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Splenic marginal zone lymphoma (SMZL) is a mature B-cell neoplasm characterized by rather indolent clinical course. However, nearly one third of patients experience a rapidly progressive disease with a dismal outcome. Despite the characterization of clone geneticsandthe recognition of deregulated immunologic stimulation in the pathogenesis of SMZL, little is known about microenvironment dynamics and their potential biological influence on disease outcome. Here we investigate the effect of stroma-intrinsic features on SMZL disease progression by focusing on the microenvironment of the bone marrow (BM), which represents an elective disease localization endorsing diagnostic and prognostic relevance. We show that the quality of the BM stromal meshwork of SMZL infiltrates correlates with time to progression. In particular, we describe the unfavorable prognostic influence of dense CD40 expression by BM stromal cells, which involves the contribution of CD40 ligand (CD40L)-expressing bystander mast cells infiltrating SMZL BM aggregates. The CD40/CD40L-assisted crosstalk between mesenchymal stromal cells and mast cells populating the SMZL microenvironment finds correlation in p53-/- mice developing SMZL and contributes to the engendering of detrimental proinflammatory conditions. Our study highlights a dynamic interaction, playing between nonneoplastic elements within the SMZL niche, toward disease progression. © 2014 by The American Society of Hematology.

The current classification of pulmonary neuroendocrine tumours includes four subtypes: low-grade typical carcinoid tumour (TC), intermediate-grade atypical carcinoid tumour (AC), and two high-grade malignancies: large cell neuroendocrine carcinoma and small cell lung cancer (SCLC). Unfortunately, with the exclusion of SCLC, no large phase II and III trials for pulmonary neuroendocrine tumours have been published. Thus, several treatment approaches are available for their treatment but none of them has been validated in appropriately designed and adequately sized clinical trials. The main problem of the published studies is that they include neuroendocrine tumours from various sites of origin with different clinical behaviour. It is important that future studies consider these tumours separately. In this regard, increased awareness and referral of these patients to tertiary centres, in which a multidisciplinary management is available, may be of value. The aim of this review is to evaluate the state of the art and discuss future developments in the management of pulmonary neuroendocrine tumours excluding SCLC which we consider should be addressed in a different issue.

BACKGROUND Epidermal growth factor receptor (EGFR) mutations are reliably detected by referral laboratories, even if most lung cancer cytology specimens sent to such laboratories contain very few cells. However, EGFR mutations may be distributed heterogeneously within tumors, thereby raising concerns that mutations detected on cytology are not representative of the entire tumor and, thus, are less reliable in predicting response to tyrosine kinase inhibitor (TKI) treatment than mutations detected on histology. To address this issue, the authors reviewed their clinical practice archives and compared the outcome of TKI treatment among patients who were selected by cytology versus patients who were selected by histology. METHODS From July 2010 to July 2012, 364 cytology samples and 318 histology samples were received. Exon 19 deletions and the L858R point mutation in exon 21, detected by fragment assay and TaqMan assay, respectively, were confirmed by direct sequencing; discrepancies were resolved by cloning polymerase chain reaction products. The response rate (RR) and progression-free survival (PFS) at 12 months (range, 3-34 months) were evaluable in 13 EGFR-mutated patients who were selected for treatment by cytology and 13 patients who were selected by histology. RESULTS The mutation rate was similar in histology samples (8.5%) and cytology samples (8.8%). The RR (54%) and PFS (9.2 months) were similar in histologically selected patients and cytologically selected patients (RR, 62%; PFS, 8.6 months; P = .88). The disease control rate (responsive plus stable disease) was 92% in histologically selected patients and 100% in cytologically selected patients. CONCLUSIONS EGFR mutations detected on cytology specimens by a centralized laboratory can predict TKI treatment response equally well as mutations identified on histology samples. Cancer (Cancer Cytopathol) 2013;121:552–560. © 2013 American Cancer Society.

In advanced non-small-cell lung carcinomas epidermal growth factor receptor (EGFR) and KRAS testing is often performed on cytology. Liquid-based cytology (LBC), which eliminates the need for slide preparation by clinicians, may be very useful. In 42 LBC DNA was extracted twice. One sample was obtained directly from CytoLyt solution, whereas the other DNA sample was derived after smear preparation and laser capture microdissection (LCM) of Papanicolaou-stained cells. EGFR and KRAS mutational analyses were performed by direct sequencing. On CytoLyt-derived DNA four EGFR (9%) and five KRAS (12%) gene mutations were found. When direct sequencing was performed after LCM, the rate of cases that displayed either EGFR or KRAS mutations increased from 21% to 40%. Although time-consuming, LCM makes direct sequencing highly sensitive even on LBC preparations containing only a few cells.

Background: Erlotinib demonstrated significantly prolonged survival versus placebo in patients with advanced NSCLC who had progressed after standard chemotherapy. TRUST is a phase IV trial initiated to provide erlotinib access to patients with advanced NSCLC. We report the interim analysis for patients enrolled in the TRUST trial in Italy. Patients and methods: Eligible patients had stage IIIB/IV NSCLC and had failed or were unsuitable for chemotherapy. Erlotinib (150 mg/day orally) was given until disease progression or unacceptable toxicity. Patients were monitored monthly. Results: At time of this analysis, data from 651 patients were available. Patient characteristics were: median age 66 years (range 30-87), male 69%, former or current smoker 71%, ECOG PS 0-1 81%, adenocarcinoma histology 52% and stage IV 82%. Erlotinib was administered as first-, second-, third- or other-line in 12, 45,43 and

Purpose Two phase I/II trials were done to evaluate the feasibility of cisplatin combined with gemcitabine or vinorelbine in elderly patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with advanced NSCLC who were older than 70 years of age and who had a performance status of 0 to 1 were eligible. Cisplatin was given on day 1 (a starting dose of 50 mg/m2 with increasing increments of 10 mg/m2 at each level) and gemcitabine (1,000 mg/m2) or vinorelbine (25 mg/m2) on days 1 and 8. Cycles were repeated every 21 days. A two-stage flexible optimal design was applied in the phase II study, and unacceptable toxicity was the primary end point. Results Overall, 159 patients were enrolled: 38 in phase I and 121 in phase II studies. Cisplatin was feasible at 60 mg/m2 with gemcitabine and at 40 mg/m2 with vinorelbine. With the former combination, 50 of 60 (83.3%) patients were treated without unacceptable toxicity; objective responses were reported in 26 of 60 patients (43.5%; 95% CI, 30.6 to 56.8); median progression-free and overall survivals were 25.3 and 43.6 weeks, respectively. With the latter combination, 50 (82.0%) of 61 patients were treated without unacceptable toxicity; objective responses were reported in 22 of 61 patients (36.1%; 95% CI, 24.2 to 49.4); median progression-free and overall survivals were 21.1 and 33.1 weeks, respectively. Conclusion Both cisplatin (60 mg/m2) plus gemcitabine and cisplatin (40 mg/m2) plus vinorelbine are feasible and active in the treatment of elderly patients with advanced NSCLC. The former combination, which provides a higher dose of cisplatin, deserves comparison versus single-agent chemotherapy in this setting of patients.

Summary Background Chemotherapy is the standard treatment for advanced non-small-cell lung cancer, and myelosuppression is a common side-effect. We aimed to assess whether haematological toxic effects could be a biological measure of drug activity and a marker of efficacy. Methods We analysed data for 1265 patients who received chemotherapy (vinorelbine, gemcitabine, gemcitabine and vinorelbine, cisplatin and vinorelbine, or cisplatin and gemcitabine) within three randomised trials. Primary landmark analyses were restricted to 436 patients who received all six planned chemotherapy cycles and who were alive 180 days after randomisation. Neutropenia was categorised on the basis of worst WHO grade during chemotherapy: absent (grade 0), mild (grade 1–2), or severe (grade 3–4). All statistical analyses were stratified by treatment allocation. Analyses were repeated in the out-of-landmark group (829 patients), stratifying by treatment allocation and number of chemotherapy cycles. The primary endpoint was overall survival. Findings In the landmark group, hazard ratios of death were 0·65 (0·46–0·93) for patients with severe neutropenia and 0·74 (0·56–0·98) for those with mild neutropenia. Median survival after the landmark time of 180 days was 31·4 weeks (95% CI 25·7–39·6) for patients without neutropenia compared with 42·0 weeks (32·7–59·7) for patients with severe neutropenia, and with 43·7 weeks (36·6–66·0) for those with mild neutropenia (severe vs mild vs no neutropenia p=0·0118). Findings were much the same for the out-of-landmark group. Interpretation Neutropenia during chemotherapy is associated with increased survival of patients with advanced non-small-cell lung cancer, and its absence might be a result of underdosing. Prospective trials are needed to assess whether drug dosing guided by the occurrence of toxic effects could improve efficacy of standard regimens.

We describe a 67-year-old woman with primary Sjögren's syndrome who developed a splenic marginal zone B-cell lymphoma, and complained of a dry mouth and Raynaud's phenomenon. She had splenomegaly, swollen lymph nodes and monoclonal IgM-kappa cryoglobulin. After splenectomy, Raynaud's phenomenon had improved with the decrease of cryoglobulin. This is the first case of primary Sjögren's syndrome with splenic marginal zone B-cell lymphoma to be reported.

Pleomorphic Hyalinizing Angiectatic Tumor (PHAT) is a rare benign lesion characterized by slow growth, infiltrative behavior and high rate of local recurrences. Only one case has been described in retroperitoneum, at renal hilum, but not involving pelvis or parenchyma. Here we present the first case of PHAT arising in the renal parenchyma. A nodular lesion in right kidney lower pole was diagnosed to a 61 year old woman. The patient underwent right nephrectomy. Microscopically, the lesion showed solid and pseudo-cystic components with hemorrhagic areas characterized by aggregates of ectatic blood vessels. Pleomorphic cells were characterized by large eosinophilic cytoplasm with irregular and hyperchromatic nuclei. Immunohistochemistry was performed and the lesion was classified as a Pleomorphic Hyalinizing Angiectatic Tumor (PHAT). Due to the clinical behavior of this tumor, in spite of its benign nature, review of the surgical margins and close follow up after partial nephrectomy are mandatory.