A hallmark of neoplasia is dysregulated apoptosis, programmed cell death. Apoptosis is crucial for normal tissue homeostasis. Dysregulation of apoptotic pathways leads to reduced cytocidal responses to chemotherapeutic drugs or radiation and is a frequent contributor to therapeutic resistance in cancer. The literature pertaining to detection of apoptotic pathway constituents in cytologic specimens is reviewed herein. Virtually all methods for detecting apoptosis, including classic cytomorphologic evaluation, TUNEL assay, immunocytochemistry, and gene sequence analysis, may be applied to cytologic samples as well as tissue. Components of both intrinsic and extrinsic apoptotic pathways have been studied, including many reports examining p53 and bcl‐2, as well as studies of caspase inhibitory proteins XIAP and survivin, death receptors and ligands such as Fas, Fas‐ligand, and TRAIL. p53 undergoes oncogenic alteration more than any other protein; its immunocytochemical detection almost always connotes loss of its physiologic role as an inducer of apoptosis in response to a damaged genome. Several reports establish cytologic sampling as being as useful as tissue sampling. In one respect cytologic sampling is superior to tissue sampling in particular, by allowing clinicians to repeat sampling of the same tumor before and after administration of therapy; a number of reports use this approach to attempt to predict tumor response by assaying the effect of chemotherapy on the induction of apoptosis. Diagn. Cytopathol. 2010;38:685–697. © 2010 Wiley‐Liss, Inc.

Treatment of primary central nervous system lymphoma (PCNSL) in elderly patients remains unsatisfactory. To develop a new high-dose methotrexate (HD-MTX)-based regimen including idarubicin, a phase 1 multicenter dose escalation study was conducted to determine the maximum-tolerated dose (MTD) of idarubicin. Thirty-five immunocompetent patients with PCNSL were enrolled. The median age was 65 years (range, 60-70 years). MTX and vindesine (VDS) were given at the fixed dose of 3 g/m 2 (6-hr intravenous [IV]) and 3 mg/m 2 IV on day 1, respectively. Prednisolone (PRED) was given at the fixed dose of 60 mg/m 2 (IV or orally) on days 1-5. Idarubicin was escalated in increments of 2 mg/m 2 with doses ranging from 12-18 mg/m 2 IV on day 1. Treatment was repeated three times every 3 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for more than 7 days, thrombocytopenia grade 4 or nonhaematological toxicity more than grade 2. The MTD of idarubicin was reached at 16 mg/m 2 . At this level, the main haematological toxicities were thrombocytopenia grade 4: 5% and neutropenia grade 3 or 4 (52%); the main nonhaematological toxicities were grade 3 or 4 infectious disease (5%) and grade 2 renal failure (9%). For the study population, median overall and progression-free survival were 19 and 13 months, respectively. Our study suggests that the MTD of idarubicin in combination with HD-MTX, VDS, and PRED, should be 16 mg/m 2 . Further studies will be necessary to challenge a standard treatment in elderly patients with PCNSL.

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BACKGROUND This Phase II study was performed in patients with advanced or bulky Hodgkin disease (HD) to evaluate the results of a 7‐drug chemotherapy (CT) regimen that was administered over 12 weeks according to 2 randomized modalities followed by high‐dose lymph node irradiation. METHODS From 1990 to 1996, 162 patients with HD at clinical stages (CS) I–III with bulky disease (mediastinal mass ratio ≥ 0.45 and/or unilateral or bilateral pelvic plus lumboaortic disease; 86 patients) or CS IV (76 patients) were randomized to receive the same cumulated dose of a CT regimen consisting of epirubicin (240 mg/m2), bleomycin (60 mg/m2), vinblastine (20 mg/m2), vincristine (4 mg/m2), cyclophosphamide (4000 mg/m2), etoposide (900 mg/m2), and methotrexate (180 mg/m2) plus methylprednisolone (1500 mg/m2) over 12 weeks either every 4 weeks (Arm Y, 79 patients) or every 3 weeks (Arm Z, 83 patients). Patients with disease in complete remission (CR) or partial remission after CT received extended‐field lymph node irradiation (involved areas, 40 grays [Gy]; noninvolved areas, 30 Gy). RESULTS Forty‐two percent of patients achieved a post‐CT CR, and 86% of patients achieved a CR after the completion of irradiation (there was no difference between Arm Y and Arm Z). Thirty‐five patients developed recurrent disease; most of those patients were in post‐CT partial remission. The 10‐year freedom from first progression rate was 63.9% (there was no difference between Arm Y and Arm Z). Thirty‐eight patients died: 24 patients from HD, 3 patients from CT‐related early sepsis, 1 patient from radiation‐induced pneumonitis, 6 patients from a second malignancy, and 4 patients from causes unrelated to treatment. The overall 10‐year survival rate was 76.7%. Survival was slightly higher among patients in Arm Y (83.3%) compared with patients in Arm Z (70.2%; P = 0.12). CONCLUSIONS No differences were found when the same amount of CT was delivered in three courses or in four courses. In 1997, because most recurrences of the H90‐A/B trial occurred in patients who achieved a post‐CT partial remission, the authors decided to reinforce the intensity of the initial CT and designed a new randomized study comparing two modalities of more intensive CT plus consolidative radiotherapy (H97‐LM trial). Cancer 2002;95:2169–79. © 2002 American Cancer Society. DOI 10.1002/cncr.10932

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