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.

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.

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.

Isolation and characterization of microsatellite marker loci in the greylag goose (Anser anser).

Ten novel polymorphic microsatellite loci were isolated and characterized from the greylag goose, Anser anser, a long-term monogamous and biparental bird. Additionally, five new primers pairs were designed based on previously published microsatellite locus sequences from closely related species. Multiplex polymerase chain reactions conditions were optimized for all 15 primer pairs. The number of alleles ranged from two to 12 per locus with an observed heterozygosity ranging from 0.07 to 0.85. This marker set will be used to determine rates and origins of extra-pair and parasitic young in a population of individually banded greylag geese with known life histories.

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.