the control group at 1 and 6 h of perfusion. Corrected for hemodilution, vasopressin percentage changes were not different in the two groups. ANP, despite atrial unloading, rose similarly in both groups. There was a tendency to poorly sustained ANP response (control greater than heparin-coated) after 6 h of perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved biocompatibility of heparin surface-coated ventricular assist devices.

Heparin surface coated ventricular assist devices (VADs) and cannulas were evaluated in comparison to uncoated VADs in 10 bovine experiments (body weight 77 +/- 6 kg). All systems were primed with cristalloid solution. No systemic heparin was given. Left ventricular assist was started with a blood flow of 4.2 +/- 0.4 l/min and maintained over 6 hours. Besides hemodynamic monitoring, blood samples were taken at regular intervals for blood gas, hematological, biochemical and coagulation studies. All animals in the study group (coated) were assisted for the scheduled 6 hours without device failure. In the control group, however, total occlusion occurred in 1 VAD after 1 hour of left ventricular assist whereas the other 4 VADs remained functional throughout the protocol. Mixed venous oxygens saturation was preassist 56 +/- 12% for coated versus 63 +/- 11% for uncoated and the final value at 60 minutes after weaning was 58 +/- 16% versus 59 +/- 5% (NS). Mean hematocrit dropped from a baseline value of 33 +/- 4% for coated versus 29 +/- 8% for uncoated to 29 +/- 7% versus 30 +/- 5% (NS) after 6 hours of assist. There was no significant difference between the baseline values (5.7 +/- 3.0 mumol/l for coated versus 4.6 +/- 3.1 mumol/l for uncoated) and the 6-hour values (3.8 +/- 3.7 mumol/l versus 7.6 +/- 6.4 mumol/l) for mean plasma hemoglobine. The normalized platelet levels dropped after 10 minutes of assist to 91 +/- 21% for coated versus 94 +/- 49% for uncoated (NS) and 89 +/- 29% versus 65 +/- 44 at 6 hours (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiotomy suction versus red cell spinning during repair of descending thoracic aortic aneurysms.

Two consecutive series of patients undergoing repair of descending thoracic and thoracoabdominal aortic aneurysms with partial cardiopulmonary bypass and low systemic heparinization (activated coagulation time: ACT greater than 180 sec) for proximal unloading and distal protection were analyzed. During the surgical procedures, thoracic shed blood was recovered either with a red cell spinning autotransfusion device (n=10) or two pump suckers and Duraflo II heparin surface coated cardiotomy reservoirs (n=10). There were 5/10 acute lesions and 1/10 ruptures for the autotransfusion group versus 5/10 acute lesions and 2/10 ruptures for the cardiotomy group (NS). Extension of aortic resection (range 1-8) was 3.6+/-1.2 for autotransfusion versus 3.5+/-1.4 for cardiotomy suction (NS). Mean number of reimplanted patches for intercostal and visceral reperfusion was 0.3+/-0.6 for autotransfusion versus 0.6+/-1.0 for cardiotomy (NS). Perfusion time was 41+/-17 min for autotransfusion versus 60+/-19 min for cardiotomy (p less than 0.05) and cross clamp time was 33+/-14 min for autotransfusion versus 43+/-17 min for cardiotomy (p less than 0.01). Total heparin dose was for 9500+/-2100 IU for autotransfusion versus 9800+/-1300 IU for cardiotomy (NS). The mean of the lowest ACTs measured during perfusion was 281+/-121 sec for autotransfusion versus 258+/-58 sec for cardiotomy (NS). The total protamine dose given was 7800+/-2100 IU for autotransfusion versus 9700+/-1900 IU for cardiotomy (p less than 0.05). The volume of washed red cells prepared was 3186+/-1318 ml for autotransfusion versus 0 for cardiotomy (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Cyanotic congenital heart disease and pregnancy: natural selection, pulmonary hypertension, and anesthesia.

Pregnancy carries substantial maternal and fetal risks in patients with uncorrected or palliatively corrected cyanotic congenital heart disease (CHD). In tricuspid valve Ebstein's anomaly, pregnancy is well tolerated. Maternal mortality in tetralogy of Fallot seems to be less than 10%, but it exceeds 50% in Eisenmenger's syndrome and primary pulmonary hypertension (PPH). Maternal hematocrit greater than 60%, arterial oxygen saturation lower than 80%, right ventricular hypertension, and syncopal episodes are poor prognostic signs. Maternal risk could be reduced by vaginal delivery. Continuous monitoring of arterial and central venous pressure, electrocardiography, and pulse oximetry are recommended for every anesthetic procedure. The use of a pulmonary artery catheter is controversial and probably should be avoided in parturients with cyanotic CHD or PPH. The choice of anesthetic technique and drugs per se is of secondary importance and should be governed by individual preferences. Titration of anesthetic drugs, general anesthesia with controlled ventilation, or, preferably, regional anesthesia with spontaneous breathing should be used cautiously to avoid worsening of the preexisting condition. Prevention of excessive erythrocytosis, volume and blood loss substitution, cardiocirculatory pharmacologic support, prophylaxis of infective endocarditis, and judicious use of anticoagulant drugs should be applied as indicated by the type and presentation of CHD. Poor outcome of pregnancy in PPH requires an early consideration of heart-lung or lung transplantation. Multidisciplinary team effort and prolonged monitoring in the intensive care unit are mandatory to ensure a favorable outcome for cyanotic CHD and PPH parturients.

Intercostal nerve block for lumpectomy: superior postoperative pain relief with bupivacaine.

STUDY OBJECTIVES: To investigate whether equipotent doses of lidocaine and bupivacaine were equally effective for intercoastal nerve blockade (ICNB) and whether a lower amount of lidocaine would be comparably effective. To see whether plasma levels of lidocaine with and without epinephrine and of plain bupivacaine would reach toxic ranges. Finally, to evaluate the duration of postoperative analgesia following general anesthesia and regional anesthesia with two different local anesthetics. DESIGN: Randomized, double-blind study, with control group administered general anesthesia. SETTING: Gynecologic operating room of a university hospital. PATIENTS: 48 adult ASA physical status I and II otherwise healthy patients undergoing lumpectomy. INTERVENTIONS: 36 patients received ICNB of T3-T6 unilaterally using either 4 ml/segment of 1.5% lidocaine with epinephrine 3.75 micrograms/ml (n = 10, Group A), 4 ml/segment of 2% lidocaine with epinephrine 5 micrograms/ml (n = 13, Group B), or 4 ml/segment of plain 0.5% bupivacaine (n = 13, Group C). The control group consisted of 12 patients (Group D) who received a general anesthetic using propofol, alfentanil, and nitrous oxide in oxygen for induction and maintenance of anesthesia. MEASUREMENTS AND MAIN RESULTS: In all three ICNB groups, the highest plasma concentrations were reached after 5 to 10 minutes following ICNB--i.e., a lidocaine plasma level of 2.77 +/- 0.5 micrograms/ml (mean +/- SEM) in Group A, a lidocaine plasma level of 2.78 +/- 0.2 micrograms/ml in Group B, and a bupivacaine plasma level of 1.44 +/- 0.2 micrograms/ml in Group C. There were no significant differences in plasma levels between 1.5% lidocaine and 2% lidocaine. For the first 90 minutes after surgery, higher postoperative pain scores were found in the control group than in the ICNB groups. Notably longer-lasting postoperative pain relief was achieved with plain bupivacaine. The number of women requiring postoperative analgesic medication, the time of first request, and the total amount of analgesic drugs administered during the 24 hours postoperatively were significantly lower in the regional anesthesia groups than in the general anesthesia group (p < 0.05). CONCLUSIONS: ICNB is an alternative to general anesthesia for female breast surgery. Both lidocaine with epinephrine and plain bupivacaine in the doses used did not raise venous plasma concentrations to levels considered potentially toxic. With respect to duration of postoperative pain relief and analgesic drug request, the local anesthetics (in particular, bupivacaine) were found to be superior to general anesthesia.

Lidocaine plasma levels following two techniques of obturator nerve block.

STUDY OBJECTIVES: To assess plasma levels and the potential toxicity of lidocaine following two different approaches to the obtruator nerve. DESIGN: Prospective, randomized, clinical trial. SETTING: Operating rooms of a university hospital. PATIENTS: 45 ASA physical status I, II and III patients over 40 years of age, and undergoing transurethral resection of urinary bladder tumors. INTERVENTIONS: A prospective study compared lidocaine plasma levels following direct and indirect (3-in-1) obturator nerve block using lidocaine 1.5% plus 1:200,000 epinephrine. Patients with unilateral urinary bladder tumors were randomized to receive direct obturator nerve block with 15 ml of lidocaine (Group A, n = 20), while those with bilateral tumors received a bilateral direct obturator nerve block with 30 ml (2 x 15 ml) of lidocaine (Group B, n = 12). A third group of patients with unilateral bladder tumors received 3-in-1 indirect) obturator nerve block with 40 ml of lidocaine (Group C, n = 17). Plasma lidocaine concentration was determined every 5 minutes for 30 minutes, and at 45, 60, and 90 minutes after the block. MEASUREMENTS AND MAIN RESULTS: In Group A, mean (+/- SD) peak plasma lidocaine level of 1.35 +/- 0.5 micrograms/ml (range 0.61 to 2.41 micrograms/ml) occurred 45 minutes after injection. In Group B, a peak of 3.63 +/- 2.07 micrograms/ml (0.75 to 7.21 micrograms/ml) occurred 15 minutes after injection. Mean peak level in Group C of 2.08 +/- 0.77 micrograms/ml (0.84 to 3.21 micrograms/ml) occurred 60 minutes after injection Lidocaine concentrations were significantly higher in Groups B and C than in Group A, and they were higher in Group B than in Group C. No patient had any signs of symptoms of local anesthetic toxicity. CONCLUSIONS: Despite a lower total dose of lidocaine administered (450 mg), higher mean and peak plasma levels were reached sooner with bilateral direct obturator nerve block compared with the indirect obturator nerve block (600 mg), indicating a faster blood absorption of lidocaine following direct block. Both types of obturator nerve block prevented adductor muscle contraction in a large percentage of cases.

Trimming the fat: obesity and hematopoietic cell transplantation.

Obesity, increasing worldwide, is common in patients undergoing hematopoietic cell transplantation (HCT). This complex physiological state may alter the outcome of cancer therapies by many mechanisms including direct effects on pathogenesis, host responses to disease and altered pharmacology of chemotherapy. Obesity has been associated with multiple adverse health outcomes. Reports of obese patients undergoing HCT are challenging to interpret because of the heterogeneity of obesity definitions, underlying diseases, graft sources and chemotherapy regimens employed. Compared with normal-weight patients, it appears that obese patients undergoing allogeneic HCT have a higher risk of non-relapse mortality and inferior survival whereas those receiving autologous HCT appear to have equivalent outcomes. These findings are also difficult to interpret because there is no consistent standard for calculating chemotherapy dose in this group and future studies on specific regimens in this population are urgently needed. Patients who have undergone bariatric surgery may be at risk for unexpected events because of impaired nutritional state and altered pharmacokinetics of oral drugs. We recommend that future studies utilize more consistent and biologically relevant definitions of obesity and that the pharmacokinetics and pharmacodynamics of specific conditioning regimens be studied. Until more evidence is available, a rationale is presented for dosing based on adjusted body weight. Moreover, recommendations are provided to guide future research efforts based on more definitive measurements of body fat and its distribution available through modern quantitative imaging techniques using dual energy X-ray absorptiometry or magnetic resonance imaging scanning.

Cellular immunotherapy for plasma cell myeloma.

Allogeneic hematopoietic cell transplantation for plasma cell myeloma can lead to graft-vs-myeloma immunity and long-term survivorship, but limited efficacy and associated toxicities have prevented its widespread use. Cellular immunotherapies seek to induce more specific, reliable and potent antimyeloma immune responses with less treatment-related risk than is possible with allogeneic transplantation. Strategies under development include infusion of vaccine-primed and ex vivo expanded/costimulated autologous T cells after high-dose melphalan, genetic engineering of autologous T cells with receptors for myeloma-specific epitopes, administration of DC/plasma cell fusions and administration expanded marrow-infiltrating lymphocytes. In addition, novel immunomodulatory drugs such as inhibitors of the programmed death-1 T cell regulatory pathway may synergize with cellular immunotherapies.