Andrea Bruzzone

Thymidylate Synthase and Excision Repair Cross-Complementing Group-1 as Predictors of Responsiveness in Mesothelioma Patients Treated with Pemetrexed/Carboplatin

Purpose: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients. Results: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome. Conclusions: In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted. Clin Cancer Res; 17(8); 2581–90. ©2011 AACR.

Impaired Response to Influenza Vaccine Associated with Persistent Memory B Cell Depletion in Non-Hodgkin’s Lymphoma Patients Treated with Rituximab-Containing Regimens

Influenza vaccination is generally recommended for non-Hodgkin’s lymphoma (NHL) patients, but no data are available about the activity of this vaccine after treatment with rituximab-containing regimens. We evaluated the humoral response to the trivalent seasonal influenza vaccine in a group of NHL patients in complete remission for ≥6 mo (median, 29 mo) after treatment with rituximab-containing regimens (n = 31) compared with age-matched healthy subjects (n = 34). B cell populations and incidence of influenza-like illness were also evaluated. For each viral strain, the response was significantly lower in patients compared with controls and was particularly poor in patients treated with fludarabine-based regimens. In the patient group, the response to vaccination did not fulfill the immunogenic criteria based on the European Committee for Medicinal Products for Human Use requirements. Among the patients, CD27+ memory B cells were significantly reduced, and their reduction correlated with serum IgM levels and vaccine response. Episodes of influenza-like illness were recorded only in patients. These results showed that NHL patients treated with rituximab-containing regimens have persisting perturbations of B cell compartments and Ig synthesis and may be at particular risk for infection, even in long-standing complete remission.

Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma

Background:The aim of this open label phase II study (NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM).Methods:Eligible patients received pemetrexed 500 mg m−2, carboplatin area under the plasma concentration–time curve (AUC) 5 mg ml−1 per minute and bevacizumab 15 mg kg−1, administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated.Results:Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7–46.0%). Forty-four (57.9%, 95% CI 46.0–69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3–4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred.Conclusion:The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.

Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division

In this study, we analysed 30 patients with B-cell chronic lymphocytic leukaemia (CLL), compared with 10 healthy donors, for the expression and function of the leukocyte-associated Ig-like receptor-1 (LAIR-1). LAIR-1 is an inhibitory receptor containing a cytoplasmic tyrosine-based inhibitory motif (ITIM) that binds to the SH2 domain of phosphatases, leading to dephosphorylation of different kinases. Constitutive activation of c-Jun aminoterminal kinase (JNK), p38 mitogen-activated protein kinase and extracellular signal-regulated kinase, has been reported in CLL. We show that LAIR-1 is absent in high–risk (HR) CLL and differently expressed on intermediate- and low-risk CLL and the intensity of expression, which is always significantly lower than in healthy donors, correlates with disease stage and progression. Interestingly, both constitutive and sIgM-induced phosphorylation of p38 and JNK is inhibited by LAIR-1 through an ITIM-dependent signal, as demonstrated by the use of specific ITIM-binding peptides; importantly, this inhibitory signal is missing when LAIR-1 is not expressed as occurs in HR CLL. Moreover, engagement of LAIR-1 blocks constitutive and sIgM-induced Akt phosphorylation, besides nuclear factor κ-B nuclear translocation, and prevents CLL division. These results suggest that CLL lacking LAIR-1 may miss one of the molecular mechanisms controlling B-cell activation and proliferation.

Solitary fibrous tumor

Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm which may be found everywhere in the body. It is now distinguished into two forms, pleural and extrapleural, which morphologically resemble each other. Abdominal localizations are quite rare, with 10 cases only reported in bladder; rarely they can be source of paraneoplastic syndromes (i.e., hypoglycemia secondary to insulin-like growth factor). In April 2006 a 74-year-old white male presented with chills, diaphoresis and acute abdominal pain with hematuria. At admission in emergency he underwent an abdominal Xray (no pathological findings) and an ultrasound examination of the kidneys and urinary tract, which revealed a pelvic hyperechogenic neoformation measuring approximately 10×8×7 cm, compressing the bladder. Blood chemistry at admission revealed only a mild neutrophilic leucocytosis (WBC 16600, N 80%, L 11%), elevated fibrinogen and ESR, and hypoglycemia (38 mg/dL). Macro scopic hematuria was evident, while urinocolture was negative. Contrast enhanced CT scan of the abdomen and pelvic region revealed a large round neoformation dislocating the bladder, with an evident contrast-enhanced periphery and a central necrotic area. Continuous infusion of glucose 5% solution was necessary in order to maintain blood glucose levels above 50 mg/dL. The patient underwent complete surgical resection of an ovoidal mass coated by adipose tissue, with well delimited margins; histological findings were consistent with solitary fibrous tumor (SFT). Hypoglycemia resolved completely with removal of the growth. In this case report we describe a SFT growing in the bladder, a quite rare localization, which presented a unique hypoglycemia. In contrast to the majority of cases reported in the literature, the behavior of this SFT was not aggressive, and, since the patient is still alive, surgical resection was considered conclusive.

Is Soluble Mesothelin-Related Protein an Upfront Predictive Marker of Pleural Mesothelioma? A Prospective Study on Italian Workers Exposed to Asbestos

Objective: Soluble mesothelin-related peptide (SMRP) may be useful in the diagnosis and detection of early stage mesothelioma. We investigated the SMRP upfront predictive role for mesothelioma in asbestos-exposed workers. Methods: A total of 1,715 subjects underwent a first visit and were invited for a follow-up after 1 and 2 years, with a clinical examination and blood sampling. SMRP was measured by an ELISA assay. Results: Median SMRP at the first visit was 0.45 [interquartile range (IQR) i.e. 25th-75th percentile: 0.30-0.67 nmol/l]. In all, 1,676 subjects (97.8%) were followed up for a median period of 47.1 months. SMRP was measured at the first visit and at both follow-up visits in 1,536 subjects. At follow-up, 3 subjects were diagnosed with an epithelioid mesothelioma. In these cases, SMRP at the first visit ranged from 0.17 to 0.52 nmol/l. Malignant pleural mesothelioma was diagnosed 9-17 months after the last SMRP evaluation. No SMRP variation was observed during the follow-up. Other 61 miscellaneous cancers were diagnosed (median SMRP at first visit: 0.50 nmol/l, IQR: 0.34-0.71 nmol/l). Conclusions: Our results did not support the usefulness of SMRP as an early marker for the detection of the disease for a time interval of 1 year.

Purpura as the Initial Presentation for Small-Cell Lung Cancer

Background: Causes of thrombocytopenia (TP) in patients affected by smallcell lung cancer (SCLC) include myelophtysis, immunomediated TP, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, drugrelated TP, and amegakaryocytic TP. However, isolated TP is an exceedingly rare presentation of SCLC. Case Report: Here, we report on a 78-year-old Caucasian man with SCLC whose only clinic manifestation at the beginning of his clinical course was a diffuse purpuric rash, indeed due to severe isolated TP. A thorough clinical workup led us to the diagnosis of secondary amegakaryocytic TP, which resolved after chemotherapy. Conclusion: To the best of our knowledge, this is the first described case of SCLC presenting with amegakaryocytic TP. SCLC should be considered in the differential diagnosis of isolated TP, as should rare triggering conditions like amegakaryocytic TP when evaluating therapeutic opportunities in thrombocytopenic patients.

Unusual myeloma relapse after thalidomide therapy: The dark side of the moon?

In the last issue, Katodritou et al. describe a series of unusual xtramedullary plasmacytomas (EMPs) occurring in multiple yeloma (MM) patients who relapsed after treatment with priarily thalidomide-containing regimens (TCRs), and provide new iological insights for the comprehension of this phenomenon [1]. Since the late 1990s MM patient survival has progressively ncreased, firstly due to the introduction of autologous transplantaion following high doses of melphalan-based chemotherapy (HDT), nd because of the availability of several effective new drugs in he last decade, the first of them being thalidomide [2]. Neverheless, even after intensive therapy and subsequent maintenance reatment, most patients eventually relapse and MM almost always emains an incurable disease [3]. In this new scenario, MM relapse increasingly occurs with nusual clinical presentations. In particular, extramedullary elapses with plasmablastic transformation of neoplastic plasma ells, very uncommon until the end of 1990s, were first described in eavily pre-treated MM patients this century [4,5], and new cases ave been increasingly reported in recent years [6–8], especially n patients treated with TCR. Common clinical characteristics of hese relapses are: the presence of extramedullary, often multile, unusual (cutaneous, hepatic, renal, etc.) localisations of the isease with anaplastic transformation of plasma cells, often in he absence of bone marrow involvement; a decrease (or even bsence) of previous monoclonal component coupled to a rise in erum free light chain concentrations; high concentrations of lacate dehydrogenase, and, most importantly, an aggressive clinical ourse frequently characterised by acute renal failure. Usually, these elapses have a very poor prognosis. The reasons for this new phenomenon of disease presentation re still unclear. Katodritou et al. confirm previous more anecdotal bservations, while additionally providing several biological details f their series of 9 EMP-relapse patients, of 185 MM patients (4.9%), iagnosed and treated at their institution during the last 5 years, orrelating these findings with therapy and clinical outcome. Pathologically, EMP-relapse was characterised, in most of the ases, by plasma cell dedifferentiation with anaplastic morphology,