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.

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.

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.

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.

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.

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.

The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network.

BACKGROUND: Bisphosphonates (BPs) prevent, reduce, and delay multiple myeloma (MM)-related skeletal complications. Intravenous pamidronate and zoledronic acid, and oral clodronate are used for the management of MM bone disease. The purpose of this paper is to review the current evidence for the use of BPs in MM and provide European Union-specific recommendations to support the clinical practice of treating myeloma bone disease. DESIGN AND METHODS: An interdisciplinary, expert panel of specialists on MM and myeloma-related bone disease convened for a face-to-face meeting to review and assess the evidence and develop the recommendations. The panel reviewed and graded the evidence available from randomized clinical trials, clinical practice guidelines, and the body of published literature. Where published data were weak or unavailable, the panel used their own clinical experience to put forward recommendations based solely on their expert opinions. RESULTS: The panel recommends the use of BPs in MM patients suffering from lytic bone disease or severe osteoporosis. Intravenous administration may be preferable; however, oral administration can be considered for patients unable to make hospital visits. Dosing should follow approved indications with adjustments if necessary. In general, BPs are well tolerated, but preventive steps should be taken to avoid renal impairment and osteonecrosis of the jaw (ONJ). The panel agrees that BPs should be given for 2 years, but this may be extended if there is evidence of active myeloma bone disease. Initial therapy of ONJ should include discontinuation of BPs until healing occurs. BPs should be restarted if there is disease progression. CONCLUSIONS: BPs are an essential component of MM therapy for minimizing skeletal morbidity. Recent retrospective data indicate that a modified dosing regimen and preventive measures can greatly reduce the incidence of ONJ.

Validation of the European Organization for Research and Treatment of Cancer QLQ-LMC21 questionnaire for assessment of patient-reported outcomes during treatment of colorectal liver metastases.

BACKGROUND: There is a lack of valid patient-reported outcome (PRO) measures for hepatectomy or palliative treatment of colorectal hepatic metastases. This study examined the validity and reliability of the European Organization for Research and Treatment of Cancer Quality of Life questionnaire liver module (QLQ-LMC21) in patients with liver metastases from colorectal cancer. METHODS: Some 356 patients completed the core questionnaire (QLQ-C30), QLQ-LMC21 and a debriefing questionnaire before and 3 months after hepatectomy or palliative treatment. Construct, criterion and clinical validity were evaluated before and after treatment. RESULTS: Questionnaire compliance was high; less than 1 per cent of data were missing from individual items. Modifications to the hypothesized scale structure produced four scales and nine single items with good reliability, clinical, criterion and construct validity. The QLQ-LMC21 distinguished between patients selected for surgery or palliative treatment in nine of these 13. Significant changes in PROs were observed before and after treatment. The new module discriminated between clinically distinct groups of patients and measured aspects of quality of life not covered in the core questionnaire. CONCLUSION: The EORTC QLQ-LMC21 is a valid and reliable questionnaire module to use with the QLQ-C30 in assessing PROs in hepatectomy or palliative treatment for colorectal liver metastases.

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.

Two cases of 9p deletion syndrome and a case of partial trisomy 8 and partial monosomy 9p.

Two cases of 9p deletion syndrome anda case of partial trisomy 8 and partial monosomy 9p: We report 3 girls with mental retardation (MR), distinctive malformations of the skull and facial region, including trigonocephaly, small palpebral fissures, and unusually midface hypoplasia, congenital heart defects which are characteristics of monosomy 9p. We performed GTG banding and fluorescence in situ hybridization (FISH) method in all cases. By using cytogenetic methods, three terminal deletions of the short arm of the chromosome 9 were identified and in 2 patients the deletion was de novo, and one patient inherited deletion. FISH analysis showed 46,XX,del(9)(pter-p22).ish del(9)(pter-->p22) in two patients and 46,XX,-9,+der(9)t(8;9)(q24.3;p22)pat.ish der(9)t(8;9)(q24.3;p22)pat (305J7-T7x1,wcp8+,wcp9+) in the third patient. This report compares the symptoms and features of our patients with previously reported patients with a 9p deletion syndrome.

The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma.

Immunomodulatory drugs (IMiDs) and bortezomib have been recently used in the management of patients with both newly diagnosed and relapsed/refractory multiple myeloma. Except of their direct anti-myeloma effect, these agents also alter the interactions between myeloma cells and marrow microenvironment. Several recent studies have investigated their potential effect on myeloma bone disease. Preclinical studies have demonstrated that IMiDs reduce osteoclast formation and function in vitro. Clinical studies have confirmed that thalidomide reduces markers of bone resorption, while lenalidomide induces osteoclast arrest in myeloma patients. However, IMiDs seem to have no effect on osteoblast exhaustion present in myeloma. The proteasome inhibitor bortezomib restores abnormal bone remodeling through the inhibition of osteoclast function and the increase in osteoblast differentiation and activity in vitro. In myeloma patients, bortezomib reduces biochemical markers of bone resorption and normalizes the RANKL/osteoprotegerin ratio, while at the same time increases bone formation markers reducing levels of dickkopf-1 protein. Whether these effects are direct and not only a consequence of the agents' antimyeloma activity is not totally clear. This review summarizes all available data for these attractive agents that combine potent anti-myeloma activity with beneficial effects on bone and may alter the way of management of myeloma-related bone disease.

Bortezomib inhibits human osteoclastogenesis.

In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL) leads to the induction of NF-kappaB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to compare the outcome of proteasome versus selective NF-kappaB inhibition using bortezomib (PS-341) and I-kappaB kinase inhibitor PS-1145. Primary human osteoclasts were derived from CD14+ precursors in presence of RANKL and macrophage colony-stimulating factor (M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose- and time-dependent manner and furthermore, the bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to the inhibition of p38 mitogen-activated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP-1 and NF-kappaB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic option of cancer-induced lytic bone disease.

Successful treatment of advanced endometriosis with extremely high CA 125 and moderately elevated CA 15-3 levels.

We present the case of a patient with advanced endometriosis who presented with chronic pelvic pain, bilateral unruptured ovarian endometrioma, massive peritoneal implants and extremely elevated CA 125, and also elevated CA 15-3 levels. Laparoscopy revealed bilateral unruptured ovarian endometrioma and diffuse peritoneal endometriotic implants. Increased association of elevated levels of CA 125 and CA 15-3 is not so common in advanced endometriosis. The case was successfully treated with laparoscopy and combined low-dose oral contraceptive with one year of follow-up. To the best of our knowledge among the reported cases this is the highest CA 15-3 level ever reported with an extremely elevated CA 125 level.

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.

The EORTC QLQ-HDC29: a supplementary module assessing the quality of life during and after high-dose chemotherapy and stem cell transplantation.

High-dose chemotherapy followed by haematopoietic stem cell transplantation can be associated with high physical and emotional distress levels and reduced quality of life. Systematic prospective measurement of impact of therapy on patient quality of life can aid treatment choices and provide better patient information. We describe the development of a high-dose chemotherapy questionnaire module to supplement the European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30). Phases 1-3 of module development were conducted in United Kingdom, Germany, Austria and Norway, according to EORTC QOL Group guidelines. Forty-eight quality of life (QOL) issues were generated from the literature searches and interviews with health care professionals (n=24) and patients (n=92). This produced a 50 item provisional module. Further testing in 169 patients resulted in the QLQ-HDC29 module, containing 29 items, conceptualised into six multi-item scales and eight single items. The EORTC QLQ-C30, supplemented by QLQ-HDC29 will provide a comprehensive QOL measure for the international clinical trials of high-dose chemotherapy.

Assessing quality of life in patients with colorectal cancer: an update of the EORTC quality of life questionnaire.

The European Organisation for Research and Treatment of Cancer (EORTC) has a portfolio of questionnaire modules to supplement the QLQ-C30 to assess patient reported outcomes in cancer clinical trials. This study updated the module for colorectal cancer. A review of the literature identified 20 articles that used the EORTC colorectal module. Eight papers did not report data from scales addressing sexual function and 8 added additional scales to assess ano-rectal function. Interviews with patients (n=79) and professionals (n=11) informed item selection, reduction and modification. A new 29 item module was devised and further patient interviews (n=120) examined its format and content validity. Patients found the new module acceptable with relevant content. The new module, the EORTC QLQ-CR29, is hypothesised as containing 6 scales and 11 single items. An international study examining its clinical and psychometric validity will be performed.

An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma.

AIM: To test the reliability, validity and sensitivity of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-MY24 questionnaire, designed to assess the quality of life of myeloma patients with the QLQ-C30. METHODS: The study was carried out through the EORTC Quality of Life Group using clinical trials in seven countries. All trials used the QLQ-C30 and QLQ-MY24 at baseline and a follow-up timepoint. RESULTS: Two hundred and forty patients participated. The questionnaires were acceptable to patients. The hypothesised scale structure (disease symptoms, side-effects, body image and future perspective) was confirmed by multi-trait scaling, internal consistency and correlation analysis. Most scales demonstrated sensitivity to change and discriminated between clinically different patients. The social support scale (4 items) was removed due to observed ceiling effects. CONCLUSION: The final questionnaire contains 20 items, QLQ-MY20, and is a reliable and valid instrument recommended for use with the QLQ-C30 in myeloma patients.

Determinants of patient satisfaction in oncology settings from European and Asian countries: preliminary results based on the EORTC IN-PATSAT32 questionnaire.

The aim of this study was to identify factors associated significantly with hospitalised cancer patients' satisfaction with care. Patients were recruited from four geographical/cultural groups, including five European countries and Taiwan. They rated their level of satisfaction by completing the EORTC IN-PATSAT32 questionnaire at home. Additionally, data were collected on the sociodemographic and clinical characteristics and the quality of life of the patients, as well as on institutional characteristics. Of 762 patients recruited, 647 (85%) returned a completed questionnaire. The number of nurses and doctors per bed, institution size, geo-cultural origin, ward setting, teaching/non-teaching setting, treatment toxicity, global health status, participation in clinical trials and education level were all associated significantly at the multivariate level with satisfaction with doctor and nurse interpersonal skills, information provision, availability, and/or overall satisfaction. A number of patient-, institutional- and culture-related factors are associated with the perceived quality of cancer care. Future studies, with appropriate sampling frames and stratification procedures, are needed to better understand cross-national and cross-cultural differences in cancer patient satisfaction.