Heidi Nyman

A High Tumor-Associated Macrophage Content Predicts Favorable Outcome in Follicular Lymphoma Patients Treated with Rituximab and Cyclophosphamide-Doxorubicin-Vincristine-Prednisone

Purpose: Tumor-associated macrophage (TAM) content predicts survival in follicular lymphoma (FL) patients treated with chemotherapy. The aim of this study was to determine how combination of rituximab with chemotherapy influences TAM-associated clinical outcome. Experimental Design: Expression of a macrophage marker, CD68, was determined immunohistochemically from FL samples of 96 patients treated with rituximab and cyclophosphamide-Adriamycin-vincristine-prednisone regimen. Of them, 71 received therapy at diagnosis and 25 at relapse. Neutrophil and CD3+ lymphocyte counts were also measured. The median follow-up time for the cohort was 54 months. Fourty-five patients previously treated with chemotherapy served as a control group. Results: Consistent with previous studies, high TAM amount was associated with adverse outcome in chemotherapy-treated patients (P = 0.026). In contrast, after rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone regimen, high TAM content correlated with longer survival rates. According to Kaplan Meier estimates, the median progression free survival (PFS) was not reached for patients with high TAM content compared with 45 months for patients with low TAM scores (P = 0.006). A trend toward a better overall survival (OS) at 5 years was also observed for patients with high TAM content (OS, 97% versus 90%, P = 0.116). The positive prognostic value of TAMs was seen both for the patients treated at diagnosis and at relapse. In multivariate analyses, TAM content remained an independent prognostic factor for OS and PFS. Neutrophil and CD3+ lymphocyte counts did not correlate with outcome. Conclusions: The data suggest that high TAM score is associated with a favorable prognosis in FL patients treated with immunochemotherapy.

Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP

Gene expression profiling studies initially enabled diffuse large B-cell lymphoma to be divided into germinal center and activated B-cell-like subtypes, which define high- and low-risk patient groups when treated with chemotherapy. Attempts to reproduce the prognostic classification immunohistochemically have, however, provided inconsistent results. The aim of this study was to determine whether modified immunohistochemical classification of cell of origin focusing on activated B-cell-like markers could be used to predict the outcome of immunochemotherapy-treated diffuse large B-cell lymphoma patients. The expression of CD10, Bcl-6, MUM1/IRF4, Bcl-2, and FOXP1 was determined immunohistochemically from 88 samples of diffuse large B-cell lymphoma patients treated uniformly with R-CHOP. When the modified classification using MUM1/IRF4 and FOXP1 positivities as activated B-cell-like markers was applied to distinguish the patients between the activated B-cell-like and other diffuse large B-cell lymphoma subtypes, a significantly worse outcome was seen for the patients with the activated B-cell-like phenotype (3-year failure-free survival 63 vs 82%, P=0.048, overall survival 69 vs 85%, P=0.110). Similarly, according to the Muris algorithm, the group 2 patients representing Bcl-2-positive post-germinal center patients showed an inferior outcome in comparison to the group 1 patients (failure-free survival 59 vs 81%, P=0.041, overall survival 67 vs 82%, P=0.159). In contrast, when the classification of the same cohort was performed according to the Hans algorithm, no significant difference in survival was observed between the germinal center and non-germinal center patients. In conclusion, the data suggest that both the modified activated B-cell-like and Muris classifications define the non-germinal center phenotype as an adverse risk factor in R-CHOP-treated diffuse large B-cell lymphoma patients.

Bcl-2 but not FOXP1, is an adverse risk factor in immunochemotherapy-treated non-germinal center diffuse large B-cell lymphomas

Objectives:  Non‐germinal center (non‐GC) phenotype, high level expression of the transcription factor forkhead box protein P1 (FOXP1) and anti‐apoptotic protein Bcl‐2 have been identified as unfavorable prognostic factors for diffuse large B‐cell lymphoma (DLBCL) patients treated with chemotherapy. Our aim was to re‐evaluate the prognostic impact of these biologic factors on the survival of the patients treated with immunochemotherapy.

Late non‐relapse mortality among adult autologous stem cell transplant recipients: a nation‐wide analysis of 1482 patients transplanted in 1990–2003

Introduction:  Data on the incidence and causes of late (>100 d) non‐relapse mortality (NRM) in autologous stem cell transplant (ASCT) recipients is limited.

Differential gene expression in non‐malignant tumour microenvironment is associated with outcome in follicular lymphoma patients treated with rituximab and CHOP

Rituximab in combination with chemotherapy (immunochemotherapy) is one of the most effective treatments available for follicular lymphoma (FL). This study aimed to determine whether differences in gene expression in FL tissue correlate with outcome in response to rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy (R–CHOP). We divided 24 patients into long‐ [time to treatment failure (TTF) >35 months] and short‐term (TTF <23 months) responders, and analysed the gene expression profiles of lymphoma tissue using oligonucleotide microarrays. We used a supervised learning technique to identify genes correlating with outcome, and confirmed the expression of selected genes with quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Among the transcripts with a high correlation between microarray and qPCR analyses, we identified EPHA1, a tyrosine kinase involved in transepithelial migration, SMAD1, a transcription factor and a mediator of bone morphogenetic protein and transforming growth factor‐β signalling, and MARCO, a scavenger receptor on macrophages. According to Kaplan–Meier estimates, high EPHA1, and low SMAD1 and MARCO expression were associated with better progression‐free survival (PFS). Immunohistochemistry showed that EphA1 was primarily localised in granulocytes. In addition, both EphA1 and Smad1 were expressed in vascular endothelia. However, no difference in vasculature was detected between long‐ and short‐term responders. In a validation set of 40 patients, a trend towards a better PFS was observed among patients with high EphA1 expression. We conclude that gene expression in non‐malignant cells contributes to clinical outcome in R–CHOP‐treated FL patients.

Prognostic impact of protein kinase C beta II expression in R-CHOP-treated diffuse large B-cell lymphoma patients

Development of targeted agents for the treatment of diffuse large B-cell lymphoma includes clinical evaluation of enzastaurin, an agent that suppresses signaling through protein kinase C-β and AKT pathways. To determine whether protein kinase C-β expression has prognostic significance for diffuse large B-cell lymphoma patients treated with immunochemotherapy, we analyzed the expression of protein kinase C-β II, BCL-2 and cell of origin immunohistochemically from pretreatment samples of 95 diffuse large B-cell lymphoma patients. All patients received rituximab with CHOP or CHOEP. According to Kaplan–Meier analyses, overall survival at 3 years was better among the patients with low than high protein kinase C-β II protein levels (94 vs 76%, P=0.036). The prognostic value of protein kinase C-β II expression on survival was seen in the patients with low and high International Prognostic Index risk groups, and in all molecular entities. Gene expression data from an independent set of 233 diffuse large B-cell lymphoma patients treated with a combination of rituximab and CHOP-like chemotherapy was analyzed in comparison. Accordingly, a better 3-year overall survival was observed among the subgroup with low protein kinase C-β II mRNA levels (84 vs 68%, P=0.005). In multivariate analysis with cell of origin, protein kinase C-β II mRNA expression remained as an independent predictor for overall survival. Together, the data show that protein kinase C-β II expression has prognostic significance in diffuse large B-cell lymphoma patients treated with immunochemotherapy.

Submandibular gland-sparing intensity modulated radiotherapy in the treatment of head and neck cancer: Sites of locoregional relapse and survival

Abstract Background and purpose. To evaluate the patterns of locoregional relapse and survival following submandibular gland (SMG)-sparing intensity modulated radiotherapy (IMRT). Patients and methods. Eighty patients with laryngeal (n = 15), oropharyngeal (n = 50), hypopharyngeal (n = 11) or nasopharyngeal cancer (n = 4) were treated by submandibular gland-sparing IMRT for head and neck squamous cell cancer between July 2000 and December 2008. All patients were treated by bilateral IMRT. Thirty-nine (49%) received definitive radiotherapy (RT) and 41 (51%) postoperative RT. The contralateral parotid gland (PG) and SMG were included in the dose optimization planning program with intent to keep the mean doses for PG and SMG below 23 Gy and 28–30 Gy, respectively. The ipsilateral glands were also spared when considered feasible. Results. During a median follow-up time of 51 months (range, 24–117 months) nine local recurrent tumors were observed. Four of these nine patients were salvaged by surgery with no further recurrence. All local recurrences were located within the high-dose CTVs. None of the locally recurrent cancers were located at the vicinity of the spared PGs or SMGs. No recurrent tumors were observed in the contralateral neck. The Kaplan-Meier estimate for local control at five years following IMRT was 88% for the whole cohort and the corresponding figure for local control following salvage surgery was 94%. The estimates for five-year overall survival and disease-specific survival were 85% and 90%, respectively. Conclusion. In selected head and neck cancer patients who are estimated to have a low risk of cancer recurrence at the nodal levels I–II and who are treated with SMG-sparing IMRT the risk of cancer recurrence at the vicinity of the spared salivary glands is low.

Impact of germinal center and non-germinal center phenotypes on overall and failure-free survival after high-dose chemotherapy and auto-SCT in primary diffuse large B-cell lymphoma

Non-germinal center (non-GC) phenotype is an adverse prognostic factor in chemotherapy (CT)-treated diffuse large B-cell lymphoma (DLBCL) patients. To determine how high-dose therapy (HDT) supported with auto-SCT as first line therapy influences GC-associated outcome in young high-risk DLBCL patients GC and non-GC phenotypes were determined immunohistochemically from 63 patients. Of these, 29 primary high-risk DLBCL patients were treated with auto-SCT, whereas 34 CT-treated patients served as a control group. Consistent with previous studies, non-GC phenotype was associated with adverse outcome in CT-treated high-risk patients. In contrast, immunohistochemical classification by cell of origin did not associate with survival after auto-SCT. When the impact of treatment on the predictive value of cell of origin was analyzed, the non-GC patients, who received HDT, had a better failure-free survival (FFS) and overall survival (OS) than the patients treated with CT alone. In multivariate analyses, both age-adjusted International Prognostic Index (aaIPI) and treatment were independent prognostic factors for FFS and OS. For the patients with GC phenotype, the influence of auto-SCT on survival was not significant. The data imply that auto-SCT can overcome the adverse prognostic impact of the non-GC phenotype in patients with high-risk DLBCL and warrant additional prospective studies.

Linac-based isocentric electron-photon treatment of radically operated breast carcinoma with enhanced dose uniformity in the field gap area.

BACKGROUND AND PURPOSE Isocentric treatment technique is a standard method in photon radiotherapy with the primary advantage of requiring only a single patient set-up procedure for multiple fields. However, in electron treatments the size of the standard applicators does not generally allow to use an isocentric treatment technique. In this work we have modified and dosimetrically tested electron applicators for isocentric treatments in combination with photons. An isocentric treatment technique with photons and electrons for postmastectomy radiation therapy (PMRT) has been developed with special emphasis on improving the dose uniformity in the field gap area. MATERIALS AND METHODS Standard electron applicators of two Varian Clinac 2100CD linear accelerators were shortened by 10cm allowing isocentric treatments of 90cm<SSD<100cm in electron fields. Shortened applicators were commissioned and configured for the electron calculation algorithm of the treatment planning system. The field arrangement of PMRT was modified by combining three photon field segments with different gaps and overlaps with the electron field to improve dose uniformity. The developed technique and two other methods for PMRT were compared with each other in the group of 20 patients. RESULTS Depth dose characteristics of the shortened applicators remained unchanged from those of the standard applicators. Penumbrae were broadened by 0-3mm depending on electron energy and depth as the air gap was increased from 5cm (standard applicator at SSD=100cm) to 10cm (shortened applicator at SSD=95cm). The dose calculation performance of the modified applicators at 95cm<SSD<100cm was considered similar as with standard applicators at SSD=100cm using the Gaussian pencil beam electron dose calculation algorithm of the treatment planning system (Varian Eclipse). The modified isocentric treatment technique for PMRT was superior than the traditional two-dimensional technique. However, with the tangential photon fields without electrons the even better dose uniformity within PTV could be achieved but with increased irradiation of healthy tissues (lung, heart, and contralateral breast). The modified isocentric technique was also found faster than the traditional technique with SSD=100cm fields. CONCLUSIONS It is possible to apply an isocentric treatment technique in PMRT with electrons and photons. The homogeneity of the dose distribution can be improved by adding more photon field segments. With the isocentric technique it is possible to achieve even some time sparing in treatment delivery compared with the traditional SSD=100cm technique.

CD40 is a potential marker of favorable prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy.

We have previously shown that expression of CD40 has a favorable prognostic impact in diffuse large B-cell lymphoma (DLBCL) after anthracycline-based chemotherapy. Here we examined the prognostic value of immunohistochemically defined CD40 expression in 95 patients with DLBCL treated with both anthracycline-based chemotherapy and rituximab. Using a 10% cut-off level, 77% of the patients had CD40-positive tumors and showed a superior overall survival (p = 0.02 log-rank, hazard ratio 0.35, 95% CI 0.14–0.88, p = 0.03 Cox regression). When adjusted for International Prognostic Index in multivariate analysis, CD40 was not an independent prognostic factor (hazard ratio 0.39, 95% CI 0.15–1.04, p = 0.06 Cox regression). However, even after the introduction of immunochemotherapy, CD40 has a potential prognostic impact in DLBCL. Additional and larger studies are necessary, regarding the immunohistochemical robustness of CD40 and the biological mechanisms that contribute to the superior prognosis in CD40-expressing DLBCL.