Diagnosis, treatment, and response assessment in solitary plasmacytoma: updated recommendations from a European Expert Panel.

Solitary plasmacytoma is an infrequent form of plasma cell dyscrasia that presents as a single mass of monoclonal plasma cells, located either extramedullary or intraosseous. In some patients, a bone marrow aspiration can detect a low monoclonal plasma cell infiltration which indicates a high risk of early progression to an overt myeloma disease. Before treatment initiation, whole body positron emission tomography-computed tomography or magnetic resonance imaging should be performed to exclude the presence of additional malignant lesions. For decades, treatment has been based on high-dose radiation, but studies exploring the potential benefit of systemic therapies for high-risk patients are urgently needed. In this review, a panel of expert European hematologists updates the recommendations on the diagnosis and management of patients with solitary plasmacytoma.

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.

Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

Significance of TNM staging, Demographic and Histologic Features in Predicting the Prognosis of Renal Cell Carcinoma.

BACKGROUND: The aim of this study was to evaluate the prognostic significance of clinical, demographic and detailed histopathological parameters in renal cell carcinoma (RCC). METHODS: A total of 102 patients who underwent partial or radical nephrectomy for a renal mass between 2008 and 2013 were evaluated retrospectively. Fuhrman grade, TNM stage, macroscopic satellite tumor nodule formation, histopathological subtype, renal vein invasion (RVI), necrosis, microvessel invasion (MVI), sarcomatoid differentiation and overall survival (OS) were evaluated to determine prognostic factors. RESULTS: The 102 patients consisted of 73 with clear cell tumor, 15 with papillary tumor, 12 with chromophobe tumor and 2 collecting duct RCC cases. A statistically negative relationship was observed between increasing age and OS when the patients were grouped as above and under 40 years of age. There was no statistical relationship between OS and histopathological subtype, adrenal gland invasion, and lymph node metastasis. The risk of death was 10-fold increased in patients with stage 4 tumor compared to patients with stage 1 tumor. Statistically significant macroscopical parameters for OS were satellite tumor nodule presence, Fuhrman grade, tumor size, renal sinus and perinephric fat invasion, distant metastasis, and RVI. The risk of death was 13-fold higher in cases with sarcomatoid differentiation. There was a strong correlation between the presence of a satellite tumor nodule, necrosis, sarcomatoid differentiation and the tumor stage. A statistically negative correlation was observed between OS and the MVI, sarcomatoid differentiation, and necrosis. CONCLUSION: We found the Fuhrman grade, tumor size, renal sinus and perinephric fat invasion, distant metastasis, RVI, MVI, sarcomatoid differentiation, necrosis and satellite tumor nodule to be all statistically significant parameters for OS. The addition of other variables to the TNM stage and grade may improve the prediction of outcomes for RCC patients.

Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group.

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.

Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project.

The combination of serum ß2-microglobulin and albumin levels has been shown to be highly prognostic in myeloma as the International Staging System (ISS). The aim of this study was to assess the independent contributions of ISS stage and cytogenetic abnormalities in predicting outcomes. A retrospective analysis of international studies looking at both ISS and cytogenetic abnormalities was performed in order to assess the potential role of combining ISS stage and cytogenetics to predict survival. This international effort used the International Myeloma Working Group database of 12 137 patients treated worldwide for myeloma at diagnosis, of whom 2309 had cytogenetic studies and 5387 had analyses by fluorescent in situ hybridization (iFISH). Comprehensive analyses used 2642 patients with sufficient iFISH data available. Using the comprehensive iFISH data, combining both t(4;14) and deletion (17p), along with ISS stage, significantly improved the prognostic assessment in terms of progression-free survival and overall survival. The additional impact of patient age and use of high-dose therapy was also demonstrated. In conclusion, the combination of iFISH data with ISS staging significantly improves risk assessment in myeloma.

Impact of Factor V Leiden, prothrombin and methylenetetrahydrofolate reductase gene mutations on infant birth weight in women with recurrent fetal loss and women with successful pregnancies.

PURPOSE: The aim of this study was to verify whether FV Leiden, PT G20210A, MTHFR C667T or MTHFR A1298C mutations influence the risk of recurrent fetal loss in a sample of Turkish women who had experienced recurrent fetal loss and to evaluate whether the aforementioned thrombophilias and recurrent fetal loss may affect the birth weight of subsequent pregnancies. METHODS: Fifty-eight women with recurrent pregnancy loss and 30 women with successful pregnancies were evaluated. RESULTS: The average birth weights for infants of all women in the study group and for infants of thrombophilia-positive women in the study group were markedly lower than the birth weight of infants in the control group (p<0.001 and p<0.001, respectively). CONCLUSION: Successful pregnancies in women with a history of recurrent fetal losses may be associated with lower birth weights compared to controls, irrespective of thrombophilia status. This conclusion warrants further research.

Expectant management of preterm premature rupture of membranes remote from term with exiguous amniotic fluid and a prolonged latency period: report of two cases.

Management of preterm premature rupture of membranes (PPROM) is a very challenging issue for the obstetricians. We report two cases of PPROM occurring in early gestation remote from term (both < 26 weeks) with exiguous amniotic fluid (amniotic fluid index of < or =2 cm) that were managed successfully by conservative treatment and resulted in a latency period of almost two months. This treatment option might be feasible in carefully selected patients following meticulous evaluation and warrants further research.

Management of treatment-emergent peripheral neuropathy in multiple myeloma.

Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.

Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study.

Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T(0)). The median age at diagnosis was 58 years, and time from diagnosis to T(0) was 3.3 years. Following T(0), 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T(0) in 94 patients (44%) including ≥ partial response in 69 (32%). The median overall survival and event-free survival from T(0) were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.

An audit of seafood consumption awareness during pregnancy and its association with maternal and fetal outcomes in a Turkish population.

This study was conducted to audit maternal seafood intake awareness during pregnancy and to determine whether there is an association between fish consumption and various pregnancy outcomes. In total, 553 low-risk and healthy pregnant women were given a questionnaire concerning fish consumption. Pregnant women who developed gestational diabetes mellitus, pre-term labour-birth, macrosomia, low birth weight and small for gestational age were analysed. Fatty fish consumers tended to have higher birth weight infants than lean fish consumers. Low fish consumption was significantly correlated with low birth weight and small for gestational age (SGA) infants. The more fatty fish that the low fish consumers consumed, the more likely they were to have SGA infants. Fish consumption did not have an impact on the development of gestational diabetes mellitus, macrosomia or pre-term labour-birth. Low fish consumption during pregnancy may be associated with the development of low birth weight and SGA infants in a Turkish population.

Development of a questionnaire (EORTC module) to measure quality of life in patients with cholangiocarcinoma and gallbladder cancer, the EORTC QLQ-BIL21.

BACKGROUND: Quality of life measurement in cholangiocarcinoma and gallbladder cancer involves the assessment of patient-reported issues related to the symptoms, disease and treatment of these tumours. This study describes the development of the disease-specific quality of life (QoL) questionnaire for patients with cholangiocarcinoma and gallbladder cancer to supplement the European Organization for Research and Treatment of Cancer (EORTC)-QLQ C30 core cancer questionnaire. METHODS: Phases 1-3 of the guidelines for module development published by the EORTC were followed, with adaptations for incorporation of questions from existing modules. RESULTS: A total of 47 QoL issues (questions) were identified; 44 questions from the two related validated questionnaires, the EORTC QLQ-PAN26 (pancreatic module) and the EORTC QLQ-LMC21 (liver metastases module), two from the Functional Assessment of Cancer Therapy hepatobiliary module questionnaire in the literature search and one from healthcare professional interviews. Following phase 1 and 2 interviews with patients (n=101) and health care professionals (n=6), a 23-question provisional questionnaire was formulated. There were five questions from PAN26, 15 from LMC21 and three extra questions. In phase 3, the provisional item list was pre-tested in 52 patients in four languages and this resulted in a 21-item module. CONCLUSION: This is the only disease-specific QoL questionnaire for patients with cholangiocarcinoma and gallbladder cancer, and initial assessments show it to be accurate and acceptable to patients in reflecting QoL in these diseases.

The use of biochemical markers of bone remodeling in multiple myeloma: a report of the International Myeloma Working Group.

Lytic bone disease is a frequent complication of multiple myeloma (MM). Lytic lesions rarely heal and X-rays are of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone resorption (amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX and CTX, respectively) or CTX generated by matrix metalloproteinases (ICTP)) and bone formation provide information on bone dynamics and reflect disease activity in bone. These markers have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity and response to anti-resorptive treatment in MM. Urinary NTX, serum CTX and serum ICTP are elevated in myeloma patients with osteolytic lesions and correlate with advanced disease stage. Furthermore, urinary NTX and serum ICTP correlate with risk for skeletal complications, disease progression and overall survival. Bone markers have also been used for the early diagnosis of bone lesions. This International Myeloma Working Group report summarizes the existing data for the role of bone markers in assessing the extent of MM bone disease and in monitoring bone turnover during anti-myeloma therapies and provides information on novel markers that may be of particular interest in the near future.

Emergent intrauterine resuscitation in a fetus with transient congenital anemia--case report.

A 24-week gestation complicated by fetal hydrops was prepared for intrauterine transfusion to treat possible fetal anemia. During the therapeutic transfusion procedure, blood samples could be not taken from the umbilical vein, and severe fetal bradycardia developed. Given the severity of the condition and the fetal position, transfusion was performed through the most accessible part of the fetal heart, which was the right atrium. Just after the transfusion procedure, fetal cardiac tamponade developed, and the fetal heart collapsed. Subsequently, urgent fetal pericardiac tamponade decompression was performed.

Clinical and psychometric validation of the EORTC QLQ-CR29 questionnaire module to assess health-related quality of life in patients with colorectal cancer.

This international study aimed to test the measurement properties of the updated European Organisation for Research and Treatment of Cancer (EORTC) questionnaire module for colorectal cancer, the QLQ-CR29. The QLQ-CR29 was administered with the QLQ-C30, core questionnaire, to 351 patients from seven countries. Questionnaire scaling and reliability were established and clinical and psychometric validity examined. Patient acceptability and understanding were assessed with a debriefing questionnaire. Multi-trait scaling analyses and face validity refined the module to four scales assessing urinary frequency, faecal seepage, stool consistency and body image and single items assessing other common problems following treatment for colorectal cancer. Scales distinguished between clinically distinct groups of patients and did not correlate with QLQ-C30 scales, demonstrating construct validity. The QLQ-CR29 scores were reproducible over time in stable health. The EORTC QLQ-CR29 demonstrates sufficient validity and reliability to support its use to supplement the EORTC QLQ-C30 to assess patient-reported outcomes during treatment for colorectal cancer in clinical trials and other settings.

Peripheral immune response in pulmonary tuberculosis.

Cellular immune response and delayed-type hypersensitivity reactions are considered to play a major role in the immunopathogenesis of pulmonary tuberculosis (PTB). But the exact mechanism is still to be clarified. Th1 cells are mainly involved in cellular immune responses in PTB and provide a normal healing process with minimal or no sequela whereas Th2 cell and CD8(+) T lymphocyte responses may lead to more severe type of disease. In this study, we investigated the peripheral blood immune responses in PTB. The study group consisted of acid fast positive young male soldiers with PTB and a negative HIV serology. The control group included healthy young volunteer male soldiers without a history of PTB. Intracytoplasmic cytokine content of CD8(+) T cells and lymphocytes, including IL-2, IL-4, IL-5, IL-10 and IFN-gamma were determined by flow cytometry, and IL-2, IL-4, IL-5, IL-10, IFN-gamma and TNF-alpha serum levels were measured by cytometric bead array (CBA). No difference was observed between the percentages of T, B, NK cells and HLA-DR expression in both groups, however, the number of CD3(+)HLA-DR(+) activated T cell percentages was higher in PTB group as compared to healthy subjects. IL-2, IL-4, IL-5, IL-10 contents of lymphocytes and IFN-gamma(+)CD8(+) T cells were found to be significantly lower in PTB patients when compared with healthy subjects, and in parallel, serum IL-2, IL-4, IL-5 and TNF-alpha levels were also significantly lower in PTB patients. In conclusion we suggest that, CD8(+) T cells producing both Th1 and Th2 type cytokines, may play important role in the peripheral immune response to mycobacteria.

International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100).

Multiple myeloma is the most common indication for high-dose chemotherapy with autologous stem cell support (ASCT) in North America today. Stem cell procurement for ASCT has most commonly been performed with stem cell mobilization using colony-stimulating factors with or without prior chemotherapy. The target CD34+ cell dose to be collected as well as the number of apheresis performed varies throughout the country, but a minimum of 2 million CD34+ cells/kg has been traditionally used for the support of one cycle of high-dose therapy. With the advent of plerixafor (AMD3100) (a novel stem cell mobilization agent), it is pertinent to review the current status of stem cell mobilization for myeloma as well as the role of autologous stem cell transplantation in this disease. On June 1, 2008, a panel of experts was convened by the International Myeloma Foundation to address issues regarding stem cell mobilization and autologous transplantation in myeloma in the context of new therapies. The panel was asked to discuss a variety of issues regarding stem cell collection and transplantation in myeloma especially with the arrival of plerixafor. Herein, is a summary of their deliberations and conclusions.