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International audience; Background: Lymphomas are costly diseases that suffer from a lack of detailed economic information, notably in a real-world setting. Decision-makers are increasing the search for Real-World Evidence (RWE) to assess the impact, in real-life, of healthcare management and to support their public decisions. Thus, we aimed to assess the real-world net costs of the active treatment phases of adult Hodgkin Lymphoma (HL), Follicular Lymphoma (FL) and Diffuse Large B Cell Lymphoma (DLBCL).Methods: We performed a retrospective cohort study using population-based data from a national representative sample of the French population covered by the health insurance system. Cost analysis was performed from the French health insurance perspective and took into account direct and sick leave compensation costs (e2,018). Healthcare costs were studied over the active treatment phase. We used multivariate modeling to adjust cost differences between lymphoma subtypes.Results: Analyses were performed on 224 lymphoma patients and 896 controls. The mean additional monthly costs due to HL, FL and DLBCL patients were respectively e5,188, e3,242 and e7,659 for the active treatment phase. The main additional cost driver was principally inpatient stay (hospitalization costs and costly cancer-related drugs), followed by outpatient medication and productivity loss. When adjusted, DLBCL remains significantly the most costly lymphoma subtype.Conclusion: This study provides an accurate assessment of the main lymphoma subtypes related cost with high magnitude of details in a real-world setting. We underline where potential cost saving could be realized via the use of biosimilar medication, and where lymphoma management could be improved with the early management of adverse events.

Background Previous studies have suggested that lymphoma survivors commonly display altered Health-Related Quality of Life (HRQoL). Because these were predominantly cross-sectional studies, the dynamic of events as well as the factors which influence HRQoL remain to be determined. Methods We conducted a prospective study on a cohort of 204 Hodgkin and non-Hodgkin lymphoma survivors who remained disease-free 2 years after undergoing chemotherapy (referred to the M0-M12-M24 periods). Results We found that although Physical and Mental Component Scores (PCS and MCS) of HRQoL significantly improved from M0 to M24 in the vast majority of patients (favorable group), approximately 20% of patients displayed severe alterations in HRQoL (global SF-36 scores Conclusions Although the HRQoL of lymphoma survivors generally improved over time, persistent and severe HRQoL alterations still affected approximately one fifth of patients, resulting in important social consequences. This specific group, which presents with identifiable risk factors, may benefit from early, targeted psycho-social support.

Delivering of 80% planned relative dose intensity (RDI) of fludarabine-cyclophosphamide-rituximab (FCR) is key to benefit from longer progression free survival (PFS) and survivals in CLL. In this randomized trial, we sought to investigate whether a telephone intervention strategy (called AMA) delivered by an oncology nurse could reduce the risk of RDI 80% by alleviating adverse events and supporting patients' adherence. Sixty FCR patients were randomized 1:1 for AMA (stratified on Binet stage C). As per guidelines, patients received pegfilgrastim as primary prophylaxis of febrile neutropenia. At the end of therapy, RDI 80% was reported in 31% of patients, shortening PFS (median 26 months versus not reached, P = 0.021) and OS at 3 years (100 vs 70%, P = 0.0089). Oncology nurse interventions tended to significantly reduce this event (RDI 80%: 41.4% in non-AMA versus 20.7% in AMA patients (p = 0.09)). By adjusting our logistic regression model on published parameters exposing to RDI 80%, we found that AMA protected significantly against the risk of reduced RDI (OR = 0.22, IC95% 0.05-0.84, p = 0.04), independently of grade 3/4 neutropenia ( 15% per cycle) and febrile neutropenia ( 5% per cycle) events. As a conclusion, we confirmed that 20% reduction of FCR dose-intensity was detrimental for PFS/OS, but that oncology nurse interventions reduced the risk of dose concessions.

The aim of this study was to measure the prevalence of FCR among a sample of French lymphoma survivors and to determine factors associated with clinical levels of FCR. The study was conducted with two cross-sectional measures: sociodemographic and anxiety, depression as well as health-related quality of life (HRQoL) scores were measured at the baseline of the post-cancer period and FCR was evaluated during the first 3 years of survivorship. The prevalence of clinical levels of FCR (≥13) was evaluated by the Fear of Cancer Recurrence Inventory - Short Form (FCRI-SF) among non- and Hodgkin lymphoma survivors undergoing prior first-line chemotherapy. Among 108 lymphoma survivors with an average follow-up of 1.6 years (range 0.3-3.0 years), clinical levels of FCR (≥13) were observed for 44.4% (n = 48). Multivariate analysis indicated that baseline anxiety and low quality of life were related to clinically significant FCR levels.

The cancer experience may be marked by repeat stressors and/or traumas. The aim of our study was to assess traumatic events in a group of patients diagnosed with lymphoma and to determine which of these contribute to the development of Post-Traumatic Stress Disorder/PTSD. Two weeks after receiving a diagnosis of lymphoma, patients were referred for an assessment of peritraumatic distress (using the Peritraumatic Distress Inventory/PDI) and peritraumatic dissociation (using the Peritraumatic Dissociative Experiences Questionnaire/PDEQ). Three months after the diagnosis, we recorded the following parameters: the patients' worst experiences, the presence of PTSD symptoms, using the PTSD CheckList/PCL, as it related to the diagnosis, and symptoms of anxiety using the Hospital Anxiety and Depression/HAD scale and of depression using the Beck Depression Inventory/BDI-II. The study recruited 129 patients, with a mean age of 46 years (SD = 17.3); 70 (54%) men, 87 (67.5%) with Non-Hodgkin's lymphoma, and 42 with Hodgkin's lymphoma. Two weeks after the diagnosis, 49% of patients reported peritraumatic distress, and 20% peritraumatic dissociation, during or immediately after being informed of the lymphoma diagnosis. Three months after the diagnosis, the severity of PTSD symptoms was evaluated. At this stage none of the patients suffered PTSD, but 29 (23%) individuals exhibited partial PTSD: 13.4% correlated it to receiving the lymphoma diagnosis, 8% to telling family members, and 1.6% to adverse effects. Peritraumatic distress and dissociation as a result of receiving a lymphoma diagnosis, as well as anxiety and a mucositis within the first 3 months post-diagnosis, were factors that were significantly associated with PTSD symptoms, accounting for 35.8% in PTSD symptom load. Our study reveals that clinicians should assess the impact of a number of stressors, which are risk factors for PTSD symptoms, starting from the time point of the initial lymphoma diagnosis.

Background Previous studies have indicated that accompanying socially underserved cancer patients through Patient Navigator (PN) or PN-derived procedures improves therapy management and reassurance. At the Cancer Institute of Toulouse-Oncopole (France), we have implemented AMA (Ambulatory Medical Assistance), a PN-based procedure adapted for malignant lymphoma (ML) patients under therapy. We found that AMA improves adherence to chemotherapy and safety. In low-middle income countries (LMIC), refusal and abandonment were documented as major adverse factors for cancer therapy. We reasoned that AMA could improve clinical management of ML patients in LMIC. Methods This study was set up in the Abidjan University Medical Center (Ivory Coast) in collaboration with Toulouse. One hundred African patients were randomly assigned to either an AMA or control group. Main criteria of judgment were refusal and abandonment of CHOP or ABVD chemotherapy. Results We found that AMA was feasible and had significant impact on refusal and abandonment. However, only one third of patients completed their therapy in both groups. No differences were noted in terms of complete response rate (CR) (16% based on intent-to-treat) and median overall survival (OS) (6 months). The main reason for refusal and abandonment was limitation of financial resources. Conclusion Altogether, this study showed that PN may reduce refusal and abandonment of treatment. However, due to insufficient health care coverage, its ultimate impact on OS remains limited.

Few recent studies from registries have reported an improvement in overall survival of younger patients with acute myeloid leukemia (AML). However, reasons for this improvement are not defined. We analyzed the therapeutic course and outcome of 976 patients treated by intensive chemotherapy between 2000 and 2014. The number of patients receiving allogeneic stem cell transplantation in first or second response significantly increased over time whereas autologous transplantation was progressively abandoned. In the 513 younger patients, there were no differences in first complete response, induction failure, incidence of relapse, or non-relapse mortality over time. The period of time was significantly associated with a better overall survival especially in 2010–2014. The 2010–2014 period effect was still significant in multivariate analysis and was independent of allogeneic stem cell transplantation. In the 463 older patients, there was a significant interaction between the period and leukocytosis in multivariate analysis meaning that the 2010–2014 period had only an impact in patients with white blood cell count >50 giga/L for response and overall survival. Progresses have been made in each phase of the therapeutic course of younger AML patients resulting in survival improvement. In older patients, the outcome of hyperleukocytic patients has significantly improved in 2010–2014.

// Sarah Bertoli 1, 2, 3 , Arthur Sterin 4 , Suzanne Tavitian 1 , Lucie Oberic 1 , Loic Ysebaert 1, 2, 3 , Reda Bouabdallah 4 , Francois Vergez 3, 5 , Audrey Sarry 1 , Emilie Berard 6, 7 , Francoise Huguet 1 , Guy Laurent 1, 2 , Thomas Prebet 4, 8 , Norbert Vey 4, 8, 9, * , Christian Recher 1, 2, 3, * 1 Service d'Hematologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France 2 Universite Toulouse III Paul Sabatier, Toulouse, France 3 Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Toulouse, France 4 Service d’Hematologie, Institut Paoli-Calmettes, Marseille, France 5 Laboratoire d’Hematologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France 6 Service d’Epidemiologie, Centre Hospitalier Universitaire de Toulouse, Toulouse, France 7 UMR 1027, INSERM-Universite de Toulouse III, Toulouse, France 8 Departement d'Oncologie Moleculaire, Centre de Recherche en Cancerologie de Marseille (CRCM), Institut Paoli-Calmettes, UMR1068 Inserm, Marseille, France 9 Aix-Marseille University, Marseille, France * co-senior authors Correspondence to: Christian Recher, email: recher.christian@iuct-oncopole.fr Keywords: leukemia, therapy-related acute myeloid leukemia, second cancer, lymphoma, chronic lymphocytic leukemia Received: May 26, 2016 Accepted: November 01, 2016 Published: November 10, 2016 ABSTRACT Therapy-related acute myeloid leukemia (t-AML) is a heterogeneous entity most frequently related to breast cancer or lymphoproliferative diseases (LD). Population-based studies have reported an increased risk of t-AML after treatment of lymphomas. The aim of this study was to describe the characteristics and outcome of 80 consecutive cases of t-AML following treatment of LD. t-AML accounted for 2.3% of all AML cases, occurred 60 months after LD diagnosis, and were characterized by a high frequency of FAB M6 AML and poor-risk cytogenetic abnormalities. Time to t-AML diagnosis was influenced by patient age, type of LD, and treatment. Among the 48 t-AML patients treated with intensive chemotherapy, median overall survival (OS) was 7.7 months compared to 26.1 months in de novo , 4.2 months in post-myeloproliferative neoplasm, 9.4 months in post-myelodysplastic syndrome, 8.6 months in post-chronic myelomonocytic leukemia AML, 13.4 months in t-AML secondary to the treatment of solid cancer, and 14.7 months in breast cancer only. OS of post-LD t-AML patients was significantly influenced by age, performance status, myelodysplastic syndrome prior to LD/t-AML, and treatment regimen for LD. Thus, t-AML following lymphoid malignancies treatment should be considered as very high-risk secondary AML. New treatment strategies in patients with LD/t-AML are needed urgently.

Macrophage migration inhibitory factor (MIF) was originally identified in 1966 by Bloom and Bennett as a pro-inflammatory cytokine involved in the inhibition of macrophage motility. Since then, studies have investigated the functional contribution of this pro-inflammatory cytokine in several immune diseases, including rheumatoid arthritis and lupus erythematous. Recently, MIF has been reported to be involved in a variety of neoplastic diseases. The present review discusses previous cancer research studies that have investigated the involvement of MIF in carcinogenesis, disease prognosis, tumor cell proliferation and invasion, and tumor-induced angiogenesis. Finally, potential therapeutic approaches based on the use of MIF antagonists and neutralizing antibodies are examined. The review concludes that MIF could be a good prognostic biomarker in several types of cancer, but also that the inhibition of MIF could represent a novel therapy against cancer.

The objective of our study was to assess the rate of work adjustments 1 year after the diagnosis in a population of female breast cancer (BC) survivors, in the context of the French system of social protection. We also characterised these adjustments and their influence on the reduction of professional exclusion of patients 1 year after the diagnosis. This observational, prospective study was conducted from February 2015 to April 2016 among female patients with BC. Inclusion criteria were women aged between 18 and 65 years, treated for BC and integrated into the labour market at the time of diagnosis (working or on sick leave). Exclusion criteria were metastatic BC, retired patients and refusal to participate. A 1-year follow-up was scheduled, and data collection was performed with questionnaires. In total, 213 patients were included between February 2015 and April 2016. One year after the diagnosis (T1), among 185 BC survivors, 78 (42.2%) patients were working. Among them, 13 patients did not interrupt their occupational activity and 65 returned to work after a period of sick leave. Sixty-four patients returned to work after the end of chemotherapy (after 6 months), and one returned to work before this therapeutic threshold. Sixty-six patients (35.7%) benefited from at least one adjustment of their work conditions to facilitate their return to work (RTW) or maintenance at work: working hours were decreased for 43 patients, and workstation changes were performed for 22 patients. An occupational health physician was involved for some patients; work adjustments were prescribed to 42 patients, 7 patients had medical restrictions for physical reasons and 4 patients had restrictions for psychological reasons. Forty-three patients benefited from part-time work prescribed for therapeutic reasons. Referral to occupational health physicians and work adjustments remain limited in the process of RTW or maintenance at work after BC in France, despite their positive impact.

Therapeutic blockade of PD-1/PD-L1 shows promising results in Hodgkin&rsquo, s lymphoma (HL) and in some diffuse large B-cell lymphoma (DLBCL) patients, but biomarkers predicting such responses are still lacking. To this end, we recently developed a transcriptional scoring of immune escape (IE) in cancer biopsies. Using this method in DLBCL, we identified four stages of IE correlated with overall survival, but whether Hodgkin&rsquo, s lymphomas (HL) also display this partition was unknown. Thus, we explored the transcriptomic profiles of ~1000 HL and DLBCL using a comparative meta-analysis of their bulk microarrays. Relative to DLBCL, the HL co-clustered at the advanced stage of immune escape, displaying significant enrichment of both IE and T-cell activation genes. Analyses via transcriptome deconvolution and immunohistochemistry showed more CD3+ and CD4+ tumor-infiltrating lymphocytes (TILs) in HL than DLBCL. Both HL and non-GCB DLBCL shared a high abundance of infiltrating CD8+ T-cells, but HL had less CD68+CD163+ macrophages. The same cellular distribution of PD-1 and TIM-3 was observed in HL and DLBCL, though HL had more PD-L1 tumor cells and LAG-3 ME cells. This study illuminates the advanced stage of immune activation and escape in HL, consistent with the response to checkpoint blockade therapies for this type of lymphoma.

International audience; Alteration in the DNA replication, repair or recombination processes is a highly relevant mechanism of genomic instability. Despite genomic aberrations manifested in hematologic malignancies, such a defect as a source of biomarkers has been underexplored. Here, we investigated the prognostic value of expression of 82 genes involved in DNA replication-repair-recombination in a series of 99 patients with chronic lymphocytic leukemia without detectable 17p deletion or TP53 mutation. We found that expression of the POLN gene, encoding the specialized DNA polymerase ν (Pol ν) correlates with time to relapse after first-line therapy with fludarabine. Moreover, we found that POLN was the only gene up-regulated in primary patients’ lymphocytes when exposed in vitro to proliferative and pro-survival stimuli. By using two cell lines that were sequentially established from the same patient during the course of the disease and Pol ν knockout mouse embryonic fibroblasts, we reveal that high relative POLN expression is important for DNA synthesis and cell survival upon fludarabine treatment. These findings suggest that Pol ν could influence therapeutic resistance in chronic lymphocytic leukemia. (Patients’ samples were obtained from the CLL 2007 FMP clinical trial registered at: clinicaltrials.gov identifer: 00564512).

Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma (NHL) subtype, accounting for approximately 20% of all NHLs [1]. This indolent and incurable disease usually displays a low...

Glucocorticoids (GCs) are used in the treatment of cancer to induce programmed cell death in the transformed cells of the hematopoietic system and to reduce side effects. Additionally, GCs are described as an inhibitor of certain chemotherapy or radiation-induced apoptosis and also an inhibitor of cancer progression by downregulating or upregulating the expression of several genes. The present study used immunofluorescence to investigate the presence of the glucocorticoid receptor (GR) in MCF-7 cells, and the cell culture growth was determined by cell counting the number of cells following exposure to GC and/or dexamethasone (Dex). The presence and immunoreactivity of the GR were confirmed, and treatment with Dex (10-8-10-7 M) caused an inhibitory effect (30-35%) on the proliferative activity of the MCF-7 cells. This growth inhibitory effect was possibly produced by the pro-apopotic effect of Dex. Since Dex is administered systematically prior to breast cancer chemotherapy, the possible interactions between these drugs require further investigation., SCOPUS: ar.j, info:eu-repo/semantics/published

International audience; BackgroundBlood eosinophilia is a common laboratory abnormality, and its characterization frequently represents a quandary for primary care physicians. Consequently, in France, specialists and particularly hematologists, often must investigate patients who present with blood eosinophilia that often, but not always, occurs because of allergic causes. Both the Departments of Hematology and Parasitology at Toulouse University Hospitals established a collaboration to rule out allergic causes of eosinophilia, particularly helminthiases, prior to initiating more sophisticated investigations.MethodsSince 2004, the authors employed the same protocol to investigate eosinophilic outpatients who attended the clinic of Parasitology at Toulouse University Hospitals, and they reported the performance of this diagnostic procedure that was designed to be rapid (no hospitalization required) and only moderately expensive.ResultsA total of 406 patients who presented with blood eosinophilia greater than 0.5 (×109, giga cells per litter, G/L) had an allergic etiology in 350 (86.2%) cases. Among the remaining 56 subjects, 17 did not undergo a follow-up and 39 were referred to another specialized department, mostly Hematology. However, only 21 patients attended then were subsequently investigated. Non-allergic causes of eosinophilia, including 3 cases of the lymphoid variant of hypereosinophilic syndrome and 2 cases of myeloproliferative disorder, were identified in 14 patients, whereas 7 remained diagnosed as having idiopathic eosinophilia.ConclusionThis study underlines the need to investigate patients presenting with even moderate blood eosinophilia. The work-up that was employed appears to be efficient and versatile and may be used by any medical specialist, such as in hematology, infectious disease, or internal medicine departments, who needs to investigate eosinophilic patients and should initially rule out any etiology of allergic eosinophilia.

Agentle ultrafiltration can be achieved using a long and slow hemodialysis. It is easier to achieve gentle ultrafiltration if the interdialytic weight intake is moderate ( i.e., if the patient maintains a low sodium diet) and if diffusion allows for a negative or nil sodium balance during the session ( i.e., dialysate sodium < 140 mmol/L). A gentle ultrafiltration allows control of blood pressure by reducing the extracellular volume to its ideal level, the "dry weight," at the end of the session. Controlling blood pressure reduces cardiovascular mortality, which is by far the foremost cause of death in hemodialysis. Controlling blood pressure means reducing the occurrence of both hypertension and hypotension. Hypotension has been reported to correlate with mortality in hemodialysis as much as or more than hypertension itself. This "U-curve" phenomenon is not paradoxical. It displays two distinct facts on the same figure: an increased early mortality in hypotensive patients (hypotension is a marker of frailty or congestive heart failure, both of which cause increased mortality) and, on the other hand, the well-established, long-term increased mortality in hypertensive patients. Hypotension is not a mandate to undertreat hypertension.

Long, slow hemodialysis (3 × 8 hours/week) has been used without significant modification in Tassin, France, for 30 years with excellent morbidity and mortality rates. A long dialysis session easily provides high Kt/Vurea and allows for good control of nutrition and correction of anemia with a limited need for erythropoietin (EPO). Control of serum phosphate and potassium is usually achieved with low-dose medication. The good survival achieved by long hemodialysis sessions is essentially due to lower cardiovascular morbidity and mortality than in short dialysis sessions. This, in turn, is mainly explained by good blood pressure (BP) control without the need for antihypertensive medication. Normotension in this setting is due to the gentle but powerful ultrafiltration provided by the long sessions, associated with a low salt diet and moderate interdialytic weight gains. These allow for adequate control of extracellular volume (dry weight) in most patients without important intradialytic morbidity. Therefore, increasing the length of the dialysis session seems to be the best way of achieving satisfactory long-term clinical results.

Summary Purpose This study explored the use of non-cancer drugs in lymphoma survivors during the early trajectory (0 to 2 years) of cancer survivorship and determined the factors that influenced this consumption. Methods Between January and March 2014, a cross-sectional survey was conducted to assess drug consumption in adult lymphoma survivors at the Toulouse University Hospital. This study was based on a questionnaire consisting of ten open questions related to medical prescription and/or self-medication occurring within the last 3 months. Results A total of 83/103 lymphoma survivors returned the questionnaire. This study showed that 91.6% of patients were drug consumers (about twice more than the general French population). Twenty percent of patients were treated with ≥ 5 drugs. Overall drug consumption mainly concerned analgesics, anti-inflammatory drugs and psychotropics. The presence of comorbidity, urban residence and female gender were associated with overall drug consumption. Moreover, half of survivors required at least one self-medication. Finally, only seven survivors (8.4%) reported no use of any medication. Conclusion This study shows that, at least during the early trajectory of cancer survivorship, lymphoma patients are heavily treated with non-cancer drug therapy. This drug consumption profile may have serious implications in terms of safety, overall benefit and health economics.

Macrophage migration inhibitory factor (MIF) and its receptor CD74 appear to be involved in tumorigenesis. We evaluated, by immunohistochemical staining, the tissue expression and distribution of MIF and CD74 in serial sections of human invasive breast cancer tumor specimens. The serum MIF level was also determined in breast cancer patients. We showed a significant increase in serum MIF average levels in breast cancer patients compared to healthy individuals. MIF tissue expression, quantified by a modified Allred score, was strongly increased in carcinoma compared to tumor-free specimens, in the cancer cells and in the peritumoral stroma, with fibroblasts the most intensely stained. We did not find any significant correlation with histoprognostic factors, except for a significant inverse correlation between tumor size and MIF stromal positivity. CD74 staining was heterogeneous and significantly decreased in cancer cells but increased in the surrounding stroma, namely in lymphocytes, macrophages and vessel endothelium. There was no significant variation according to classical histoprognostic factors, except that CD74 stromal expression was significantly correlated with triple-negative receptor (TRN) status and the absence of estrogen receptors. In conclusion, our data support the concept of a functional role of MIF in human breast cancer. In addition to auto- and paracrine effects on cancer cells, MIF could contribute to shape the tumor microenvironment leading to immunomodulation and angiogenesis. Interfering with MIF effects in breast tumors in a therapeutic perspective remains an attractive but complex challenge. Level of co-expression of MIF and CD74 could be a surrogate marker for efficacy of anti-angiogenic drugs, particularly in TRN breast cancer tumor., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Background and Purpose Follicular lymphoma is the second most common non-Hodgkin's lymphoma and, despite the introduction of rituximab for its treatment, this disease is still considered incurable. Besides genetic alterations involving Bcl-2, Bcl-6 or c-Myc, follicular lymphoma cells often display altered B-cell receptor signalling pathways including overactive PKC and PI3K/Akt systems. Experimental Approach The effect of enzastaurin, an inhibitor of PKC, was evaluated both in vitro on follicular lymphoma cell lines and in vivo on a xenograft murine model. Using pharmacological inhibitors and siRNA transfection, we determined the different signalling pathways after enzastaurin treatment. Key Results Enzastaurin inhibited the serine-threonine kinase p90RSK which has downstream effects on GSK3β. Bad and p70S6K. These signalling proteins control follicular lymphoma cell survival and apoptosis; which accounted for the inhibition by enzastaurin of cell survival and its induction of apoptosis of follicular lymphoma cell lines in vitro. Importantly, these results were replicated in vivo where enzastaurin inhibited the growth of follicular lymphoma xenografts in mice. Conclusions and Implications The targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.

A large number of anticancer drugs have been introduced during the two last decades with significant impact for survival, making cancer a chronic disease in a growing number of indications. However, these drugs are costly, induce adverse effects and their efficacy frequently depends on the dose. For all these reasons, adherence in cancer therapy is critical for an optimal benefit-risk ratio. Patient adherence remains virtually unexplored in many cancers, such as malignant blood diseases. When measured, adherence is poor, especially when the drug is administered as oral and prolonged therapy (hormonotherapy in breast cancer, imatinib). Physician nonadherence represents another form of drug misadministration; poorly documented, its mechanism remains obscure. Adherence may be measured by a panel of methods, each of them displaying limits and pitfalls, suggesting that several complementary methods should be used in the context of prospective studies. Risk factors are age, socio-educative profile, disease stage and physician profile. This review emphasizes some methods to prevent nonadherence. Finally, this review argues for prospective studies, which should integrate a social pharmacology approach, including medicine, psycho-sociology and economics.

In acute myeloid leukemia (AML), new strategies assess the potential benefit of genetically targeted therapy at diagnosis. This implies waiting for laboratory tests and therefore a delay in initiation of chemotherapy. We studied the impact of time from diagnosis to treatment (TDT) on overall survival, early death, and response rate in a retrospective series of 599 newly diagnosed AML patients treated by induction chemotherapy between 2000 and 2009. The effect of TDT was assessed using multivariate analysis. TDT was analyzed as a continuous variable using a specific polynomial function to model the shape and form of the relationship. The median TDT was 8 days (interquartile range, 4-16) and was significantly longer in patients with a white blood cell count (WBC)50 Giga per liter (G/L) (P.0001) and in older patients (P = .0004). In multivariate analysis, TDT had no impact on overall survival (P = .4095) compared with age60 years, secondary AML, WBC50 G/L, European LeukemiaNet risk groups, and Eastern Cooperative Oncology Group performance status. Furthermore, TDT was not associated with response rate and early death. Thus, waiting a short period of time for laboratory tests to characterize leukemias better and design adapted therapeutic strategies at diagnosis seems possible.

International audience; During the last several years, research has produced a significant amount of knowledge concerning the characteristics of human γδ T lymphocytes. Findings regarding the immune functions of these cells, particularly their natural killer cell-like lytic activity against tumor cells, have raised expectations for the therapeutic applications of these cells for cancer. Pharmaceutical companies have produced selective agonists for these lymphocytes, and several teams have launched clinical trials of γδ T cell-based cancer therapies. The findings from these studies include hematological malignancies (follicular lymphoma, multiple myeloma, acute and chronic myeloid leukemia), as well as solid tumors (renal cell, breast and prostate carcinomas), consisting of samples from more than 250 patients from Europe, Japan and the United States. The results of these pioneering studies are now available, and this short review summarizes the lessons learned and the role of γδ T cell-based strategies in the current landscape of cancer immunotherapies.

Purpose [18F]Fluorodeoxyglucose positron emission tomography (PET) is widely used for the staging and restaging of patients with aggressive lymphoma, but less is known about the utility of PET in patients with follicular lymphoma (FL). In a prospective study, we evaluated the prognostic value of PET performed during treatment and at the end of treatment in 121 patients with FL treated with first-line immunochemotherapy. Patients and Methods Patients with previously untreated high–tumor burden FL were treated with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) plus two cycles of rituximab, without rituximab maintenance. PET was performed before treatment, after four cycles of R-CHOP (interim PET), and at the end of treatment (final PET). PET scans were centrally reviewed. Results The total number of patients included was 121. Median age was 57 years. After central review, interim PET (n = 111) was negative in 76% of patients, and final PET (n = 106) was negative in 78%. With a median follow-up of 23 months, 2-year progression-free survival rates were 86% for interim PET–negative versus 61% for interim PET–positive patients (P = .0046) and 87% for final PET–negative versus 51% for final PET–positive patients (P < .001), respectively. Two-year overall survival also significantly differed according to final PET results: 100% versus 88% (P = .0128). Conclusion PET performed either after four cycles of R-CHOP or at the end of therapy was strongly predictive of outcome in this prospective study. Therapeutic intervention based on PET results during or after inductive treatment should be evaluated.

Fludarabine-cyclophosphamide-rituximab is the most efficient first-line treatment for chronic lymphocytic leukemia patients. Many dose adjustments of the original MD Anderson Cancer Center regimen have been proposed. However, whether fludarabine-cyclophosphamide-rituximab relative dose intensity may have an impact on outcome has not yet been investigated. We retrospectively assessed relative dose intensity in 106 community-based patients included in our regional healthcare network from 2004-11, all receiving fludarabine-cyclophosphamide-rituximab as first-line treatment outside clinical trials. Dose reductions were observed in 51.4% of patients, mainly decided by the individual physician and not based on recommendations (52.7%), while there were fewer reports of toxicity or dose reduction because of impaired renal function. Progression-free survival was significantly reduced in patients who had a reduction in dose intensity of more than 20% in fludarabine-cyclophosphamide and/or rituximab. Multivariate analysis showed dose of rituximab had a significant impact on minimal residual disease and progression-free survival. Although prophylactic granulocyte-colony stimulating factor significantly reduced the rate of grade 3-4 neutropenia and febrile neutropenia, it had no impact on relative dose intensity and outcome. This study shows that, in routine clinical practice, there is low adherence to the original MD Anderson Cancer Center fludarabine-cyclophosphamide-rituximab schedule, and that the decision to modify dosage was mostly taken by the individual physician and was based on anticipated toxicity. This study shows that reduction of fludarabine-cyclophosphamide and, more importantly, of rituximab doses seriously interferes with progression-free survival.

International audience; AbstractBackgroundAdherence to therapy has been established for years as a critical parameter for clinical benefit in medical oncology. This study aimed to assess, in the current practice, the influence of the socio-demographical characteristics and the place of treatment on treatment adherence and overall survival among diffuse large B-cell lymphoma patients.MethodsWe analysed data from 380 patients enrolled in a French multi-centre regional cohort, with diffuse large B-cell lymphoma receiving first-line treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CHOP-like regimens. Direct examination of administrative and medical records yielded the date of death. We studied the influence of patients’ socio-demographic characteristics and place of treatment on the treatment adherence and overall survival, adjusted for baseline clinical characteristics. Treatment adherence was measured by the ratio between received and planned dose Intensity (DI), called relative DI (RDI) categorized in “lesser than 85%” and “at least 85%”.ResultsDuring the follow-up, among the final sample 70 patients had RDI lesser than 85% and 94 deceased. Multivariate models showed that advanced age, poor international prognosis index (IPI) and treatment with R-CHOP 14 favoured RDI lesser than 85%. The treatment in a public academic centre favoured RDI greater than or equal to 85%. Poor adherence to treatment was strongly associated with poor overall survival whereas being treated in private centres was linked to better overall survival, after adjusting for confounders. No socioeconomic gradient was found on both adherence to treatment and overall survival.ConclusionsThese results reinforce adherence to treatment as a critical parameter for clinical benefit among diffuse large B-cell lymphoma patients under R-CHOP. The place of treatment, but not the socioeconomic status of these patients, impacted both RDI and overall survival

Background Specific sunscreens against ultraviolet (UV) A and B radiations are essential to prevent matrix degradation and the activation of intracellular signaling pathways involved in photoaging and photocarcinogenesis. Matrix degradation results from UVA-induced production of matrix metalloproteinases (MMP) and activation of intracellular pathways in fibroblasts and keratinocytes. In particular, in keratinocytes, UVA radiation induces β-catenin nuclear translocation and stimulates MMP gene transcription. Our study was aimed at assessing the efficacy of a specific broad-spectrum sunscreen in preventing β-catenin translocation and MMPs enhanced expression in cultured keratinocytes after UVA irradiation. Methods Sunscreen or the vehicle was spread on quartz sheet. Irradiation of HaCaT cells with 6 J/cm2UVA was performed through the sheet, and cells were collected for β-catenin immunostaining then visualization by confocal microscopy, and quantitative real-time polymerase chain reaction analysis of MMP-1, -3 and -9 gene expression. Results As shown by immunostaining and confocal microscopy, the sunscreen abrogated UVA-induced beta-catenin translocation to the nucleus, in comparison with control groups. MMP-1, -3 and -9 mRNA expression was enhanced by 7, 7 and 4 folds (P

The anti-CD20 monoclonal antibody rituximab is the backbone of treatment for the B-cell malignancies non-Hodgkin lymphoma and chronic lymphocytic leukemia. However, there is a wide variability in response to rituximab treatment, and some patients are refractory to current standard therapies. Rituximab kills B cells by multiple mechanisms of action, including complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which are immune-mediated mechanisms, as well as by direct effects on cell signaling pathways and cell membranes following CD20 binding. A large number of events that are affected by rituximab binding have been identified, including lipid raft modifications, kinase and caspase activation, and effects on transcription factors and apoptotic/antiapoptotic molecules. Studies on cell lines and isolated tumor cells have shown that by targeting these pathways, it may be possible to increase or decrease susceptibility to rituximab cell killing. An increased understanding of the direct effects of rituximab may therefore aid in the design of new, rational combinations to improve the outcome of CD20-based therapy for patients who currently have suboptimal outcome following standard treatments. Mol Cancer Res; 9(11); 1435–42. ©2011 AACR.

Background During chemotherapy, patients experience disabling side effects or even sometimes life-threatening treatment-related complications, contributing to poor quality of life, reduced therapeutic compliance, decreased relative dose-intensity, and ultimately poorer outcomes. Objectives The Ambulatory Medical Assistance (AMA) project, a monitoring procedure based on a standardized telephone intervention, was aimed to improve ambulatory care quality in aggressive B-cell lymphomas treated with standard front-line R-CHOP therapy. Design Non-comparative prospective study. Setting and participants Over a three-years period, one hundred diffuse large B cell lymphoma (DLBCL) patients were treated in a single hospital and monitored in an ambulatory setting through planned telephone interventions delivered by a single nurse under the supervision of an oncologist. Methods In addition to biological monitoring, patients received a bi-weekly telephone call from an oncology-certified nurse. All events were recorded on a call form, which was forwarded to a supervisor oncologist. Nurse calls resulted in one of the following: no intervention, grade 1 intervention based on a pre-established protocol managed by the nurse under oncologist supervision, or grade 2 intervention related to more severe complications, managed directly by the oncologist, and mostly resulting in secondary hospitalization. Results The AMA procedure consisted of 3592 phone calls (600h) resulting in 989 interventions (27.5%). Grade 1 intervention represented 950 cases whereas grade 2 intervention was noted in only 39 cases (3.9%). AMA also appeared to improve medical management. Indeed, compared to the literature, we observed lower incidence in secondary hospitalization (6%), delayed treatment (6%), reduced relative dose-intensity (RDI) (no patient with RDI Conclusions AMA appears to improve R-CHOP therapy management. However, comparative studies are needed to demonstrate the advantage of the AMA over standard management, in terms of therapeutic compliance, progression-free survival, and medico-economics efficacy.

Introduction Comorbidity management is set to play an increasing role in modern health services due to the population ageing and the increasing incidence of cancer. Previous work suggested that cancer incidence, detection, treatment and evolution may be influenced by comorbidity. Study focusing specifically on whether and how these influences take place are still rare. This can be explained by the difficulty of apprehending patients care trajectories to control for adequate confounders and disentangle statistical association from causal relationships. The present study aims at testing for the effect modification of the chemotherapy efficacy by comorbidity among patients treated for diffuse large B cells lymphoma (DLBCL). Methods We used data from the AMARE cohort, which is a prospective cohort of DLBCL patients in the Midi-Pyrenees region (South-West biggest region in France). Patients diagnosed between May 2006 and February 2017 and treated in the main centres of the region were included (n = 732). For each of the chemotherapy protocol received by the patients we built two models to estimate the effect of the treatment: model 1 with treatment only, and model 2 with treatment by comorbidity level. We used inverse probability of treatment weighting (IPTW) to control for confounders in the estimation of the treatment effect in each model. Models were compared using Bayesian Information Criteria (BIC). Comorbidity was measured using the Charlson Comorbidity Index (CCI) with the weights corrections proposed by Quan et al. in 2011 and codded in three categories (score = 0, score = 1, score ≥ 2). Treatment efficacy criteria was the complete response at the end of the treatment. Results Regarding RCHOP 21, we observed that this treatment increased the probability of complete response independently of comorbidity. No modification effect by comorbidity was found for this protocol. However, we found that RCHOP 14 increased the probability of complete response only among patients without comorbidity indicating a modification effect for this protocol. Conclusion These preliminary results suggest that comorbidity may influence chemotherapy efficacy in different way depending of its effect on the choice of treatment strategy. Work is still underway to test for intermediate factor, which may explain the influence of comorbidity on treatment effect. We are giving a special attention to dose concession and toxicity.

Purpose Anaplastic lymphoma kinase (ALK) –positive diffuse large B-cell lymphoma (DLBCL) is a rare variant of DLBCL that has been described only in small case reports. To shed more light on the clinical and pathologic features and outcome of these tumors, we reviewed data from 38 patients. Patients and Methods We retrospectively analyzed 38 patients with ALK-positive DLBCL treated with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or CHOP-like regimens from different institutions to better define the presenting features, clinical course, and response to treatment. Results The histologic findings in all patients were similar. All patients expressed ALK fusion proteins, but virtually all were CD30 and CD20 negative. The median age was 43 years with a 5:1 ratio of males to females. Most patients (60%) followed an aggressive clinical course with advanced stage at diagnosis, frequent marrow infiltration, and poor outcome. Overall survival was 20.3 months (95% CI, 12.2 to 42.6 months). Of note, the median survival was only 12.2 months (95% CI, 9.1 to 32.5 months) in patients with advanced-stage disease. Conclusion ALK-positive DLBCLs display clinicopathologic features that distinguish them from common DLBCL. Conventional therapy, as used for typical DLBCL, is of limited efficacy. Recognition of this new entity and the characteristic lack of CD20 expression are paramount. Novel front-line intensive chemotherapy regimens should be evaluated in this group of patients.

Previous studies have established that UV irradiation results in epidermal growth factor receptor (EGFR) activation in keratinocytes. However, the signaling pathways and cellular effects related to this process remain incompletely elucidated. Herein, we describe for the first time that UVA-mediated EGFR activation results in β-catenin tyrosine phosphorylation at the Y654 residue responsible for the dissociation of E-cadherin/α-catenin/β-catenin complexes. Moreover, UVA induces an EGFR-dependent, but Wnt-independent, β-catenin relocalization from the membrane to the nucleus followed by its association with T-cell factor 4 (TCF4). This newly formed β-catenin/TCF4 complex binds to a specific site on matrix metalloproteinase 1 (MMP1) promoter and governs MMP1 gene and protein expression, as well as cell migration in collagen and gelatin. Altogether, these results suggest that UVA stimulates keratinocyte invasiveness through two coordinated EGFR-dependent processes: loss of cell-to-cell contact due to β-catenin/E-cadherin/α-catenin dissociation and increased cell migration through extracellular matrix component degradation due to β-catenin/TCF4–dependent MMP1 regulation. These events may represent an important step in epidermis repair following UVA injury and their abnormal regulation could contribute to photoaging and photocarcinogenesis. [Cancer Res 2009;69(8):3291–9]

Since the histological expression of galectins is increased in thyroid carcinoma, determination of their serum levels may provide useful preoperative information. The goal of this study was to determine if a difference in galectin serum levels could be detected between benign and malignant nodular thyroid diseases.Using validated ELISAs, the concentrations of several galectins were prospectively measured in serum samples from 30 healthy individuals and preoperatively in 90 patients with thyroid disease. Seventy-one patients had multiple thyroid nodules (MTN), 13 patients had a single thyroid nodule (STN), and 6 patients had Graves' disease. Nine of 71 patients with MTN had fine-needle aspiration biopsy (FNAB) of their nodules and in 7 patients a "benign" diagnosis was made, in 0 patient a "malignant" diagnosis was made, and in 2 patients a "suspicious" diagnosis was made. Six of 13 patients with STN had FNAB of their nodules and in 2 patients a "benign" diagnosis was made, in 3 patients a "malignant" diagnosis was made, and in 1 patient a "suspicious" diagnosis was made.Thyroid disease was associated with higher levels of galectins-1 and -3 compared to normal subjects. Using a threshold value of 3.2 ng/mL as a cut-off point, the measurement of serum galectin-3 separated micro- and macropapillary thyroid carcinoma (PAP_CA) from patients with nonmalignant thyroid disease with 74% specificity, 73% sensitivity, 57% positive predictive value, and 85% negative predictive value. Elevated serum galectin-3 concentrations (3.2 ng/mL) detected 87% of macropapillary thyroid carcinomas and 67% of micropapillary thyroid carcinomas.Serum levels of galectins-1 and -3 are relatively high in patients with thyroid malignancy but there is considerable overlap in serum galectin-3 concentrations between those with benign and malignant nodular thyroid disease and, to a lesser extent, between those with and without nodular thyroid disease.

International audience; The farnesoid X receptor (FXR, NR1H4), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, is normally produced in the liver and the gastrointestinal tract, where it acts as a bile acid sensor. It has been recently detected in breast cancer cell lines and tissue specimens. The expression of FXR was scored (0–8) by immunohistochemistry on 204 breast cancer samples and correlated with established cancer biomarkers. Moreover, the effect of the FXR activator chenodeoxycholic acid (CDCA) was determined on cell proliferation and estrogen receptor regulation/activation in breast cancer cell lines. FXR was detected in 82.4% of samples with a high median expression score of 5. FXR expression significantly correlated with estrogen receptor (ER) expression ( = 0.009) and luminal-like markers. In ER-positive tumors, FXR expression was significantly correlated with the proliferation marker Ki-67 (

To evaluate galectin-1, -3 and -7 serum levels as diagnostic and/or prognostic markers for head and neck squamous cell carcinomas (HNSCCs). ELISA was employed to test sera from 102 patients with HNSCCs and from 38 healthy control volunteers for galectin-1, -3 and -7 serum levels. Serum galectin levels were assayed by ELISA and the levels of galectin expression in HNSCCs were determined by means of immunohistochemistry. HNSCCs display significant immunohistochemical amounts of galectin-7, but this galectin cannot be detected in the blood of HNSCC patients. Galectin-3 levels differ significantly (p=0.03) in healthy volunteers and HNSCC patients. Using a threshold value of 4.3 ng/ml, galectin-3 serum level enabled a significant level of discrimination (p=0.03) to be established between the cancer patients and the healthy volunteers, with 90% level of specificity and 36% level of sensitivity. The discrimination was even better when using a threshold value of 13.5 ng/ml for galectin-1 (p=0.001), with 100% level of specificity and 22% level of sensitivity. A subgroup of stage IV HNSCC patients displayed significantly reduced levels of circulating galectin-1 (p=0.003) and galectin-3 (p=0.001) after treatment as opposed to before. Galectin-3 concentrations in sera from the patients with a metastatic disease were significantly (p=0.01) higher than in sera from the patients with localized tumors. The determination of circulating levels of galectin-1 and -3 could be used to monitor the progression of their disease or their response to therapy.

Myelodysplastic syndromes (MDS) are clonal hematological disorders characterized by ineffective hematopoiesis. Their increased prevalence is associated with the aging of the population. The aim of this article is to analyze the available literature about MDS - its classification, pathophysiology, prognosis and recent progress in treatment - and report our experience with it. Its diagnosis and classification are based on the morphological features of blood and bone marrow cells. The World Health Organization (WHO) working group has proposed a new classification to improve the homogeneity of the categories in the widely-used French-American-British classification in term of pathophysiology and prognosis. This new classification permits the consideration of clinical, etiologic, and cytogenetic data, including complex and heterogeneous cytogenetic abnormalities. The International Scoring System for evaluating Prognosis (IPSS), which has proven highly useful for this purpose, is a risk-based classification system for MDS, based on these cytogenetic abnormalities. It can be used to help guide therapeutic choices. For MDS with low IPSS scores (low-risk), appropriate treatment includes best supportive care, hematopoietic growth factors, and immunomodulatory drugs. For MDS with high IPSS scores, chemotherapy is appropriate at low or intense doses. For younger patients, allogeneic bone marrow transplantation, the only truly curative treatment, may be considered. Better understanding of the pathophysiology of MDS, including the role of oncogenes and various cytokines, is required to develop new treatments and treatment targets. The new classification and prognosis scoring system should lead to new therapeutic strategies that may modify the overall prognosis and quality of life of patients with MDS.

Background Cancer survivorship has emerged as an important aspect of oncology due to the possibility of physical and psychosocial complications. The purpose of this study was to assess the feasibility of the Ambulatory Medical Assistance for After Cancer (AMA-AC) procedure for monitoring lymphoma survivorship during the first year after chemotherapy. Methods AMA-AC is based on systematic general practitioner (GP) consultations and telephone interventions conducted by a nurse coordinator (NC) affiliated to the oncology unit, while an oncologist acts only on demand. Patients are regularly monitored for physical, psychological and social events, as well as their health-related quality of life (HRQoL). Inclusion criteria were patients newly diagnosed with non-Hodgkin or Hodgkin lymphomas, who had been treated with anthracycline-based chemotherapy and were in complete remission after treatment. Results All 115 patients and 113 collaborating GPs agreed to participate in the study. For patients who achieved one year of disease-free survival (n = 104) their assessments (438 in total) were fully completed. Eleven were excluded from analysis (9 relapses and 2 deaths). The most frequent complications when taking into account all grades were arthralgia (64.3 %) and infections (41.7 %). About one third of patients developed new diseases with cardiovascular complications as the most common. Psychological disorders such as anxiety, depression and post-traumatic stress disorder were diagnosed in 42.6 % of patients. The data collected showed that Hodgkin lymphoma patients, females, and patients with lower HRQoL (mental component) at study entry were at greater risk for developing at least one psychological disorder. Conclusion This study showed that AMA-AC is a feasible and efficient procedure for monitoring lymphoma survivorship in terms of GP and patient participation rates and adherence, and provides a high quality of operable data. Hence, the AMA-AC procedure may be transferable into clinical daily practice as an alternative to standard oncologist-based follow-up. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1815-7) contains supplementary material, which is available to authorized users.

International audience; Salvage of young patients with follicular lymphoma (FL) after R-CHOP includes salvage immunochemotherapy followed by autologous stem cell transplantation (ASCT). Previous studies dealing with relapsed Hodgkin lymphoma have shown the prognostic value of PET/CT prior to ASCT. We retrospectively analysed 59 patients with refractory/relapsed FL after first-line R-CHOP who were chemosensitive (as evaluated by CT) to the salvage treatment and who proceeded to ASCT. The role of PET/CT in this setting to define chemosensitivity is not definitely established. So we focused on the prognostic value of PET/CT performed after salvage treatment, before ASCT. The estimated 3-year progression-free survival (PFS) and overall survival were 63.1% (50.9-78.3%) and 90.5% (82.8 - 98.8%), respectively, and did not differ significantly according to their Follicular Lymphoma International Prognostic Index at relapse, conditioning regimen, or type of salvage. PFS was significantly lower in PET/CT-positive patients, according to the International Harmonization Project revised response criteria, with a 3-year PFS of 45.5% (26.6 - 77.8%) versus 72.6% (58.5 - 90.0%; p = 0.039). To better refine prognosis, we applied two types of throsholds: a Deauville five-point scale positive threshold of ≥3 (3-year PFS of 74.9%, range 61.0 - 92.1% %, versus 42.8%, range 24.7 - 74.4%; p = 0.02), and a ≥70% ∆SUVmax threshold between presalvage and pre-ASCT PET/CT (3-year PFS of 72.4%, range 57.5 - 91.3% versus 13.3%, 2.2 - 81.7%; p

Activation of the Wnt/beta-catenin pathway has recently been shown to be crucial to the establishment of leukemic stem cells in chronic myeloid leukemia. We sought to determine whether beta-catenin was correlated to clonogenic capacity also in the acute myeloid leukemia (AML) setting. Eighty-two patients were retrospectively evaluated for beta-catenin expression by Western blot. beta-Catenin was expressed (although at various protein levels) in 61% of patients, and was undetectable in the remaining cases. In our cohort, beta-catenin expression was correlated with the clonogenic proliferation of AML-colony forming cells (AML-CFC or CFU-L) in methylcellulose in the presence of 5637-conditioned medium, and more strikingly with self-renewing of leukemic cells, as assessed in vitro by a re-plating assay. In survival analyses, beta-catenin appeared as a new independent prognostic factor predicting poor event-free survival and shortened overall survival (both with P

Several tyrosine kinase genes are involved in chromosomal translocations in chronic myeloproliferative disorders, but there are still uncharacterized translocations in some cases. We report two such cases corresponding to atypical chronic myeloid leukaemia with a t(8;9)(p22;p24) translocation. By fluorescence in situ hybridisation (FISH) on the corresponding metaphases with a bacterial artificial chromosome probe encompassing the janus kinase 2 (JAK2) gene at 9p24, we observed a split for both patients, suggesting that this gene was rearranged. The locus at 8p22 contains different candidate genes including the pericentriolar material 1 gene (PCM1), already implicated in reciprocal translocations. The rearrangement of the PCM1 gene was demonstrated by FISH, for both patients. By RT-PCR, we confirmed the fusion of 3' part of JAK2 with the 5' part of PCM1. Sequence analysis of the chimeric PCM1-JAK2 mRNA suggests that the putative protein displays the coiled-coil domains of PCM1 and the tyrosine kinase domain of JAK2. This new translocation identifies JAK2 as a possible therapeutic target for compounds with anti-tyrosine kinase activity.

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase playing an important role in cell motility and survival. However, very little is known about FAK in normal and leukemic myeloid cells. In this study, FAK protein expression and mRNA were detected in 25 of 60 cases (42%) of acute myeloid leukemia (AML). Whereas FAK was expressed in 46% of CD34+ AML cells, it was not detected in normal purified CD34+ cells. Conversely, the FAK homologue proline-rich tyrosine kinase 2 (PYK2) was found to be expressed both in normal and leukemic myeloid cells. When expressed, FAK displayed phosphorylation on Tyr-397, an important step for its activation. Moreover, FAK expression was correlated with the phosphorylation of PYK2 on Tyr-881, a critical site for the PYK2 function in cell migration. FAK+ AML cells displayed significantly higher migration capacities and resistance to daunorubicin, compared with FAK− cells. The implication of FAK in both cell motility and drug resistance was demonstrated by small interfering RNA experiments with the FAK-positive KG1 cell line. However, adhesion on fibronectin efficiently protected FAK− AML cells from daunorubicin-mediated killing, suggesting that cellular adhesion mediated-drug resistance is not mediated by FAK. Finally, in a retrospective cohort of 60 AML patients, FAK expression was significantly correlated with high blast cell count, early death, and shorter survival rate. Altogether, this study shows that FAK is aberrantly expressed and activated in about half of the cases of AML and suggests that FAK may contribute to the regulation of AML cell transit from the marrow to blood compartment and that it may influence clinical outcome.

The DNA mismatch repair (MMR) proteins are essential for the maintenance of genomic stability of human cells. Compared with hereditary or even sporadic carcinomas, MMR gene mutations are very uncommon in leukemia. However, genetic instability, attested by either loss of heterozygosity or microsatellite instability, has been extensively documented in chronic or acute malignant myeloid disorders. This observation suggests that in leukemia some internal or external signals may interfere with MMR protein expression and/or function. We investigated the effects of protein kinase C (PKC) stimulation by 12-O-tetradecanoylphorbol-13-acetate (TPA) on MMR protein expression and activity in human myeloid leukemia cell lines. First, we show here that unstimulated U937 cells displayed low level of PKC activity as well as MMR protein expression and activity compared with a panel of myeloid cell lines. Second, treatment of U937 cells with TPA significantly increased (3-5-fold) hMSH2 expression and, to a lesser extent, hMSH6 and hPMS2 expression, correlated to a restoration of MMR function. In addition, diacylglycerol, a physiological PKC agonist, induced a significant increase in hMSH2 expression, whereas chelerythrine or calphostin C, two PKC inhibitors, significantly decreased TPA-induced hMSH2 expression. Reciprocally, treatment of HEL and KG1a cells that exhibited a high level of PKC expression, with chelerythrine significantly decreased hMSH2 and hMSH6 expression. Moreover, the alteration of MMR protein expression paralleled the difference in microsatellite instability and cell sensitivity to 6-thioguanine. Our results suggest that PKC could play a role in regulating MMR protein expression and function in some myeloid leukemia cells.

Infection, mainly related to vascular access, is one of the main causes of morbidity and a preventable cause of death in hemodialysis patients. From January 1994 to April 1998 we conducted a prospective study to assess the incidence and risk factors of catheter-related bacteremia. One hundred and twenty-nine tunneled dual-lumen hemodialysis catheters were inserted percutaneously into the internal jugular vein in 89 patients. Bacteremia (n = 56) occurred at least once with 37 (29%) of the catheters (an incidence of 1.1/1,000 catheter-days); local infection (n = 45, 1/1,000 catheter-days) was associated with bacteremia in 18 cases. Death in 1 case was directly related to Staphylococcus aureus (SA) septic shock, and septicemia contributed to deaths in 2 additional cases. Catheters were removed in 48% of the bacteremic episodes. Treatment comprised intravenous double antimicrobial therapy for 15–20 days. Bacteriological data of bacteremia showed 55% involvement of SA. Nasal carriage of SA was observed in 35% of the patients with catheters. Bacteremic catheters were more frequently observed in patients with diabetes mellitus (p = 0.03), peripheral atherosclerosis (p = 0.001), a previous history of bacteremia (p = 0.05), nasal carriage of SA (p = 0.0001), longer catheter survival time (p = 0.001), higher total intravenous iron dose (p = 0.001), more frequent urokinase catheter infusion (p < 0.01), and local infection (p < 0.001) compared with non-bacteremic catheters. Monovariate survival analysis showed that significant initial risk factors for bacteremia were nasal carriage of SA (p = 0.00001), previous bacteremia (p = 0.0001), peripheral atherosclerosis (p = 0.005), and diabetes (p = 0.04). This study confirms the relatively high incidence of bacteremia with tunneled double-lumen silicone catheters and its potential complications. Possible preventive actions are discussed according to the risk factors.

This work explores the phenotypic changes affecting transformed cells in an experimental model of diethylstilbestrol (DES)-induced renal tumours in male Syrian hamster. This estrogen-induced neoplasm presents an important cytological pleomorphism and its origin remains largely controversial. In order to characterize phenotypic variations during tumour progression, the occurrence of seven lineage markers was analysed by a morphometric approach in kidney sections of DES-exposed hamsters (6–;11 months). S100 protein, neuron-specific enolase (NSE) and vimentin are expressed by a large percentage of malignant cells during tumour development. Glial fibrillary acidic protein (GFAP), protein gene product 9.5 (PGP 9.5) and desmin are mostly evidenced in advanced neoplasm whereas Leu 7 always presents a focal expression. As evidenced by double-label immunofluorescence, the coexpression of three important neuroectodermal lineage markers (S100, NSE and PGP 9.5) in earliest tumour buds points to a peripheral nerve sheath origin for this neoplasm thus confirming previously published data. For each marker, the fluctuations of expression levels during tumour progression as well as the spatial heterogeneity of distribution suggest variable phenotypic differentiation of transformed cell populations. This observation is largely corroborated by double-label immunofluorescence showing coexpression modification of several markers during tumour progression. This points to a complex dynamic and spatial self-organization of different phenotypes within neoplasms. Altogether, these results support the concept that DES-induced kidney tumours are not made of unstructured cell populations but represent adaptive complex dynamic biosystems.

Summary Belinostat is a pan-histone deacetylase inhibitor with antitumour and anti-angiogenic properties. An open label, multicentre study was conducted in patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥1 prior systemic therapy and were treated with belinostat (1000 mg/m2 intravenously ×5 d of a 21-d cycle). The primary endpoint was objective response rate (ORR). Patients with PTCL (n = 24) had received a median of three prior systemic therapies (range 1–9) and 40% had stage IV disease. Patients with CTCL (n = 29) had received a median of one prior skin-directed therapy (range 0–4) and four prior systemic therapies (range 1–9); 55% had stage IV disease. The ORRs were 25% (PTCL) and 14% (CTCL). Treatment-related adverse events occurred in 77% of patients; nausea (43%), vomiting (21%), infusion site pain (13%) and dizziness (11%) had the highest incidence. Treatment-related serious adverse events were Grade 5 ventricular fibrillation; Grade 4 thrombocytopenia; Grade 3 peripheral oedema, apraxia, paralytic ileus and pneumonitis; and Grade 2 jugular vein thrombosis. Belinostat monotherapy was well tolerated and efficacious in patients with recurrent/refractory PTCL and CTCL. This trial was registered at www.clinicaltrials.gov as NCT00274651.

Optimal treatment strategies are lacking in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Gemcitabine has shown activity and acceptable safety profile in B-cell lymphomas. We present a retrospective case review of gemcitabine and alemtuzumab, every 21 d (for up to six courses) in 27 community-based patients with high-risk R/R CLL. Median age was 70 yr (44-83 yr), 55% patients had Binet stage C, deletion 17p (del(17p)) and/or deletion 11q (del(11q)) were found in 65% and 27%, bulky disease in 55.5%, and fludarabine-refractoriness in 48% of cases, respectively. Overall response rate was 63% (29.6% clinical CR and 33.4% PR). At a median follow-up of 31 months, median PFS and OS were 15.4 and 24 months. In multivariate analysis, median OS is influenced by prior lines of treatment = 3 and bulky disease. Combination of alemtuzumab and gemcitabine appears to be an active, easy to administrate treatment in routine practice, high-risk R/R CLL patients.

International audience; Lymphomas grow as dense aggregates in patients, but whether this spatial organization affects lymphoma cell biology is unknown. We grew follicular lymphoma (FL) cells in vitro as multicellular aggregates of lymphoma cells to investigate this question. Gene expression analysis revealed that 612 genes were differentially expressed when cells grew in multicellular aggregates of lymphoma cells rather than in suspension. These genes correspond to several GO biological processes, such as hypoxia, activation of NF-κB pathway, and negative regulation of cell cycle, a gene signature also found in the transcriptomes from FL biopsies. Pimonidazole staining, HIF-1A accumulation, and VEGFA release confirmed that cells in multicellular aggregates of lymphoma cells actually respond to hypoxia. In adaptation to such conditions, they also displayed an activated NF-κB pathway and a quiescent status far more frequently than in suspension. When cultured in three dimensions, FL cells display resistance to doxorubicin and bendamustine, two drugs largely used in FL therapy, compared to FL cultured in suspension. Finally, multicellular aggregates of lymphoma cells were also found to be less sensitive to purified natural killer cells. To conclude, our study shows that in FL, spatial organization results in dramatic changes in FL biology, including gene expression, proliferation, drug resistance, and immune escape.

While macrophage migration inhibitory factor (MIF) has been extensively studied in the context of inflammation and inflammatory disorders, less work has been devoted to its involvement in cancer, notably in neoplastic progression. In a previous study, we have found evidence that MIF plays a role in head and neck squamous cell carcinomas (HNSCC). The current investigations were undertaken in order to estimate the importance of the MIF receptor, CD74 in the progression of HNSCC. In a cohort of 46 cases of oral cavity carcinomas, immunohistochemical staining revealed an increase in CD74 expression during progression from benign lesions to carcinoma. As shown by cell culture experiments using squamous carcinoma cell line (SCCVII) transduced with anti-CD74 shRNA, the amount of cell-produced VEGF was lower in SCCVII CD74KD cell line compared with control SCCVII CD74sc cell line, suggesting that CD74 could be implicated in angiogenesis in vivo. Furthermore, knockdown of CD74 decreased proliferation of SCCVII cells in vitro. The migration of SCCVII cells, as well as the cell secretion of matrix metallopeptidase 9, was also negatively affected by CD74 knockdown. These observations in vitro were confirmed in an orthotopic mouse model of SCC where tumors produced by SCCVII CD74KD cell inoculation were found to grow more slowly than tumors generated by SCCVII CD74sc cells. The clinical observations and experimental data reported here suggest that CD74, as well as MIF, plays a pivotal role in HNSCC progression.

Chronic myelogenous leukemia (CML) is characterized by the Philadelphia chromosome resulting from the translocation t(9-22) producing the chimeric 190 and 210 kDa BCR – ABL fusion proteins. Evolution of the CML to the more agressive acute myelogenous leukemia (AML) is accompanied by increased cellular proliferation and genomic instability at the cytogenetic level. We hypothezised that genomic instability at the nucleotide level and spontaneous error in DNA replication may also contribute to the evolution of CML to AML. Murine Ba/F3 cell line was transfected with the p190 and p210-encoding BCR – ABL oncogenes, and spontaneous mutation frequency at the Na-K-ATPase and the hypoxanthine guanine phosphoribosyl transferase (HPRT) loci were measured. A significant 3 – 5-fold increase in mutation frequency for the transfected cells relative to the untransfected control cells was found. Furthermore, we observed that BCR – ABL transfection induced an overexpression of DNA polymerase β, the most inaccurate of the mammalian DNA polymerases, as well as an increase in its activity, suggesting that inaccuracy of DNA replication may account for the observed mutator phenotype. These data suggest that the Philadelphia abnormality confers a mutator phenotype and may have implications for the potential role of DNA polymerase β in this process.