Dialysis-dependent renal failure at diagnosis continues to be associated with very poor outcome in multiple myeloma - response to Murphy et al

The study by Murphy et al supports the observation made by several groups regarding the benefit of the novel agents in both young and elderly patients affected by multiple myeloma (MM) (Kumar et al, 2008; Ludwig et al, 2008; Turesson et al, 2010; Pozzi et al, 2013). Their single institution data collected over 18 years in 262 patients shows an improvement in overall survival (OS) starting from 1995 with an OS not yet reached in the period 2007–2012, after the introduction of bortezomib in their clinical practice. However the study clearly highlights renal insufficiency as a very poor prognostic factor, with a median OS shorter than 1 year in patients requiring dialysis. In the past few years many attempts have been made to classify and stratify patients based on various refined biological characteristics, however, as clearly stated here, the clinical presentation, particularly organ damage, still represents a negative prognostic factor that not even modern medicine has been able to overcome. The introduction of the International Staging System Criteria (ISS) (Greipp et al, 2005) only indirectly takes renal function into account, while the Durie and Salmon Criteria differentiates stage ‘A’ and ‘B’ MM based on kidney damage (Durie & Salmon, 1975). However Durie-Salmon ‘B’ stage is based on a creatinine cut-off point of 177 lmol/l and it is unable to better differentiate between moderate and severe impairment of renal damage requiring dialysis. It is also unable to predict the response to the treatment and reversibility of the organ damage, between possibly transitory kidney impairment due to dehydration, hyperuricaemia and hypercalacemia, and cast nephropathy. In this subset of MM patients it would be beneficial to introduce further parameters in the staging system (i.e. glomerular filtrate; type of light chain) in order to better stratify the risks and prevent treatment-related toxicity. For this reason, ad hoc clinical trials for this group of patients are strongly needed (Haynes et al, 2012). Finally, the Murphy study highlights the selection of patients enrolled in clinical trials and the necessity to evaluate the survival in the population of every day clinical practice, together with the need to develop high resolution analysis from data collected by cancer registers. Moreover, early diagnosis, compared with late or misdiagnosis, especially for light chains MM, is mandatory to prevent severe organ damage

The undergraduate nursing student evaluation of clinical learning environment: an Italian survey [La valutazione dell'ambiente di apprendimento clinico da parte degli studenti del Corso di Laurea in Infermieristica: una indagine italiana]

BACKGROUND: Nursing students have to deal with many different clinical and practical aspects of knowledge to become skilled professionals. Student perception may be considered an indicator of teaching quality, since positive perception of students is strictly related to their effective professional learning. The Clinical Learning Environment and Supervision plus Nurse Teacher (CLES+T) scale is considered the gold standard psychometric instrument to evaluate both the quality and the climate of clinical learning environment. AIMS: To evaluate the quality of nurse teaching by means of CLES+T scale and to highlight significant correlations between CLES+T scale and selected characteristics of both students and clinical environments. METHODS: On 4 March 2013, a cross-sectional survey was conducted at University of Modena: CLES+T scale was administered during a plenary convocation to 242 nursing students who attended the second and third years of Nursing Degree. All 34 items of the scale were statistically analysed using the median test. RESULTS: The median values were uniformly represented by "4" level (on the Likert scale). The final marks of clinical learning experience were the only variable statistically significantly related to the scale scores. The paediatrics and emergency areas obtained the highest scale scores. CONCLUSIONS: The nursing student evaluations were uniformly positive and related to their positive final marks. A positive ward atmosphere was identified as especially important in this study. These data indicate that a non-hostile and hospitable environment can favour the best clinical learning. We conclude that CLES+T scale can be a useful instrument to explore the clinical climate in all hospital areas and to highlight critical clinical situations

Therapy-Related Myeloid Neoplasm in Non-Hodgkin Lymphoma Survivors

Relatively little data on secondary cancers is available regarding patients treated for non-Hodgkin lymphoma (NHL), compared with those treated for Hodgkin lymphoma. Evolving treatment regimens have improved survival outcomes for NHL patients. As a result of this improvement, secondary malignancies are becoming an important issue in NHL survivors. This review aims to report data on this topic previously published by our group, adding unpublished results from the Modena Cancer Registry (MCR). We recently performed four studies about secondary neoplasms in NHL survivors: two studies analysing the risk of secondary neoplasms in patients treated for indolent and aggressive NHL; a meta-analysis of 23 studies investigating the risk of secondary malignant neoplasm (SMN) after NHL treatment; and a still-unpublished study evaluating the incidence of therapy-related myeloid neoplasm (t-MN) in patients treated for NHL (from the MCR database). The first two studies analysed 563 patients with indolent NHL and 1280 patients with diffuse large B-cell lymphoma (DLBCL) enrolled in the Gruppo Italiano Studio Linfomi (GISL) trials. Results showed that the cumulative incidence of secondary tumours was 10.5% at 12 years for indolent NHL and 8.2% at 15 years for DLBCL. Results of the meta-analysis indicated that NHL patients experienced a 1.88-fold increased risk for SMN compared with the general population; the standardized incidence risk (SIR) for secondary acute myeloid leukaemia (AML) was 11.07. Based on data from the MCR from 2000 through 2008, we found that the SIR was 1.63 for developing a secondary malignancy after NHL, and 1.99 for developing secondary haematological malignancies. Regarding myelodysplastic syndrome and/or AML incidence, nine NHL patients developed t-MN with a higher risk than expected (SIR 8.8, 95% CI: 4.0–16.6). In conclusion, patients treated for NHL are at increased risk of developing SMN. Regarding t-MN, data from the meta-analysis and the MCR demonstrate an excessive risk of developing AML (SIR 11.07 and 5.7, respectively) compared with solid SMN after treatment for NHL. Thus long-term monitoring should be considered for NHL survivors

The histone deacetylase inhibitor romidepsin synergizes with lenalidomide and enhances tumor cell death in T-cell lymphoma cell lines

We investigated the cytotoxic interactions of romidepsin, a histone deacetylase inhibitor, and lenalidomide, an immunomodulatory agent, in a T-cell lymphoma preclinical model. Hut-78 and Karpas-299 cells were treated with romidepsin and lenalidomide alone and in combination. The interaction between romidepsin and lenalidomide was evaluated by the Chou–Talalay method, and cell viability and clonogenicity were also evaluated. Apoptosis, reactive oxygen species (ROS) levels, and cell cycle distribution were determined by flow cytometry. ER stress, caspase activation, and the AKT, MAPK/ERK, and STAT-3 pathways were analyzed by Western blot. Combination treatment with romidepsin and lenalidomide had a synergistic effect in Hut-78 cells and an additive effect in Karpas-299 cells at 24 hours and did not decrease the viability of normal peripheral blood mononuclear cells. This drug combination induced apoptosis, increased ROS production, and activated caspase-8, −9, −3 and PARP. Apoptosis was associated with increased hallmarks of ER stress and activation of UPR sensors and was mediated by dephosphorylation of the AKT, MAPK/ERK, and STAT3 pathways.The combination of romidepsin and lenalidomide shows promise as a possible treatment for T-cell lymphoma. This work provides a basis for further studies

Risk of second primary malignancy in breast cancer survivors: A nested population-based case-control study

Purpose: Evolving therapies have improved the prognoses of patients with breast cancer; and currently, the number of long-term survivors is continuously increasing. However, these patients are at increased risk of developing a second cancer. Thus, late side effects are becoming an important issue. In this study, we aimed to investigate whether patient and tumor characteristics, and treatment type correlate with secondary tumor risk. Methods: This case-control study included 305 patients with a diagnosed second malignancy after almost 6 months after the diagnosis of primary breast cancer and 1,525 controls (ratio 1:5 of cases to controls) from a population-based cohort of 6,325 women. The control patients were randomly selected from the cohort and matched to the cases according to age at diagnosis, calendar period of diagnosis, disease stage, and time of follow-up. Results: BRCA1 or BRCA2 mutation, human epidermal growth factor receptor 2 (HER2)+ status, chemotherapy, and radiotherapy were related to increased risk of developing a second cancer, whereas hormonotherapy showed a protective effect. Chemotherapy, radiotherapy, and estrogenic receptor level <10% increased the risk of controlateral breast cancer. HER2+ status increased the risk of digestive system and thyroid tumors, while BRCA1 or BRCA2 mutation increased the risk of cancer in the genital system. Conclusion: Breast cancer survivors are exposed to an excess of risk of developing a second primary cancer. The development of excess of malignancies may be related either to patient and tumor characteristics, such as BRCA1 or BRCA2 mutation and HER2+ status, or to treatments factors

Second malignancies after treatment of diffuse large B-cell non-Hodgkin's lymphoma: a GISL cohort study

BACKGROUND: Improved treatment has increased the life expectancy of patients with non-Hodgkin's lymphoma, but few studies have addressed the issue of second cancer in patients treated for diffuse large B-cell lymphoma. The aims of this study were to determine the incidence and time free of second cancers in this subset of patients. DESIGN AND METHODS: We evaluated a cohort of 1280 patients with diffuse large B-cell lymphoma who were first treated between 1988 and 2003. We utilized the central database of the Gruppo Italiano Studio Linfomi, which includes data on demographics, clinical characteristics, laboratory parameters, treatment and follow-up of all patients with non-Hodgkin's lymphoma enrolled in clinical trials. RESULTS: After a median follow-up of 51 months, 48 patients had developed a second cancer: 13 hematologic malignancies and 35 solid tumors. The overall standardized incidence ratio in our cohort (with a median age of 58 years) matched that of the general Italian population. The incidence ratio of second tumors was age related, and the age groups 20-39 and 40-59 years showed an increased risk. Overall, the cumulative incidence of second cancer was 8.2% at 15 years. A multivariate analysis showed that older age at the time of diagnosis of lymphoma had a negative influence on the time free of second tumors. CONCLUSIONS: In our cohort, only young patients showed an increased incidence ratio of second malignancies, while the incidence ratio in patients aged over 59 years matched the incidence in the Italian general population. Demographics, baseline characteristics, laboratory parameters and treatment modalities did not have any significant impact on the incidence ratio of a second cancer

The undergraduate nursing student evaluation of clinical learning environment: an Italian survey

AbstractBackground: Nursing students have to deal with many different clinical and practical aspects of knowledge to become skilled professionals. Student perception may be considered an indicator of teaching quality, since positive perception of students is strictly related to their effective professional learning. The Clinical Learning Environment and Supervision plus Nurse Teacher (CLES+T) scale is considered the gold standard psychometric instrument to evaluate both the quality and the climate of clinical learning environment. Aims: To evaluate the quality of nurse teaching by means of CLES+T scale and to highlight significant correlations between CLES+T scale and selected characteristics of both students and clinical environments. Methods: On 4 March 2013, a cross-sectional survey was conducted at University of Modena: CLES+T scale was administered during a plenary convocation to 242 nursing students who attended the second and third years of Nursing Degree. All 34 items of the scale were statistically analysed using the median test. Results: The median values were uniformly represented by "4" level (on the Likert scale). The final marks of clinical learning experience were the only variable statistically significantly related to the scale scores (p&lt;0.01). The paediatrics and emergency areas obtained the highest scale scores. Conclusions: The nursing student evaluations were uniformly positive and related to their positive final marks. A positive ward atmosphere was identified as especially important in this study. These data indicate that a non-hostile and hospitable environment can favour the best clinical learning. We conclude that CLES+T scale can be a useful instrument to explore the clinical climate in all hospital areas and to highlight critical clinical situations. Key-words: clinical learning environment, nursing student, CLES+T scale RiassuntoIntroduzione: Per divenire dei professionisti qualificati, gli studenti infermieri sperimentano diverse esperienze di tirocinio clinico. L'opinione dello studente può essere considerata un indicatore della qualití  dell'insegnamento e una percezione positiva dell'esperienza di tirocinio si correla strettamente ad un apprendimento efficace. La scala CLES+T (Clinical Learning Environment and Supervision plus Nurse Teacher) è lo strumento psicometrico "gold standard" per valutare la qualití  dell'ambiente di apprendimento clinico. Scopo: Valutare la qualití  dell'ambiente di apprendimento clinico mediante la scala (CLES+T) ed evidenziare significative correlazioni inerenti le caratteristiche degli studenti, del modello tutoriale e dell'ambiente clinico. Metodo: Il 4 marzo 2013, durante una convocazione plenaria, è stata somministrata la scala CLES+T ai 242 studenti del 2° e 3° anno del Corso di Laurea in Infermieristica di Modena (Universití  di Modena e Reggio Emilia). Tutti i risultati sono stati statisticamente analizzati (Test della mediana). Risultati: Tutti i valori mediani si sono attestati ad un livello "4" (scala di Likert). La valutazione ottenuta dallo studente al termine del tirocinio clinico è l'unica variabile statisticamente correlata ai punteggi della scala (p&lt;0.01), più il voto è basso peggiore risulta la valutazione dell'esperienza di tirocinio. In base all'opinione degli studenti le aree cliniche pediatriche e critiche hanno valutazioni più elevate. Conclusioni: Le valutazioni degli studenti erano uniformemente positive ed erano correlate al voto finale di tirocinio. Un clima di apprendimento positivo è stato considerato molto importante in questo studio. Questi risultati suggeriscono che un ambiente di apprendimento clinico favorevole e non ostile può influenzare gli esiti dell'apprendimento degli studenti. Concludiamo affermando che la scala CLES+T può essere uno strumento utile per esplorare il clima in tutte le aree ospedaliere e consentire di mettere in evidenza situazioni critiche.Parole Chiave: ambiente di apprendimento clinico, studente infermiere, scala CLES+

Absolute monocyte count at diagnosis could improve the prognostic role of early FDG-PET in classical Hodgkin lymphoma patients

Recently published international guidelines suggested that positron emission tomography (PET)-computed tomography (CT) could be utilized for response assessment using the Deauville criteria in fluorodeoxyglucose (FDG)-avid lym- phomas (Meignan et al, 2012). Interim PET (I-PET) scan- ning seems highly predictive of treatment failure in Hodgkin Lymphoma (HL) patients. We recently showed that the absolute monocyte count (AMC) has prognostic value in patients with classical HL (cHL) (Tadmor et al, 2015). Here, we show that the com- bined use of I-PET and AMC at diagnosis enables a more accurate projection of patient outcome in cHL. The present study is an ancillary branch of the analysis reported by Tadmor et al, (2015). Patients with histopatho- logical diagnosis of cHL previously enrolled in the Gruppo Italiano Studio Linfomi trials were eligible if data on all clini- cal and laboratory features and treatments, reported I-PET results, treatment response and follow-up were available. Response was defined according to the revised International Working Group guidelines (Cheson et al, 1999). An absolute lymphocyte count &lt;06 9 10 9 /l and AMC &gt; 075 9 10 9 /l were used as cut-off points. I-PET was performed after 2 cycles of treatment. A positive or negative I-PET was defined by the local investigators’ interpretation of the nuclear physi- cian’s scan report, which was based on a visual qualitative assessment. The principal end-point of the study was the impact of I-PET and AMC on progression-free survival (PFS); their impact on overall survival (OS) was the secondary end-point. Survival functions were estimated using the Kaplan–Meier method. Statistical comparisons between curves were per- formed with log-rank test, and the effect of the covariate was reported as hazard ratios (HR), from Cox regression. All patients had a diagnosis of cHL; 76% of cases had the nodular sclerosis (NS) subtype. Seventy-six patients (64%) were treated with classical ABVD (doxorubicin, bleomycin, vincristine, dacarbazine), and 23 (19%) and 19 (16%) with the more intensive BEACOPP (bleomycin, etoposide, doxoru- bicin, cyclophosphamide, vincristine, procarbazine, pred- nisone) and COPPEBVCAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, bleomycin) regimens (Federico et al, 2009), respectively. Of the entire cohort, 104 patients (88%) achieved complete remission. Twenty-six patients had a positive I-PET (22%) and 28 (24%) had AMC &gt; 075 9 10 9 /l at diagnosis. The median follow-up of the entire cohort was 88 months (range 5–142 months). The estimated 5-year OS was 91% (95% confidence interval [CI]: 84–95%). The 5-year PFS was 80% (95% CI: 71–86%). Patients with positive I-PET showed a worse PFS compared to patients with negative I-PET (51% and 88%, respectively; HR 587 [95% CI: 256–135]). Patients with AMC &gt; 075 9 10 9 /l at diagnosis had a worse PFS compared to patients with AMC ≤ 075 9 10 9 /l (58% and 87%, respectively; HR 373 [95% CI: 161–864]). Multi- ple Cox proportional hazards (PH) regression, adjusted for International Prognostic Score 3–7, confirmed the prognostic role of I-PET (HR 532 [95% CI: 230–123]; P &lt; 0001) and AMC &gt;075 9 10 9 /l (HR 319 [95% CI: 132–768]; P = 0010). Figure 1A, B shows the PFS for I-PET and AMC, and Table I shows the uni- and multivariate Cox PH regres- sion for PFS. The prognostic role of I-PET and AMC on OS was also confirmed. Given the strong predictive value of both I-PET and AMC, we stratified patients by positive or negative I-PET and AMC &gt; 075 9 10 9 /l or ≤075 9 10 9 /l into 3 groups with different levels of risk. The low risk level (negative I- PET and AMC ≤ 075 9 10 9 /l; n = 73, 62%) had a 5-year PFS of 90% (95% CI: 80–96%), the intermediate level (I-PET positive or AMC &gt; 075 9 10 9 /l; n = 36, 51%) had a 5-year PFS of 73% (95% CI: 55–85%), and the high risk level (I-PET positive and AMC &gt; 075 9 10 9 /l; n = 9, 8%) had a 5-year PFS of 17% (95% CI: 1–49%). The log-rank test between the intermediate and low levels and between the high and intermediate levels were significant (P = 0 007, P = 0001, respectively). For OS, the difference between the intermediate and low risk levels tended to narrow (P = 0232), while the difference between the high and inter- mediate levels was significantly different (P &lt; 0001). Fig- ure 1C, D shows the PFS and OS stratified by risk group. The test for trend in PFS and OS was significant (P &lt; 0001). The rationale for using AMC as a prognostic parameter in cHL is relevant because immunohistochemical and molecular data, including the gene expression profile, have identified a key role for monocytes and macrophages in the biology of cHL (Steidl et al, 2010; Porrata et al, 2012; Tan et al, 2012; Koh et al , 2015; Tadmor et al, 2015). It might therefore bepossible that AMC is associated with the number of tumour- associated macrophages (TAMs) in the microenvironment. If so, then it could be considered as a biomarker of reactive cells that is easily detectable in peripheral blood. The FDG- PET scan is currently considered the most precise staging method and may also be used to provide an early prediction of treatment efficacy There is a strong suggestion that reactive cells are respon- sible for the increased FDG uptake at baseline, as they account for 99% of Hodgkin tumours (Gallamini, 2010). Furthermore, early responses to treatment have been sug- gested to demonstrate the elimination of reactive cells, or at least the disappearance of their activity, and are indirect surrogates of tumour chemo-sensitivity (Gallamini &amp; Kostakoglu, 2012). Thus, the FDG-PET scan could be considered a biomarker of the extent and activity of the tumour microenvironment. However, in clinical practice, patients with negative I-PET can rapidly progress during induction treatment, while other patients with positive I-PET may eventually achieve a CR. Therefore, there is a need to further improve the predictive power of I-PET. By combining the AMC at diagnosis with the I-PET results, we showed that it is possible to increase the discriminatory power of I-PET alone in identifying cHL patients with poor PFS and OS. We are fully aware that our study has many weaknesses, such as its retrospective nature, the small number of patients and the lack of use of the Deauville criteria. However, our results suggest that it is pos- sible to further improve the already high predictive power of PET by combining it with a simple and inexpensive surrogate biomarker of reactive cells that are easily detectable in peripheral blood

Secondary malignancies after treatment for indolent non-Hodgkin's lymphoma: a 16-year follow-up study.

Relatively little information is available on the incidence of secondary cancer in non-Hodgkin's lymphoma. The aim of this long-term follow-up study was to determine the incidence, the time free of second tumors, and risk factors for developing secondary cancer in a homogeneous group of patients with non-Hodgkin's lymphoma. DESIGN AND METHODS: We evaluated a total of 563 patients with indolent non-Hodgkin's lymphoma enrolled in Gruppo Italiano Studio Linfomi trials from 1988 to 2003. RESULTS: After a median follow-up of 62 months, 39 patients (6.9%) developed secondary cancer: 12 myelodysplastic syndromes/acute myeloid leukemia, and 27 solid tumors. The overall standardized incidence ratio of secondary malignancy in patients with non-Hodgkin's lymphoma was higher than the risk of malignancy in the general population. The standardized incidence ratio was elevated in male patients and in patients under 65 years old at first treatment. Overall, the cumulative incidence of secondary cancer at 12 years was 10.5%, after correction in a competing-risk model. Univariate and multivariate Cox regression analyses showed that older age at the time of diagnosis, male sex, and fludarabine-containing therapy had significant negative impacts on the time free of second tumors. CONCLUSIONS: We have identified subgroups of non-Hodgkin's lymphoma patients with increased standardized incidence ratios of secondary malignancy and variables that have a negative impact on the time free of second tumors. This information could help physicians to select the most appropriate treatments. Finally, taking into account the possible occurrence of secondary neoplasia, long-term monitoring must be considered

Absolute monocyte count and lymphocyte-monocyte ratio predict outcome in nodular sclerosis Hodgkin lymphoma: Evaluation based on data from 1450 patients

Objective: To verify whether absolute monocyte count (AMC) and lymphocyte-monocyte ratio (LMR) at diagnosis are valid prognostic parameters in classical Hodgkin lymphoma (cHL). Patients and Methods: Data were collected from 1450 patients with cHL treated in Israel and Italy from January 1, 1988, through December 31, 2007. Results: The median age of the patients was 33 years (range, 17-72 years), and 70% (1017) of the patients had nodular sclerosis (NS); the median follow-up duration was 87 months. The best cutoff value for AMC was 750 cells/mm3, and the best ratio for LMR was 2.1. The adverse prognostic impact of an AMC of more than 750 cells/mm(3) was confirmed for the entire cohort, and its clinical significance was particularly evident in patients with NS histology. The progression-free survival (PFS) at 10 years for an AMC of more than 750 cells/mm(3) was 65% (56%-72%), and the PFS at 10 years for an AMC of 750 cells/mm(3) or less was 81% (76%-84%; P<.001). The overall survival (OS) at 10 years for an AMC of more than 750 cells/mm3 was 78% (70%-85%), and the OS at 10 years for an AMC of 750 cells/mm(3) or less was 88% (84%-90%; P=.01). In multivariate analysis, both AMC and LMR maintained prognostic significance for PFS (hazard ratio [HR], 1.54, P=.006, and HR, 1.50, P=.006) after adjusting for the international prognostic score, whereas the impact on OS was confirmed (HR, 1.56; P=.04) only in patients with NS and an AMC of more than 750 cells/mm(3). Conclusion: This study confirms that AMC has prognostic value in cHL that is particularly significant in patients with NS subtype histology. This finding links the known impact of macrophages and monocytes in Hodgkin lymphoma with routine clinical practice