A. Melnyk

The Revised European-American Lymphoma (REAL) classification has been criticized for its emphasis on the unproven clinical relevance of immunophenotype. A worse prognosis for peripheral T-cell non-Hodgkin's lymphomas (PTCLs) has been inconsistently reported in part because the definition of PTCL has been imprecise (eg, T-cell-rich B-cell non-Hodgkin's lymphomas [TCRBCLs] have been misdiagnosed as PTCLs in the past) and because its correlation with other known prognostic factors has not been studied by multivariate analysis. We analyzed six protocols from 1984 to 1995 with Working Formulation intermediate grade and immunoblastic lymphomas (exclusive of mantle cell) and selected only those cases in which immunophenotyping was performed and was conclusive. Of a total of 560 evaluable patients, 68 were PTCLs (12%) and the remaining 492 (88%) were B-cell non-Hodgkin's lymphomas, including 16 TCRBCLs (3% of total). The 5-year failure-free survival (FFS) for PTCLs and B-cell large-cell lymphomas (BCLCLs) is 38% and 55%, respectively (P < .0001) and the 5-year overall survival (OS) is 39% and 262%, respectively (P < .001). The M.D. Anderson prognostic tumor score (MDATS) and International Prognostic Index (IPI) for all patients was calculated. With MDATS of less than 3 (good prognosis), the 5-year FFS for PTCL and BCLCL is 56% and 69%, respectively (P = .01), and the 5-year OS is 64% and 77%, respectively (P = .06). With MDATS of greater than 2 (poor prognosis), 5-year FFS for PTCL and BCLCL is 26% and 38%, respectively (P = .03), and the 5-year OS is 24% and 41%, respectively (P = .02). With an IPI of less than 3 (good prognosis), the 5-year FFS for PTCL and BCLCL is 49% and 64%, respectively (P = .001), and the 5-year OS is 55% and 71%, respectively (P = .013). With an IPI greater than 2 (poor prognosis), the 5-year FFS for PTCL and BCLCL is 11% and 35%, respectively (P = .044), and the 5-year OS is 10% and 40%, respectively (P = .011). Multivariate analysis shows that MDATS, IPI, and T-cell phenotype are totally independent and are the most significant predictors of FFS and OS. The 68 PTCLs include 45 PTCLs unspecified, 10 Ki-1 anaplastic (ALCL), 8 angioimmunoblastic, and 5 angiocentric lymphomas. Angiocentrics were usually refractory (1 of 5 remissions only). ALCL rarely relapsed late. We conclude that the immunophenotypic basis of the REAL classification is clinically relevant and that, although other prognostic features also influence outcome, the T-cell phenotype still remains an independent and significant prognostic factor.

We highlight the influence of processing conditions on polymorphism and structure formation on the mesoscale for the family of PCPDTBT polymers with branched alkyl side chains. Direct correlations of morphology to the chemical structure and to transistor device performance are established. We found that up to four different packing motifs could be realized depending on the polymer derivative and the processing conditions: amorphous, π-stacked, cross-hatched and dimer-containing polymorphs. While C- and F-PCPDTBT display similar packing behavior organizing in π-stacked and dimer-like structures, Si-PCPDTBT gives rise to cross-hatched structures upon simple deposition from solution. The observed differences in chain packing for C-/F-PCPDTBT versus Si-PCPDTBT are attributed to differences in backbone conformations and aggregation behavior in solution. The effect of polymorphism on charge transport is probed using field-effect transistors, in which both π-stacked and cross-hatched polymer chain arrangements yield the highest hole mobilities. Mesoscopic morphology and mobility simulations rationalize our experimental findings by relating mobility to distributions of electronic coupling elements between the chains.

PURPOSE: Paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) is a novel antimicrotubule agent with anti-tumor activity against ovarian and breast carcinomas. Its activity when administered as a 3-hour intravenous infusion in patients with relapsed non-Hodgkin's lymphoma (NHL) has not been studied. PATIENTS AND METHODS: Patients with relapsed NHL were treated with a 3-hour infusion of 200 mg/m2 of Taxol every 3 weeks in an outpatient setting. All patients received premedication (dexamethasone, diphenhydramine, and cimetidine) to prevent allergic reactions. Responses were assessed after two courses of therapy, and patients who achieved at least partial remission (PR) continued to receive Taxol for a maximum of eight courses. RESULTS: Of 60 eligible patients, 54 (90%) were assessable for treatment toxicity and 53 (88%) were for treatment response (22 with primary refractory and 31 with relapsed disease). Twelve patients (23%) achieved a PR (n = 6) or complete remission (CR; n = 6) (95% confidence interval, 12% to 36%). Responses were observed in intermediate-grade (31%), low-grade (14%), and mantle-cell (17%) lymphomas. In the intermediate-grade lymphomas, there was a trend for a higher response rate in relapsed versus primary refractory disease (54% v 13%; P = .08). Treatment-related toxicity included alopecia (100%), peripheral neuropathy (37%), myalgia or arthralgia (25%), and neutropenic fever (11%). None of the patients had allergic reactions or cardiac toxicity. CONCLUSION: At this dose and schedule, Taxol is an active agent in patients with relapsed NHL and can be safely administered in an outpatient setting. Combination programs with Taxol should be investigated for treatment of NHL.

Abstract Background: Trastuzumab (T) resistance may be due to aberrant signaling through the PI3K/Akt pathway. Pre-clinical and retrospective clinical data suggest that mTOR inhibition can overcome this mechanism of trastuzumab resistance. Ridaforolimus (R), an mTOR inhibitor, in combination with HER2 inhibition offers the potential for vertical pathway synergy.Methods: A single-arm, two-stage phase 2 trial was performed to evaluate R combined with T. Eligibility criteria included: female patients with HER2+ (IHC 3+ or FISH+) metastatic breast cancer (MBC), age ≥18 years, ECOG performance status ≤ 1, RECIST criteria measurable disease, LVEF ≥ 50%, who developed T resistance (defined as disease progression on T treatment with no more than 2 prior T regimens). R was administered orally at 40 mg once daily for 5 consecutive days per week. T was administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg/wk. The treatment cycle for both agents was 4 weeks. In Stage 1 of the trial, 14 patients were assessed for safety after at least 1 cycle of therapy and objective response (OR) assessed every 2 cycles according to modified RECIST guidelines. At the time of the Stage 1 interim analysis, if one or more patients exhibited an OR, study enrollment continued to a total accrual of 33 patients. Patients continued study treatment until disease progression or other discontinuation criteria were met.Results: As of June 2009, 22 patients, median age 55 years (range 33-81), were enrolled. Thirteen and 9 pts had 1 and 2 prior T regimens, respectively. Nine patients discontinued prior to the first scheduled study assessment: 6 patients for progressive disease, 1 for AE (G2 stomatitis), 1 for a protocol violation (treatment with radiation), and 1 due to death from an intestinal perforation (diagnosed at autopsy; assessed by investigator as possibly related to R). One other patient discontinued after 7 months of treatment due to elevated transaminases related to R. Twelve patients remain on treatment. There were 2 PR (1 confirmed and 1 unconfirmed) among the first 14 patients. The prospectively defined Stage 1 safety review demonstrated mostly Grade 1/2 AEs that were within the expected safety profile of either study drug. Six related Grade 3 AEs (3 stomatitis/mucositis, 1 hyperglycemia, 1 neutropenia, and 1 dysphagia) were reported. There were no study related Grade 4 AEs. Ten SAEs have been reported in 5 patients; 2 were assessed by investigators as possibly related to R (death from intestinal perforation and venous thrombosis).Conclusions: R in combination with T is feasible and well tolerated with early evidence of encouraging anti-tumor activity in T resistant HER2+ MBC. Enrollment is ongoing and updated data will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3091.