The prevalence of signs and symptoms of childhood leukemia and lymphoma in Fars Province,Southern Iran

Background: Leukemia and lymphomas are still the common childhood cancers in Iran. This study was undertaken to determine the prevalence of signs and symptoms of these malignancies in children of Fars Province, Southern Iran. Methods: A total of 368 cases of children who were less than 15 years old and diagnosed as acute lymphocytic leukemia (ALL, n = 211), acute myeloid leukemia (AML, n = 64), Burkitt lymphoma (BL, n = 40), chronic myeloid leukemia (CML, n = 5), Hodgkin's disease (HD, n = 33) or non-Burkitt-type, non-Hodgkin's lymphoma (NBNHL, n = 15) referring to the hospitals of Shiraz University of Medical Sciences from April 1997 to March 2002 were enrolled. A questionnaire was provided to record the age, median age at the onset of the disease, sex, type of malignancy and the signs and symptoms at the time of presentation. Results: The common sign or symptoms were fever (74%), in ALL, AML, NHL, and BL patients, hepatosplenomegaly (100%) in CML patients, and lymphadenopathy (54%) and fever (54%) in Hodgkin's disease. Conclusion: Knowledge of signs and symptoms and types of presentations of childhood leukemia and lymphoma may help a physician to improve the patient's outcome. This study revealed that attention to uncommon signs and symptoms in history taking and physical examination together with laboratory tests may increase the physicians’ awareness and better diagnosis of pediatric malignancies and would also be beneficial for the patient.     

Bortezomib in combination with CHOP as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas: A multicentre,single-arm,phase 2 trial

BackgroundWe performed a phase II study to evaluate the efficacy of bortezomib in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas (PTCLs) based on our phase I study results.MethodsPatients received bortezomib on days 1 and 8 at a dose of 1.6 mg/m² in addition to CHOP every 3 weeks for a total of six cycles.ResultsForty-six patients were enrolled: PTCL, not otherwise specified (PTCL-NOS, n = 16), extranodal NK/T-cell lymphoma, nasal type (ENKTL, n = 10), angioimmunoblastic T-cell lymphoma (AITL, n = 8), ALK-negative anaplastic large-cell lymphoma (ALCL, n = 6), cutaneous T-cell lymphoma (CTCL, n = 5) and hepatosplenic T-cell lymphoma (n = 1). Thirty patients achieved complete response (CR, 65%) and the overall response rate was 76% (35/46). Although the CR rate of ENKTL was only 30% (3/10), three subtypes of PTCLs (PTCL-NOS, AITL and ALCL) showed 87% of overall response rate (ORR) (26/30) and 73% of CR rate (22/30). However, the 3-year overall survival and progression-free survival were 47% and 35%, respectively due to frequent relapse after remission. Grade 3/4 leucopenia was the most frequent toxicity whereas neurotoxicity was tolerable: grade 1 or 2 of peripheral neuropathy.ConclusionsThe combined treatment of bortezomib and CHOP is an effective and feasible regimen for advanced-stage PTCLs other than ENKTL, with acceptable toxicity. However, future studies exploring new drug combinations are warranted to overcome relapse after remission.     

Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma

BackgroundThis two-stage, phase IIa study investigated the antitumor activity and safety of MOR208, an Fc-engineered, humanized, CD19 antibody, in patients with relapsed or refractory (R-R) B-cell non-Hodgkin’s lymphoma (NHL). CD19 is broadly expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by hematological stem cells.Patients and methodsPatients aged ≥18 years, with R-R NHL progressing after ≥1 prior rituximab-containing regimen were enrolled into subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent (i)NHL and mantle cell lymphoma (MCL). Treatment was MOR208, 12 mg/kg intravenously, weekly, for 8 weeks. Patients with at least stable disease could continue treatment for an additional 4 weeks. Those with a partial or complete response after 12 weeks could receive extended MOR208 treatment (12 mg/kg, either monthly or every second week) until progression. The primary end point was overall response rate.ResultsNinety-two patients were enrolled: DLBCL (n = 35), FL (n = 34), other iNHL (n = 11) and MCL (n = 12). Responses were observed in DLBCL, FL and other iNHL cohorts (26%, 29% and 27%, respectively). They lasted ≥12 months in 5/9 responding patients with DLBCL, 4/9 with FL and 2/3 with other iNHL. Responses in nine patients are ongoing (>26 months in five instances). Patients with rituximab refractory disease showed a similar response rate and progression-free survival time to patients with non-refractory disease. The most common adverse events (any grade) were infusion-related reactions (12%) and neutropenia (12%). One patient experienced a grade 4 infusion-related reaction and eight patients (9%) experienced grade 3/4 neutropenia. No treatment-related deaths were reported.ConclusionsMOR208 monotherapy demonstrated promising clinical activity in patients with R-R DLBCL and R-R FL, including in patients with rituximab refractory tumors. These efficacy data and the favorable safety profile support further investigation of MOR208 in phase II/III combination therapy trials in R-R DLBCL.ClinicalTrials.gov numberNCT01685008.     

Pro-apoptotic effect of an anti-CD37 scFv-Fc fusion protein,in combination with the anti-CD20 antibody,ofatumumab, on tumour cells from B-cell malignancies

SMIP-016, a new anti-tumour agent, is a mouse/human chimeric fusion protein built on the ADAPTIR™ (modular protein therapeutic) platform targeting human CD37. In this study, for the first time, we examined pro-apoptotic activity of SMIP-016 in combination with monoclonal anti-CD20 antibody, ofatumumab (HuMax-CD20) in de novo chronic lymphocytic leukaemia (CLL) cells and in different B-cell neoplasm-derived lines. In CLL cells SMIP-016 exerted significant cytotoxicity (versus control – p = 0.01). In the in vitro models, SMIP-016 was also distinctly active against Raji line (Burkitt lymphoma; BL) (versus control – p = 0.007), Riva-1 line (diffuse large B-cell lymphoma; DLBCL) (versus control – p = 0.002) and RPMI 8226 line (multiple myeloma cells; MM) (versus control – p = 0.03). In studies combining SMIP-016 and ofatumumab, the cytotoxicity against CLL cells was significantly higher than the agents used alone (p < 0.03). Remarkably enhanced cytotoxic activity of SMIP-016 and ofatumumab in combination was also observed in Raji and Riva-1 cell lines (p < 0.01 and p < 0.003, respectively). Importantly, both agents induced cytotoxicity at very low concentrations which suggests that potential side-effects may be decreased in clinical practice. The mechanism responsible for cytotoxicity of SMIP-016 in all the examined models was connected with caspase-dependent apoptosis. In majority of cell types SMIP-016 induced overexpression of Bax protein, as well as downregulation of Bcl-2, cIAP1 (p < 0.03) and Smac/DIABLO (p < 0.003) apoptosis-regulating proteins.In conclusion, our study demonstrated high pro-apoptotic activity of SMIP-016, especially in combination with ofatumumab, against ex vivo CLL cells, and BL or DLBCL in vitro cell lines. Thus, further preclinical studies in in vivo models are warranted, as this combination may be a promising therapeutic concept for treatment of those malignancies.     

Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood

PurposeTo investigate the cumulative incidence of and the risk factors for developing second malignant neoplasms (SMN) in children and adolescents following treatment for relapse of acute lymphocytic leukaemia (ALL).MethodsPatients (1376) up to 18 years of age with first relapse of non-B-cell ALL were treated and achieved a 2nd complete remission (CR). The treatment followed trial protocol in five consecutive multicentre trials of the ALL-REZ BFM Study Group between March 1983 and December 2001. The incidence of SMN was analysed, correlated with clinical and therapeutic parameters, and compared to the age-specific incidence rates of cancers as cited in German cancer registries.ResultsOut of the 1376 patients 21 were diagnosed with SMN including non-lymphoblastic leukaemia/myelodysplastic syndrome (n = 6), osteo-/Ewing’s-/fibroblastic sarcoma (n = 4), B-cell ALL/lymphoma (n = 2), thyroid carcinoma (n = 2), basal cell carcinoma, adeno carcinoma, squamous cell carcinoma, meningioma, malignant histiocytosis, glioblastoma and anaplastic astrocytoma (n = 1 each). The overall cumulative risk of SMN at 15 years (median follow-up of 13.1 years) was 1.26% ± 0.38% (SE). SMN was found to be significantly associated with stem cell transplantation (SCT), and high cumulative doses of cranial irradiation, etoposide and cyclophosphamide. In multivariate analysis etoposide (VP16) and cyclophophamide (CY) were found to be independently associated with SMN (p = 0.047 and 0.002). Compared to the incidence of neoplasm in the age-matched population, there was a 10-fold increase of neoplasia.ConclusionsDespite repeated exposure to intense frontline and relapse treatment (including multiagent chemotherapy, cranial irradiation and stem cell transplantation in some patients) the cumulative incidence of SMN was unexpectedly low, though significantly higher than in the general age-matched population. The association of SMN to SCT seemed to be a secondary effect at least partially mediated by exposure to high doses of VP16 and CY given for conditioning therapy.     

Glycemic index,glycemic load and cancer risk

BackgroundDietary glycemic index (GI) and glycemic load (GL) have been related to the risk of selected cancers, but the issue remains open.Patients and methodsMailed questionnaires were completed between 1994 and 1997 in eight Canadian provinces for incident, histologically confirmed cases of the stomach (n = 1182), colon (n = 1727), rectum (n = 1447), liver (n = 309), pancreas (n = 628), lung (n = 3341), breast (n = 2362), ovary (n = 442), prostate (n = 1799), testis (n = 686), kidney (n = 1345), bladder (n = 1029), brain (n = 1009), non-Hodgkin's lymphomas (NHL, n = 1666), leukemias (n = 1069), multiple myelomas (n = 343), and 5039 population controls. Dietary information on eating habits 2 years before participants' enrollment in the study was obtained using a validated food frequency questionnaire (FFQ). Odds ratios (ORs) and 95% confidence intervals (CI) were derived by unconditional logistic regression including recognized confounding factors.ResultsDietary GI was positively associated with the risk of prostate cancer (OR, 1.26 for the highest versus the lowest quartile). A higher dietary GL significantly increased the risk of colorectal (OR, 1.28), rectal (OR, 1.44) and pancreatic (OR, 1.41) cancers. No other significant associations were found.ConclusionsOur findings suggest that a diet high in GI and GL is associated with increased risk of selected cancers.     

Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: Multicentre,open-label,phase II safety study

PurposeWe assessed the safety of the multikinase inhibitor regorafenib in patients with hepatocellular carcinoma (HCC) that had progressed following first-line sorafenib.Patients and methodsThirty-six patients with Barcelona Clinic Liver Cancer stage B or C HCC and preserved to mildly impaired liver function (Child–Pugh class A) received regorafenib 160 mg once daily in cycles of 3 weeks on/1 week off treatment until disease progression, unacceptable toxicity, death or patient/physician decision to discontinue. The primary end-point was safety; secondary end-points included efficacy (including time to progression and overall survival).ResultsThe median treatment duration was 19.5 weeks (range 2–103). At data cutoff, three patients remained on treatment. Reasons for discontinuation were adverse events (n = 20), disease progression (n = 10), consent withdrawal (n = 2) and death (n = 1). Seventeen patients required dose reductions (mostly for adverse events [n = 15]); 35 patients had treatment interruption (mostly for adverse events [n = 32] or patient error [n = 11]). The most frequent treatment-related adverse events were hand–foot skin reaction (any grade n = 19; grade ?3 n = 5), diarrhoea (n = 19; n = 2), fatigue (n = 19; n = 6), hypothyroidism (n = 15; n = 0), anorexia (n = 13; n = 0), hypertension (n = 13; n = 1), nausea (n = 12; n = 0) and voice changes (n = 10; n = 0). Disease control was achieved in 26 patients (partial response n = 1; stable disease n = 25). Median time to progression was 4.3 months. Median overall survival was 13.8 months.ConclusionRegorafenib had acceptable tolerability and evidence of antitumour activity in patients with intermediate or advanced HCC that progressed following first-line sorafenib.     

Statins and survival outcomes in patients with metastatic renal cell carcinoma

BackgroundA growing body of evidence has demonstrated the anti-neoplastic activity of statins. The objective of this study was to investigate the effect of statin use on survival in patients with metastatic renal cell carcinoma (mRCC) treated in the modern therapy era.Patients and methodsWe conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression and the Kaplan–Meier method.ResultsWe identified 4736 patients treated with sunitinib (n = 1059), sorafenib (n = 772), axitinib (n = 896), temsirolimus (n = 457), temsirolimus + interferon (IFN)-α (n = 208), bevacizumab + temsirolimus (n = 393), bevacizumab + IFN-α (n = 391) or IFN-α (n = 560), of whom 511 were statin users. Overall, statin users demonstrated an improved overall survival (OS) compared to non-users (25.6 versus 18.9 months, adjusted hazard ratio [aHR] 0.801, 95% confidence interval [CI] 0.659–0.972, p = 0.025). When stratified by therapy type, a benefit in OS was demonstrated in statin users compared to non-users in individuals receiving therapy targeting vascular endothelial growth factor (28.4 versus 22.2 months, aHR 0.749, 95% CI 0.584–0.961, p = 0.023) or mammalian target of rapamycin (18.6 versus 14.0 months, aHR 0.657, 95% CI 0.445–0.972, p = 0.035) but not in those receiving IFN-α (15.6 versus 14.8 months, aHR 1.292, 95% CI 0.703–2.275, p = 0.410). Adverse events were similar between users and non-users.ConclusionsWe demonstrate that statin use may be associated with improved survival in patients with mRCC treated in the targeted therapy era. Statins could represent an adjunct therapy for patients with mRCC; however, this is hypothesis generating and requires prospective evaluation.     

Absence of global hypomethylation in promoter hypermethylated Mixed Lineage Leukaemia-rearranged infant acute lymphoblastic leukaemia

BackgroundMixed Lineage Leukaemia (MLL)-rearranged acute lymphoblastic leukaemia (ALL) in infants represents a highly aggressive type of leukaemia that is often characterised by severe promoter CpG island hypermethylation. Consequently, MLL-rearranged ALL cells respond well to demethylating cytosine analogue drugs. In human cancer cells, enhanced promoter methylation is typically accompanied by global loss of methylation in non-promoter regions of the genome. In turn, global hypomethylation usually leads to genomic instability, which may have contributed to cancer development.Design and methodsHere we examined global methylation densities in MLL-rearranged infant ALL (n = 45) samples in comparison with germline MLL infant ALL (n = 11), non-infant B-cell precursor ALL (n = 11) and normal paediatric bone marrow (n = 9) samples. For this we performed high-resolution bisulfite pyrosequencing to determine methylation levels at the repetitive elements LINE-1, Alu and satellite α (SAT-α). As an additional measure of global methylation levels we used the LUminometric Methylation Assay (LUMA).ResultsWe found that MLL-rearranged infant ALL is not characterised by global hypomethylation, despite its characteristic promoter CpG hypermethylation patterns. Instead we observed a moderate trend towards global hypermethylation and demonstrated that these methylated non-promoter sequences are responsive to demethylating agents.ConclusionsMLL-rearranged infant ALL cells are characterised by an overall methylated genomic state, and both promoter and non-promoter methylation responds to demethylating agents, which may further explain the remarkable sensitivity of these cells for the methylation-inhibiting therapeutics.     

A phase I trial of LY2584702 tosylate,a p70 S6 kinase inhibitor,in patients with advanced solid tumours

BackgroundLY2584702 tosylate (hereafter referred to as LY2584702) is a potent, highly selective adenosine triphosphate (ATP) competitive inhibitor against p70 S6 kinase, a downstream component of the phosphatidylinositol-3-kinase signalling pathway which regulates cell proliferation and survival. LY2584702 exhibited anti-tumour activity in preclinical analysis.MethodsPatients with advanced solid tumours were treated with LY2584702 orally on a 28-day cycle until the criteria for maximum tolerated dose (MTD) were met. Skin biopsies were collected for pharmacodynamic analysis, and levels of phospho-S6 protein were examined. The primary objective was to determine a phase II dose and schedule with secondary objectives of observing safety and tolerability. Dose escalation was based upon Common Terminology Criteria for Adverse Events Version 3.0.ResultsThirty-four patients were enrolled onto this phase I study and treated with LY2584702 on a QD (once-daily) or BID (twice-daily) dosing schedule. Part A dose escalation (n = 22) began with 300 mg BID (n = 2). Due to toxicity, this was scaled back to doses of 25 mg (n = 3), 50 mg (n = 8), 100 mg (n = 3), and 200 mg (n = 6) QD. Part B dose escalation (n = 12) included 50 mg (n = 3), 75 mg (n = 3), and 100 mg (n = 6) BID. Seven patients experienced dose-limiting toxicity (DLT). All DLTs were Grade 3 and included vomiting, increased lipase, nausea, hypophosphataemia, fatigue and pancreatitis.ConclusionThe MTD was determined to be 75 mg BID or 100 mg QD. No responses were observed at these levels. Pharmacokinetic analysis revealed substantial variability in exposure and determined that LY2584702 treatment was not dose proportional with increasing dose.     

Venetoclax,bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study

BackgroundVenetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine–rituximab (BR) in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL).Patients and methodsBR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50–1200 mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy.ResultsSixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3 months [95% confidence interval (CI) 10.4–NR], not yet reached, and 10.7 months (95% CI 4.3–21.0), respectively.ConclusionsThis study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL.Trial registeredClinicaltrials.gov, NCT01594229.     

Metastasis suppressor 1 (MTSS1) demonstrates prognostic value and anti-metastatic properties in breast cancer

Metastasis suppressor 1 (MTSS1) may play an important role in cancer metastasis. Firstly, this study assessed MTSS1 expression levels within breast cancer patients to reveal any clinical relevance. Secondly, we aimed to clarify the cellular function of MTSS1 in breast cancer cells. MTSS1 expression levels were assessed in a cohort of breast cancer specimens (normal n = 33; cancer n = 127), through quantitative PCR analysis and immuno-histochemical techniques. The influence of MTSS1 was further examined via biological overexpression and knockdown within breast cancer cell lines. We report that patients with tumours expressing reduced levels of MTSS1 had a poorer prognosis (p = 0.042). High levels of MTSS1 correlated with an increased patient overall survival (p = 0.0108) and disease-free survival (p = 0.012). Furthermore, overexpression of MTSS1 significantly suppressed (p < 0.01) the invasive, migratory, growth and adherence properties of a human breast cancer cell line. In contrast, knockdown of MTSS1 dramatically enhanced these properties. We conclude that MTSS1 is a prognostic indicator of disease-free survival in breast cancer patients and demonstrates the ability to play a role in governing the metastatic nature of breast cancer cells.     

Ovarian Sertoli Leydig cell tumours in children and adolescents: An analysis of the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT)

ObjectiveTo analyse ovarian Sertoli-Leydig cell tumours (SLCTs) for potential prognostic markers and their use for treatment stratification.PatientsForty-four patients were included. Patients were prospectively reported to the German MAKEI (Maligne Keimzelltumoren) studies (n = 23), French TGM protocols (n = 10), Italian Rare Tumour Project (TREP) registry (n = 6), and the Polish Pediatric Rare Tumour Study group (n = 5). Tumours were classified according to World Health Organisation (WHO) and staged according to International Federation of Gynecological Oncology (FIGO).ResultsMedian age was 13.9 (0.5–17.4) years. All patients underwent resection by tumour enucleation (n = 8), ovariectomy (n = 17), adenectomy isolated (n = 18) or with hysterectomy (n = 1). FIGO-stage: Ia 24 pts., Ic 17 pts., II/III 3 pts. One patient had bilateral tumours. Four patients (stage Ia: 3, stage Ic: 1) developed a metachronous contralateral tumour. Otherwise, all stage Ia patients remained in complete remission. Among 20 patients with incomplete resection or tumour spread (stage Ic–III), eight relapsed, and five patients died. Eleven patients were initially treated with two to six cycles of cisplatin-based chemotherapy. Of these, seven patients are in continuous remission. Poor histological differentiation was associated with higher relapse rate (5/13) compared to intermediate (3/18) and high differentiation (0/4). Tumours with retiform pattern or heterologous elements showed a high relapse rate, too (5/11). After a median follow-up of 62 months, event-free survival is 0.70 ± 0.07, relapse-free survival 0.81 ± 0.06 and overall survival 0.87 ± 0.05.ConclusionsPrognosis of SLCTs is determined by stage and histopathologic differentiation. Complete resection with careful avoidance of spillage is a prerequisite of cure. The impact of chemotherapy in incompletely resected and advanced stage tumours remains to be evaluated.     

Mortality is persistently increased in Hodgkin’s lymphoma survivors

BackgroundNegative health outcomes of chronic fatigue (CF) in disease-free cancer survivors are mainly unexplored. Aims of this study were to examine mortality and causes of death in Hodgkin’s lymphoma survivors (HLSs) compared to controls from the general population, and to explore if CF was associated with increased mortality.MethodsHLSs (n = 557) invited to participate in a survey on late effects in 1994 were divided into three groups: participants without CF (n = 329), participants with CF (n = 113), non-participants (n = 98). Controls matched for gender and age were drawn from the general population (five per HLSs, n = 2785). Observation time was calculated from 1st January 1994 until date of death or cut-off at 1st January 2007. Kaplan–Meier plots were used for univariate analyses and Cox models for multiple covariates.ResultsCompared to controls HLSs had nearly five times higher mortality (HR = 4.93; 95% confidence interval [CI]: 3.91–6.21) and the mortality rate of HLSs was higher than the rate of their controls for the entire observation period. Mortality was increased in all groups: participants with CF: HR = 4.85 (95% CI: 3.02–7.77), participants without CF: HR = 4.35 (95% CI: 3.16–6.00), non-participants: HR = 9.45 (95% CI: 5.44–16.41).Compared to the controls HLSs had over six times increased mortality of cancer (HR: 6.6, 95% CI: 4.7–9.2) and almost five times increased mortality of cardiovascular diseases (HR: 4.9, 95% CI: 3.1–7.9).ConclusionsHLSs had almost five-time increased mortality compared to controls. CF was not associated with increased mortality rate. The high mortality among the non-participating HLSs indicates that serious health problems are underestimated in this group. This has implications for the interpretation of surveys in cancer survivors.     

Targeted therapy-induced radiation recall

IntroductionRadiation recall (RR) is an acute inflammatory reaction confined to previously irradiated areas after the administration of various pharmacological agents. A diverse range of chemotherapies has been associated with RR but no case series with targeted therapies (TT) has been reported.Patients and methodsFrom a database of 346,933 cancer patients ?18 years treated at Institut Gustave Roussy between June 1986 and August 2012, clinical data and the pattern of treatment of TT-induced RR were collected. Results were compared with those of prior TT-induced RR publications.ResultsSixteen patients with different tumour types were diagnosed with RR observed in the heart, bladder, salivary glands, skin and gastrointestinal tract. The median duration of RR was 1.7 weeks (range: 0.1–13.7) and median time to onset from TT to RR was 16.9 weeks (range: 1–86.9). TT consisted of inhibitors of the mammalian target of rapamycin (mTOR) (n = 5), endothelial growth factor receptor (EGFR) (n = 2), integrin (n = 2), histone deacetylase (HDAC) (n = 2), cell division cycle 7 (CDC7) (n = 1), insulin-like growth factor 1 receptor (IGFR1) (n = 1), cyclin-dependent kinase (CDK) (n = 1), BRAF (n = 1) and a vascular disrupting agent (VDA) (n = 1). Thirteen incriminated TT (81%) were evaluated during early clinical trials and RR led to discontinuation of TT in six patients. All patients had previously received radiotherapy at a median biologically effective dose (BED) of 47 Gy (range: 20–70). The median interval from radiation to TT was 30 months (range: 0.3–363). Immunohistochemical analysis of skin biopsy specimens did not show any transforming growth factor-beta (TGF-β) activation. TT-induced RR characteristics in our population were comparable to those of the nine other cases previously reported in the literature.ConclusionThis is the largest case series ever reported on TT-induced RR. RR could be a potential dose-limiting toxicity in early clinical trials. Research is warranted to further understand the exact pathophysiology of this rare but clinically relevant phenomenon.     

The frequency,manifestations, and duration of prolonged cytopenias after first-line fludarabine combination chemotherapy

BackgroundFludarabine-based chemoimmunotherapy has well-recognised efficacy and short-term toxicity in the treatment of lymphoid malignancies. However, the presence and significance of prolonged cytopenias after completion of treatment have not been thoroughly quantified.MethodsSixty-one patients receiving initial therapy with fludarabine-based regimens were categorised according to the presence of post-treatment cytopenias (haemoglobin <110–130 g/l depending on sex and age, neutrophils <2.0 × 10⁹/l, or platelets <140 × 10⁹/l) lasting >3 months.ResultsPersistent cytopenias unrelated to persistent disease were found in 43% of patients. Cytopenias were associated with clinically important rates of infection and transfusion requirement (P = 0.03) and predicted for worse overall survival (61% versus 96% at 60 months, P = 0.05). Increasing age predicted for persistent cytopenias (P = 0.02), but the presence of pretreatment cytopenias and delivered dose intensity were not predictive. The median times to resolution of anaemia, neutropenia, and thrombocytopenia were 7, 9, and 10 months, respectively.ConclusionsCytopenias often persist >3 months after first-line fludarabine combination therapy and can lead to important clinical sequelae. Although cytopenias generally resolve over time, treating physicians should be aware of these factors when considering fludarabine combination chemotherapy and when documenting treatment response status in chronic lymphocytic leukaemia.     

Expression and prognostic significance of the inhibitor of apoptosis protein (IAP) family and its antagonists in chronic lymphocytic leukaemia

Impaired apoptosis is still considered to be an important event in the development and progression of chronic lymphocytic leukaemia (CLL). However, mechanisms of this defect have not been fully elucidated. In this study, expression of inhibitor of apoptosis proteins, IAPs (cIAP1, cIAP2, XIAP and survivin), and their antagonists (Smac/DIABLO and HtrA2/Omi) was comprehensively analysed in 100 untreated CLL patients, using flow cytometry and Western blot techniques.Expression of anti-apoptotic cIAP1 and cIAP2 in leukaemic cells was significantly higher than in non-tumour lymphocytes (p = 0.000001 and p = 0.014, respectively), whereas the IAP-antagonist, Smac/DIABLO, was decreased in CLL (p = 0.010). Higher expression of all analysed IAPs (cIAP1, p = 0.002; cIAP2, p = 0.026; XIAP, p = 0.002; survivin, p = 0.00006) and lower levels of Smac/DIABLO (p = 0.006) were found in patients with progressive disease, compared to those with stable CLL. High baseline expression of cIAP1 and survivin correlated with worse response to treatment. Co-expression of these proteins was associated with shorter overall survival of CLL patients (p = 0.005).In conclusion, CLL cells show the apoptosis-resistant profile of IAPs/IAP-antagonist expression. Upregulation of IAPs is associated with a progressive course of the disease. Co-expression of cIAP1 and survivin seems to be an unfavourable prognostic factor in CLL patients. Further studies with longer follow up are warranted to confirm and expand these findings.     

Germline variations of the MALT1 gene as risk factors in the development of primary gastric B-cell lymphoma

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a histologically distinct tumour derived from MALT acquired as a result of Helicobacter pylori infection. The genetic susceptibility to develop primary gastric B-cell lymphoma in patients with chronic H. pylori infection is unknown. MALT1 plays a key role in malignant B-cell transformation and lymphoma progression. Thus, we investigated germline variations of MALT1 as risk factors for gastric lymphoma in a large cohort from a European multicentre study and in total 214 lymphoma patients, 593 H. pylori infected controls and 348 healthy blood donors were genotyped for four single nucleotide polymorphisms (SNPs) covering the MALT1 locus by Taqman technology. Haplotype and single marker analyses were conducted for association testing in a case-control setting. A distinct haplotype was identified that showed a trend towards protection from high-grade and low-grade lymphomas. In single marker analysis individuals homozygous for the rare allele G of SNP3 (rs12969413) were significantly protected only from gastric high-grade lymphoma compared with controls (p = 0.002, odds ratio (OR): 0.2, Wald 95% confidence interval (CI): 0.1 < OR < 0.6). This association could not be confirmed in a second independent cohort of high-grade lymphoma patients from the Lymph node registry in Kiel (p = 0.531, OR: 0.8, Wald 95% CI: 0.4 < OR < 1.5). Due to the fact that SNPs 2, 3 and 4 are arranged in one LD block exhibiting nearly complete linkage disequilibrium it is rather unlikely that germline variations of MALT1 might be involved in the pathogenesis of gastric lymphoma. This is the first genetic association study that investigated polymorphisms of MALT1 as genetic risk factors in the development of primary gastric lymphoma.