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.

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.

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.

Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis.

Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common premalignant disorders in Western countries. Recent studies show that almost every multiple myeloma (MM) case is preceded by an MGUS stage. Interestingly, prevalence and incidence patterns for MGUS and MM show striking disparity patterns across ethnic/racial groups, most notably the two- to threefold increase in both these disorders in African Americans compared with Caucasians. In contrast, studies on Asian patients show lower prevalence/incidence for MGUS/MM compared with Caucasians. Familial aggregation for both MGUS and MM has been observed; the risk for MGUS or MM in family members with these disorders is increased about two- to three fold compared with the general population. Although underlying mechanisms remain unclear, there is evidence of heterogeneity among MGUS patients from different ethnic/racial groups. For example, compared with Caucasians, African-American and African MGUS patients have reportedly lower rates of immunoglobulin M (IgM) MGUS (versus IgG/IgA MGUS) and higher rates of unquantifiable immunoglobulins (Igs). This review focuses on racial disparity and familial aggregation patterns for MGUS and MM and discusses how these observations provide novel clues with regard to pathogenesis.

Subacute thyroiditis manifesting as fever of unknown origin.

Subacute thyroiditis (SAT) usually occurs in women in middle age with a viral prodrome, thyroid or neck tenderness, classic symptoms of thyrotoxicosis, and elevated erythrocyte sedimentation rate (ESR). We report a case in an 81-year-old man who initially had 2 days of fever to 101.2 degrees F, confusion, and bilateral lower extremity weakness. Extensive evaluation was remarkable only for the following laboratory values: thyrotropin (TSH) 0.02 microIU/mL, free thyroxine (FT4) 3.1 ng/dL, free triiodothyronine (FT3) 6.0 pg/mL, and ESR 98 mm/hr. One week later, the patient had persistent fevers to 102 degrees F; no source was found. The fever resolved, and 3 months later the patient had profound hypothyroidism (TSH >44.0 microIU/mL, FT4 0.4 ng/dL, ESR 13 mm/hr). A painless thyroid gland and atypical manifestations of hyperthyroidism are unusual in SAT. When fever is of unknown origin, SAT should be considered even if classic features are absent.

Outcome of cardiovascular surgery and pregnancy: a systematic review of the period 1984-1996.

The outcomes of cardiovascular operations during pregnancy, at delivery, and post partum were reviewed from published material in the period 1984-1996. Surgery during pregnancy resulted in fetal-neonatal morbidity and mortality of 9% and 30%, respectively, and in maternal morbidity and mortality of 24% and 6%, respectively. Duration of pregnancy at surgery and duration and temperature of cardiopulmonary bypass did not influence fetal-neonatal outcome. Maternal complications and mortality of surgery immediately after delivery were 29% and 12%, respectively, and for surgery performed with a postpartum interval the respective rates were 38% and 14%. Hospitalization after week 27 of gestation and extreme emergency contributed significantly to poor maternal outcome. Maternal deaths were reported in 9% of valvular procedures and in 22% of aortic or arterial dissection repairs and pulmonary embolectomies. Fetal-neonatal risks of maternal surgery during pregnancy are high and unpredictable. Maternal risks of cardiovascular procedures during pregnancy are moderate, significantly increase if an operation is performed at or after delivery, and, overall, should be considered as higher than those in nonpregnant cardiovascular surgical patients.

Pulmonary atresia with ventricular septal defect: a case for central venous pressure and oxygen saturation monitoring.

A 21-year-old patient with pulmonary atresia and ventricular septal defect (PA-VSD) was admitted to the hospital for tubal ligation. Invasive arterial and central venous (CVP) pressure, pulse oximetric oxygen saturation (SpO2), and (from the tip of oximetric central venous catheter) central venous oxygen saturation (ScvO2) and oxygen extraction rate (ExO2) were continuously monitored. Heart rate (range: 68-75 beat/min), mean arterial pressure (80-90 mmHg), CVP (7-10 mmHg), SpO2 (79-90 percent), ScvO2 (57-70 percent), and ExO2 (21-30 percent) remained stable during epidural anesthesia and transvaginal sterilization. Following an overnight stay (peak SpO2 92 percent; peak ScvO2 71 percent; through ExO2 21 percent), the oxygen data returned to baseline on awakening (SpO2 < 80 percent, ScvO2 < 55 percent, ExO2 > 35 percent), and the patient was discharged. In PA-VSD, a single-outlet double-ventricle anomaly, CVP reflects the preload of systemic ventricle. As the mixed venous oxygen saturation cannot be defined, ScvO2 is the best available indicator of the whole body oxygen consumption. Continuous monitoring of CVP, ScvO2 and ExO2 in the superior vena cava may provide more insight into the response to anesthesia and surgery in patients with PA-VSD.

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.

Perioperative course and recovery after heparin-coated cardiopulmonary bypass: low-dose versus high-dose heparin management.

OBJECTIVE: To compare two heparin managements for a cardiopulmonary bypass (CPB) procedure with heparin-coated equipment. The hypothesis was that a lower heparin dose may reduce blood loss and homologous transfusion requirements and influence the speed of postoperative recovery. DESIGN: Prospective, randomized, and open study. SETTING: Operating room and intensive care unit in a university hospital. PARTICIPANTS: Twenty-four patients undergoing first-time elective coronary artery surgery. INTERVENTIONS: Heparin-coated CPB equipment (Duraflo II; Baxter-Bentley) was used in all patients. The study group (n = 12) received low-dose (100 IU/kg i.v. and 0 to 1,000 IU/L priming; target level of activated coagulation time [ACT] over 180 seconds during CPB; suction in a red cell washing device); and the control group (n = 12) received high-dose (300 IU/kg i.v. and 5,000 IU/L priming; ACT over 480 seconds; standard cardiotomy suction) heparin management. MEASUREMENTS AND MAIN RESULTS: ACT remained above 200 seconds after the initial heparin dose in the study group for the CPB duration up to 99 minutes. In 11 of 12 patients in the control group, additional heparin was required during CPB. Total doses of heparin and protamine (mean 8,017 v 50,508 IU and 83 v 325 mg, respectively; p < 0.0001), volume of homologous blood transfusion (median 600 v 1450 mL; p < 0.025), and blood products exposure (median 0.5 v 5.0 units/patients; p < 0.05) were significantly lower in the study group. Postoperative chest drainage showed a trend to lower volume loss (median 705 v 930 mL; p < 0.08) in patients managed with low-dose heparin. Oxygenator resistance during CPB, perioperative laboratory analyses (oxygen and metabolic data, hematocrit, platelet count, prothrombin, thrombin, activated partial thromboplastin time, fibrinogen, D-dimers, creatine kinase, and myocardial band of creatine kinase concentration), fluid balance, and the time periods required for extubation, stay in the intensive care unit, and hospital discharge were not different between the groups. There were no evidences of myocardial infarction in any of 24 patients, and all recovered after the procedure. CONCLUSION: Low-dose heparin management enabled uneventful procedures with heparin-coated CPB equipment, significantly decreased protamine and homologous blood requirements, but did not reduce chest drainage or influence the postoperative course and recovery in patients after coronary artery surgery.

Compound motor action potential recording distinguishes differential onset of motor block of the obturator nerve in response to etidocaine or bupivacaine.

The purpose of this investigation was to establish an objective (quantitative) method for determining onset time of motor block induced by different local anesthetics. Twenty-four consenting patients undergoing transurethral surgery during spinal anesthesia were randomized to receive direct obturator nerve block with 10 mL of plain bupivacaine 0.5% (n = 12) or 10 mL of plain etidocaine 1% (n = 12). Another 14 patients (control group) received obturator nerve "block" with saline. After identification of the obturator nerve, patients underwent testing of nerve conduction by recording compound motor action potentials (CMAPs) of thigh adductor muscles in response to stimulation provided by a nerve stimulator at 0.2 to 0.5-mA currents. Testing ended when CMAP amplitudes had returned to their baseline values (control group) or when motor blockade was 90% complete (local anesthetic groups). In all 38 patients, the amplitude of the thigh CMAPs decreased immediately after injection of saline or local anesthetic. While CMAP amplitudes in the control group returned to their initial (baseline) values after 3-6 min, the patients receiving etidocaine or bupivacaine achieved > or = 90% motor blockade after 6 and 13 min, respectively. In the present report, the time to > or = 90% block was significantly faster in patients given etidocaine compared with those given bupivacaine. We conclude that electromyographic recording of CMAPs can be used to compare the ability of different local anesthetics to induce motor block.

Continuous non-invasive blood pressure monitoring by brachial artery displacement method in high-risk surgical patients.

Continuous non-invasive blood pressure (CNBP) measurements were compared to invasive radial artery pressure recordings in 26 patients with cardiac, vascular and/or pulmonary disease. Patients were studied during general anaesthesia (n = 6), regional anaesthesia (n = 10), or combined technique (n = 10) for abdominal or transurethral surgery. CNBP was obtained from a cuff placed around the upper arm and simultaneously compared to invasive pressure from the ipsilateral radial artery. A CNBP device (7001 Cortronic) used intermittent oscillometric measurement for calibration. Through a cuff continuously inflated to a pressure of 20 mmHg, a microprocessor-controlled electro-pneumatic acquisition system sensed displacements of the brachial artery wall. Amplified, digitally converted, filtered and transformed data were displayed as a continuous pulse pressure waveform and digital pressure values on the screen. The CNBP method functioned without disturbances before surgery in all patients. Intra-operative use of electrocautery or a spontaneous occurrence of warning on the screen repeatedly triggered oscillometric recalibration, hence CNBP measurements were discontinued in nine patients. Coefficients of correlation (r) of all invasive and CNBP pairs (n = 1111) were 0.68, 0.58 and 0.70 for systolic, diastolic, and mean blood pressures, respectively. Prediction errors (bias, mean +/- SD) were -13.6 +/- 22.5 mmHg (on average CNBP < invasive pressure) for systolic, +13.0 +/- 12.4 mmHg (CNBP > invasive pressure) for diastolic and +5.0 +/- 13.9 mmHg (CNBP > invasive pressure) for mean CNBP, as compared to radial artery pressure values. Absolute errors (precision) were 25.3 +/- 9.4 mmHg for systolic, 17.4 +/- 4.5 mmHg for diastolic, and 13.9 +/- 4.6 mmHg for mean CNBP. During anaesthesia induction (n = 672) the difference between consecutive measurements (trend of pressure changes) with invasive and CNBP method exceeded 20 mmHg in 90 (13.3%) instances for systolic, in 33 (4.9%) instances for diastolic, and in 45 (6.6%) instances for mean blood pressure. In conclusion, the CNBP method by brachial artery wall displacement failed to measure the blood pressure reliably and to display the trend of pressure changes correctly during anaesthesia induction. In its present form this CNBP method should not replace invasive blood pressure monitoring in high-risk patients neither for anaesthesia induction nor during non-thoracic surgical procedures.

Electromyographic comparison of obturator nerve block to three-in-one block.

Obturator nerve block during spinal, epidural, or general anesthesia without muscle relaxants has been recommended for transurethral surgery to prevent thigh adductor muscle contractions during operative electrocautery. We investigated the effectiveness of direct obturator and 3-in-1 nerve motor blocks in 44 patients undergoing transurethral surgery during spinal anesthesia with isobaric bupivacaine. Patients were randomly assigned to receive 3-in-1 block with 40 mL (n = 13) or 50 mL (n = 11) of 1.5% lidocaine plus epinephrine, or direct obturator nerve block with 10 mL of 2% lidocaine plus epinephrine (n = 20). After both direct obturator and 3-in-1 blocks, compound muscle action potential (CMAP) testing of the obturator nerve was performed at 1-10-s intervals for 10 min. In patients given direct obturator nerve block (n = 20), CMAP amplitude decreased by 88.8 +/- 21% (mean +/- SD) from baseline. In contrast, 3-in-1 block reduced the evoked CMAP amplitude by 7.4 +/- 19% (P < 0.05). Peak lidocaine plasma levels of 1.6 +/- 0.2 micrograms/mL (range 1.0-2.8 micrograms/mL) were reached 60-90 min after the block in those patients receiving 50 mL of local anesthetic. The 3-in-1 technique fails to predictably result in effective motor block of the obturator nerve and thus may not prevent inadvertent thigh adductor muscle contractions during transurethral surgery. A direct approach to the obturator nerve is significantly more effective in producing motor block, and even when given in larger than recommended dosages it results in subtoxic peak plasma lidocaine concentrations.

The time course of gastric pH changes induced by omeprazole and ranitidine: a 24-hour dose-response study.

The time-course of the effects of single-dose acid-reducing therapy in surgical patients is not known. Therefore, a prospective, randomized trial compared the effects of single-dose administration of omeprazole or ranitidine on gastric pH in 52 patients undergoing lower abdominal surgery. The two drugs were administered intravenously in random fashion after placement of a gastric electrode for continuous 24-h pH monitoring In patients receiving omeprazole 20 mg (n = 13) and 40 mg (n = 13), gastric pH > or = 2.5 was achieved after a median of 80 (range 15-269) min and 40 (6-102) min (P = not significant [NS]), whereas in those receiving ranitidine 25 mg (n = 13) and 50 mg (n = 13), this pH was reached after a median of 32 (15-82) and 44 (16-84) min, respectively (P = NS). Over the first 24 h postoperatively, gastric pH remained less than 2.5 for a significantly longer time (1060 min vs 611 min), and more than 4.0 for a significantly shorter time (240 min vs 780 min) after omeprazole 20 mg than after ranitidine 50 mg. There were no other significant differences among treatment groups regarding the duration of gastric pH less than 2.5, between 2.5 and 4.0, and more than 4.0. In all treatment groups, the gastric pH returned to the baseline value of < 2.0 within 18 h. We conclude that when it is desired that gastric pH be more than 4.0 for at least 3 h, a single dose of ranitidine 25 mg or 50 mg should be administered 30-45 min prior to induction of anesthesia.

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)