High-dose Radiochemotherapy Research Articles

419P Transanal endoscopic microsurgery for local regrowth after curative radio-chemotherapy for rectal cancer

Low rectal cancer staged as T2-T3 N0-N1 is currently offered abdominoperineal resection (APR) as a standard treatment, but with a significant risk of sequalae due to the extensive surgical procedure. An alternative to upfront surgery is curatively intended radiotherapy and chemotherapy, followed by observation in cases with complete clinical response (cCR). Local regrowth during follow-up may be treated with transanal endoscopic microsurgery (TEM) and thus allowing an organ sparing option compared to extirpation. We wanted to describe the results of TEM in patients with local regrowth after cCR to radio-chemotherapy. In a phase II trial, we included patients with histopathological verified adenocarcinoma of the rectum who fulfilled criteria for APR or ultralow resection based on having a primary resectable T1-T3 N0-1 Mo category. All patients underwent 50.4 Gy/28 fractions to elective lymph node regions and 62 Gy/28 fractions as a concomitant boost to the tumour volume. Concomitant capecitabine 825 mg/m2 x 2 was given on treatment days. In the intention to treat population of 107 patients (108 included and one withdrew before any procedures) 92 patients (86.0 %, 95% CI: 78– 92) had cCR and were allocated to observation. Of 23 patients with biopsy proven local regrowth, 7 patients were referred to TEM. There were no surgical complications according to Clavien-Dindo (zero for all patients). Within a median follow-up time after TEM of 18 months (range 1 – 43 months), only one patient developed liver metastasis 10 months after TEM. The treatment was well tolerated with a low LARS score. One patient had urge symptoms within the first 30 postoperative days and one patient had urge symptoms and a low grade of proctitis at 30 months follow-up. TEM is a minimal invasive treatment modality for local regrowth after curative highdose radio-chemotherapy. There were no surgical complications and patient reported only few adverse symptoms. The rate of rectal preservation after radio-chemotherapy can be increased without impairing oncological outcome and thus treating local regrowth with TEM could be a new standard for these patients.

Positron emission tomography and computed tomographic imaging (PET/CT) for dose planning purposes of thoracic radiation with curative intent in lung cancer patients: A systematic review and meta-analysis

Background and purposePET/CT is a proposed management to improve the accuracy of high dose radiochemotherapy in lung cancer patients. This systematic review was performed to investigate the possible impact on clinical outcome and to quantify the effect on patient selection and target definition. Material and methodsSystematic literature searches were conducted, eligible full-text articles were assessed for quality and data were extracted. ResultsThirty-five cross-sectional studies and one observational study fulfilled the inclusion criteria. No randomized trials or data with regard to clinical endpoints were found. The summary estimates of a change in target definition were 36% in patients with a former staging PET, and 43% and 26% in patients without a staging PET, for non small- and small cell lung cancer respectively. The corresponding summary estimates of a change in treatment intent from curative to palliative treatment were 20% and 22% and 9% respectively. ConclusionPET/CT for dose planning improves target definition and patient selection. Approximately two in five patients had a significant change in target definition and one in five received palliative treatment instead. The proportions seem to be similar regardless of the availability of a previous staging-PET.

Rituximab and High-Dose Cytarabine Do Not Counteract the Adverse Prognostic Value of CDKN2A and TP53 Deletions in Autografted Mantle-Cell Lymphoma Patients. a European-MCL Network Study

▪IntroductionMantle-cell lymphoma (MCL) is of poor prognosis, with a median survival of about 5 years. Besides the t(11;14) translocation, several secondary genetic abnormalities have been shown to correlate with prognosis. However, most studies have analysed patients with heterogeneous treatment, mostly with anthracyclin-based regimens. In 2004, the European MCL Network started the randomized MCL Younger trial comparing R-CHOP followed by high-dose radiochemotherapy and autologous stem cell transplantation (ASCT) versus alternating R-CHOP/R-DHAP followed by a high-dose cytarabine conditioning regimen and ASCT in previously untreated MCL stage II-IV patients up to the age of 65y. The R-CHOP/R-DHAP arm showed improved time to treatment failure (TTF) and, potentially, overall survival (OS) (Hermine et al., ASH 2010, ASH 2012). Our aim was to revisit the prognostic value of some gene copy number alterations (GCNA) in this randomized trial and to determine whether high-dose cytarabine could counteract some of those factors.MethodsThe inclusion criteria for this biological study were: confirmed histological diagnosis of MCL, the availability of diagnostic tumor DNA and complete clinical data. When no frozen biopsy was available, peripheral samples with more than 50% tumor cells were considered eligible for GCNA analysis. CDKN1B, CDK2, and MDM2 were analyzed using quantitative multiplex PCR of short fluorescent fragments (QMPSF) (Jardin et al., BJH 2009), 6q25-q26, CDK4, and the 13q14 locus were analyzed by multiplex ligation-dependent probe amplification (MLPA) (MRC-Holland CLL kit), and MYC, CDKN2A, ATM, RB1 and TP53 were assessed by both methods. The analyses of the prognostic value of GCNA was adjusted for clinical prognostic factors summarized in the quantitative MIPI score (age, performance status, LDH, and WBC). The rate of proliferating tumor cells (Ki-67 index) was centrally assessed by the reference pathologists of the European MCL Pathology Panel according to published guidelines (Klapper et al., J Hematopathol 2009). Outcome variables were TTF from treatment start to stable disease, progression, or death from any cause, and OS from trial registration to death from any cause.ResultsOf 135 patients fulfilling the inclusion criteria (median age 56 years), 49%, 26%, and 25% of patients were of low, intermediate, and high MIPI risk . The most frequent amplification involved MYC (18%), whereas the most frequent deletion involved the 13q14 locus (36%), including RB1 in 26%. As expected, CDKN2A and TP53 deletions were frequently found (25% and 22%, respectively). ATM alterations mostly consist of deletion (25%), but amplification was found in 3 of 129patients. The frequencies of GCNA did not differ according to the type of sample analyzed i.e. tumor biopsies (n=79) vs. high tumor load peripheral blood or bone marrow samples (n=56). The Ki-67 index was higher in patients with CDKN2A or RB1 deletion compared to patients without, but was not different between patients with or without TP53 deletion. Only TP53 gene status was associated with MCL cytology, with more frequent deletion in blastoid forms (4/8) than in classic MCL (11/81, 14%).In univariable analyses, deletions of CDKN2A, 13q14, RB1, CDKN1B, and TP53 were associated with shorter TTF and OS, whereas GCNA of 6q25-q26, MYC, ATM, CDK2, CDK4, and MDM2 were not prognostic. In multivariable analyses, adjusting for MIPI score, CDKN2A and TP53 deletions showed independent prognostic impact with hazard ratios of 2.4 (p=0.001) and 2.3 (p=0.004) for TTF and 2.3 (p=0.007) and 2.4 (p=0.007) for OS. This effect was observed in both treatment arms (Figure 1). In addition, there was an interacting effect of CDKN2A (p16) deletion and TP53 deletion on TTF (p=0.004).ConclusionsThe introduction of high-dose cytarabine in first-line treatment of younger MCL patients did not erase the adverse prognostic value of TP53 and CDKN2A deletions observed with previous regimens. Moreover, our study identified a small patient group of very bad prognosis which could benefit of more aggressive regimens or new targeted drugs combination. [Display omitted] [Display omitted] DisclosuresFeugier:Roche: Honoraria. Haioun:Roche, Celgene, Takeda, Pfizer, Janssen,: Honoraria.

Salvage lrung resection after high-dose radiochemotherapy for lung cancer.

e18513 Background: Concurrent chemoradiotherapy (CRT) is the standard for locally advanced stage III lung cancer. However, after treatment with definitive CRT, approximately 50% of patients experie...

Ultrasound elastography in patients with rectal cancer treated with chemoradiation

ObjectiveThe current literature has described several predictive markers in rectal cancer patients treated with chemoradiation, but so far none of them have been validated for clinical use. The purpose of the present study was to compare quantitative elastography based on ultrasound measurements in the course of chemoradiation with tumor response based on T stage classification and the Mandard tumor regression grading (TRG). Materials and methodsWe prospectively examined 31 patients with rectal cancer planned for high dose radiochemotherapy. The tumor and the mesorectal fat elasticity were measured using the Acoustic Radiation Force Impulse to generate information on the mechanical properties of the tissue. The objective quantitative elastography shear wave velocity was compared to the T stage classification and TRG. ResultsThe baseline mean tumor elasticity was 3.13m/s. Two and six weeks after the start of chemoradiation the velocities were 2.17m/s and 2.11m/s, respectively. The difference between baseline velocity and velocities during the treatment course was statistically significant, (p<0.0001). Patients with tumor confined to the rectal wall at histopathology (ypT1-2) had a mean elasticity measurement after two weeks of treatment of 1.95m/s, whereas tumors invading the mesorectal fat (ypT3-4) had a velocity of 2.47m/s, (p<0.05). The mean elasticity tended to be lower (1.99m/s) after two weeks in patients with TRG 1–2 responses in contrast to 2.24m/s in those with TRG 3–4. ConclusionUltrasound elastography after two weeks of chemoradiation seems to hold early predictive information to the pathological T stage.

Mutated KRAS Is an Independent Negative Prognostic Factor for Survival in NSCLC Stage III Disease Treated with High-Dose Radiotherapy.

Background. The main attention regarding prognostic and predictive markers in NSCLC directs towards the EGFR-targeted pathway, where the most studied genetic alterations include EGFR mutations, EGFR copy number, and KRAS mutations. We wanted to explore the prognostic impact of mutated KRAS in the stage III setting treated with high-dose radiochemotherapy. Methods. Samples were obtained from patients participating in two prospective studies of locally advanced NSCLC receiving combined radiochemotherapy: the RAKET study, a randomized phase II study where patients were treated with induction chemotherapy (carboplatin/paclitaxel) followed by concurrent radiochemotherapy, and the Satellite trial, a phase II study with induction chemotherapy (cisplatin/docetaxel) followed by radiotherapy concurrent cetuximab. The samples were analysed regarding KRAS mutations, EGFR mutations, and EGFR FISH positivity. Results. Patients with mutated KRAS had a significantly inferior survival, which maintained its significance in a multivariate analysis when other possible prognostic factors were taken into account. The prevalence of KRAS mutations, EGFR mutations, and EGFR FISH positivity were 28.8%, 7.5%, and 19.7%, respectively. Conclusion. Mutated KRAS is an independent negative prognostic factor for survival in NSCLC stage III disease treated with combined radiochemotherapy. The prevalence of KRAS mutations and EGFR mutations are as expected in this Scandinavian population.

Normalization of pre-ASCT, FDG-PET imaging with second-line, non–cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma

AbstractWe previously reported that remission duration < 1 year, extranodal disease, and B symptoms before salvage chemotherapy (SLT) can stratify relapsed or refractory Hodgkin lymphoma (HL) patients into favorable and unfavorable cohorts. In addition, pre-autologous stem cell transplant (ASCT) 18FDG-PET response to SLT predicts outcome. This phase 2 study uses both pre-SLT prognostic factors and post-SLT FDG-PET response in a risk-adapted approach to improve PFS after high-dose radio-chemotherapy (HDT) and ASCT. The first SLT uses 2 cycles of ICE in a standard or augmented dose (ICE/aICE), followed by restaging FDG-PET scan. Patients with a negative scan received a transplant. If the FDG-PET scan remained positive, patients received 4 biweekly doses of gemcitabine, vinorelbine, and liposomal doxorubicin. Patients without evidence of disease progression proceeded to HDT/ASCT; those with progressive disease were study failures. At a median follow-up of 51 months, EFS analyzed by intent to treat as well as for transplanted patients is 70% and 79%, respectively. Patients transplanted with negative FDG-PET, pre-HDT/ASCT after 1 or 2 SLT programs, had an EFS of > 80%, versus 28.6% for patients with a positive scan (P < .001). This prospective study provides evidence that the goal of SLT in patients with Hodgkin lymphoma should be a negative FDG-PET scan before HDT/ASCT. The study was registered at www.clinicaltrials.gov as NCT00255723.

Analyse rétrospective monocentrique française du contrôle local des cancers bronchiques non à petites cellules de l’apex après radiothérapie de haute dose avec ou sans chimiothérapie

PurposeSuperior sulcus non-small cell lung cancer represents less than 5% of all lung cancers and is a challenge for the physicians because of clinical presentation, treatments related toxicities and poor prognosis. The aim of this preliminary retrospective report is to present outcomes of patients affected by a superior sulcus non-small cell lung cancer, treated by high dose radiotherapy (>60Gy) with or withour chemotherapy. Patients and methodsAll adult inoperable or unresectable patients (≥18years) with a clinical and radiological diagnosis of superior sulcus non-small cell lung cancer treated in our department by radiotherapy with or without chemotherapy were retrospectively analysed. Primary endpoint was the local control. Overall survival, metastasis free survival and toxicity rates were also analysed and reported. ResultsFrom January 1999 to June 2009, 12 patients were treated by exclusive high-dose radiochemotherapy. Median age was 53years (range: 33–64years); mean follow-up time was 20months (range: 2–75months). Mean local control, overall survival and metastasis free survival were 20.2, 22 and 20months, respectively. At the time of this analysis, seven patients died of cancer and three of them presented only a metastatic disease progression. One patient died of acute cardiac failure 36months after the end of radiochemotherapy and was disease free. Treatment was well tolerated and any acute and/or late G3-4 toxicity was recorded (NCI-CTC v 3.0 score). ConclusionThis analysis confirms the interest of exclusive high-dose radiochemotherapy in treating inoperable superior sulcus non-small cell lung cancer patients, in achieving good local control and overall survival rates.

Interferon Maintenance Prolongs Remission Duration After Rituximab-Containing Induction In First-Line Advanced Stage Follicular Lymphoma Patients – a Retrospective Analysis of the German Low-Grade Lymphoma Study Group (GLSG)

AbstractAbstract 2864 Background:Rituximab (R) maintenance in first remission of follicular lymphoma (FL) has recently been shown to improve remission duration as compared to observation only (Salles et al., ASCO 2010). During the nineties of the last century, maintenance using interferon alpha (IFN) had been shown to be effective in indolent lymphoma (Solal-Celigny et al., NEJM 1993, Hagenbeek et al., JCO 1998). Therefore IFN-maintenance became a standard in GLSG trials after 1995. However, data on the impact of IFN after R-containing chemotherapy are rare. We performed a retrospective analysis of GLSG trials in which we compared the outcome of patients who received IFN-maintenance and patients who did not start any form of consolidation or maintenance therapy after achieving a partial or complete remission. We adjusted the analysis for potential confounders that might have influenced the decision not to start IFN-maintenance. Methods:In the GLSG first-line trials “CHOP vs. MCP” and “CHOP vs. R-CHOP” patients younger than 60 years had been randomized between consolidating high-dose radiochemotherapy followed by autologous stem cell transplantation (ASCT) and IFN-maintenance. For all responding patients older than 60 years, IFN-maintenance was intended. All patients with FL achieving a partial or complete remission after MCP, CHOP, or R-CHOP who did not start ASCT were included in the current analysis. Patients intended for IFN who did not start IFN-maintenance were compared to patients who started IFN-maintenance. We compared patient and treatment characteristics between these groups in order to detect possible reasons why IFN-maintenance was not started. Remission duration (RD) was calculated from the end of induction to relapse or death. RD was censored at the latest follow-up date in patients without event, but also when a new antilymphoma therapy was initiated without any sign of progression. No censoring was done for any form of dose reduction or stopping of IFN, which was recommended in the trials if inacceptable side effects were observed. We compared RD with IFN-maintenance to observation only by Kaplan-Meier-curves and log rank test and we adjusted for the potential confounders FLIPI, performance status, R-containing induction and remission status in multiple Cox-Regression. In order to assess the impact of IFN-maintenance after R-containing induction, we performed a subgroup analysis of R-CHOP treated patients. Results:Of 1306 FL patients with clinical remission, ASCT was started in 306 patients and documentation concerning postremission therapy was missing in 21 patients. In 719 (73%) of the remaining 979 patients IFN-maintenance was started, whereas 260 patients did not receive IFN-maintenance. Patients in which IFN-maintenance was started were not more frequently younger than 60 years (59% vs. 55%, p=0.24), and not more frequently in a better performance status (ECOG 0–1: 93% vs. 91%, p=0.33). There was only a trend to better FLIPI (LR/IR/HR 13%/41%/46% vs. 15%/34%/52%, p=0.10) as compared to patients with observation only. Patients with IFN-maintenance had not more frequently achieved a CR (19% vs. 21%, p=0.65), but more patients had been treated without Rituximab during induction (57% vs. 37%, p<0.0001). According to our analysis patients with IFN-maintenance had a significantly prolonged RD (hazard ratio 0.73, 95% CI 0.59 to 0.91, p=0.0045) which was even more pronounced after adjustment for FLIPI factors, performance status, Rituximab containing induction, and remission status (adjusted hazard ratio 0.59, 95% CI 0.47 to 0.74, p<0.0001). In 309 (65%) of 473 patients treated with R-CHOP IFN-maintenance was started. RD after 3 years was 78% vs. 64% (p=0.0007) and the adjusted hazard ratio for IFN-maintenance was 0.57 (95% CI 0.39 to 0.84 p=0.0042). Conclusions:Although this is not a randomized comparison, our analysis shows that the impact of IFN, which was observed before using R-containing therapy may still be valid in the era of immunochemotherapy. Since R-maintenance seems more effective and has less side effects, IFN-maintenance will no longer be the first choice for maintenance therapy in FL. However, it seems relevant to keep in mind that IFN is still an active substance in lymphoma therapy and may be a therapeutic option when rituximab maintenance is not possible. It may also be relevant for future investigations in lymphoma therapy. Disclosures:Dreyling:Johnson & Johnson:.Hiddemann:Roche: Honoraria, Research Funding.

Mantle cell lymphoma: Are current therapies changing the course of disease?

Mantle cell lymphoma (MCL) is a rare entity of non-Hodgkin's lymphoma, although it seems to be increasing in incidence and severity. There is no accepted standard therapy; however, one controlled clinical trial demonstrated that intensive induction immunochemotherapy followed by high-dose radiochemotherapy and autologous stem cell transplantation was superior to conventional treatment. Moreover, uncontrolled studies of intensive immunochemotherapy followed by autologous stem cell transplantation now suggest that MCL may be cured. Insight into the biology of MCL is expanding, opening new avenues of treatment with well-defined molecular targets, including CD20, mammalian target of rapamycin, and proteasomes.

Quantitative assessment of molecular remission after high-dose therapy with autologous stem cell transplantation predicts long-term remission in mantle cell lymphoma

AbstractTo evaluate the prognostic impact of minimal residual disease (MRD), quantitative real-time polymerase chain reaction (RQ-PCR) of clonal IGH rearrangements was performed in 29 patients with mantle cell lymphoma (MCL) treated with high-dose radiochemotherapy and autologous stem cell transplantation (ASCT). Fourteen of 27 patients evaluable for MRD after ASCT achieved complete clinical and molecular remission, whereas 13 patients had detectable MRD within the first year after ASCT. Molecular remission after ASCT was strongly predictive for improved outcome, with a median progression-free survival (PFS) of 92 months in the MRD-negative group compared with 21 months in the MRD-positive group (P < .001). Median overall survival (OS) was 44 months in the MRD-positive group and has not been reached in the MRD-negative group (P < .003). In multivariate analysis, molecular remission and bulky disease were independent prognostic factors for PFS (P = .001 and P = .021, respectively). While cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP)–like cytoreduction had only modest influence, ara-C–containing mobilization and myeloablative radiochemotherapy significantly reduced MRD. Quantitative MRD measured in the stem cell products of 27 patients was not predictive for molecular remission. We conclude that sequential quantitative monitoring of residual disease after ASCT is a powerful indicator for treatment outcome in MCL and defines subgroups of patients with a significantly different prognosis.

452 PUBLICATION Correlation between 99mTc-DPD bone scan findings and CA 15-3 values in breast cancer patients after neoadjuvant chemotherapy

EFT is defined by the expression of ews/ets fusion genes. The type of the fusion transcript impacts on the clinical biology. EFT requires risk adapted treatment. A risk-adapted treatment is determined by tumor localisation, tumor stage and volume. For metastatic and relapsed disease the pattern of spread and the time of relapse are the determinants of risk stratification. Staging of Ewing tumors has been considerably improved by magnetic resonance imaging and modern isotope scanning techniques. However, the determination of the extent of the metastatic spread in particular number of involved bones remains an unresolved issue. The prognosis for high-risk Ewing tumors has been improved by multimodal and high-dose radio/chemotherapy (HDC). The concepts for high-dose therapy in Ewing tumors are based on dose response and dose intensity relationships. In single agent HDC most experience exists with Melphalan. Several chemotherapeutic agents have been used in combination HDC with or without TBI such as Adriamycin, BCNU, Busulphan, Carboplatin, Cyclophosphamide, Etoposide, Melphalan, Thiotepa Procarbazin and Vincristine. Todate, superiority of any high-dose chemotherapy regimen has not been established. However, the clinical biology, the pattern of spread and the time of relapse determine the prognosis of patient who are eligible for HDC. In particular, patients with multifocal bone or bone marrow metastases have a poorer prognosis than patients with lung metastases. In addition, patients with a relapse within 24 months have a poorer prognosis than patients with a relapse later than 24 months after diagnosis. This review will analyze the results of single- and multi-agent chemotherapy with respect to agent combination, dose and risk stratum of patient population. Future therapeutic modalities for the treatment of EFT might encompass immunotherapeutic and genetic strategies including allogeneic stem cell transplantation.

Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group

AbstractConventional chemotherapy has failed to substantially prolong survival for patients with advanced follicular lymphoma. To improve outcomes, the German Low-Grade Lymphoma Study Group (GLSG) initiated a randomized trial to compare the effect of potentially curative myeloablative radiochemotherapy followed by autologous stem cell transplantation (ASCT) with interferon-α (IFN-α) maintenance therapy in first remission. Three hundred seven patients (younger than 60 years) with follicular lymphoma were recruited into the trial from 130 institutions. After 2 cycles of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) or mitoxantrone-chlorambucil-prednisone (MCP) induction chemotherapy, patients were randomly assigned to either the ASCT or the IFN-α group. The respective therapy was started when patients achieved complete or partial remission after induction chemotherapy. Two hundred forty patients with follicular lymphoma are evaluable for the comparison of ASCT and IFN-α. In patients who underwent ASCT, the 5-year progression-free survival (PFS) rate was 64.7%, and in the IFN-α arm it was 33.3% (P < .0001). As expected, acute toxicity was higher in the ASCT group, but early mortality was below 2.5% in both study arms. In this randomized, multicenter trial, high-dose radiochemotherapy followed by ASCT significantly improved PFS compared with IFN-α in patients with follicular lymphoma when applied as consolidation in first remission. Longer follow-up is necessary to determine the effect of ASCT on overall survival. (Blood. 2004;104:2667-2674)

Aktuelle Therapiestrategien beim fortgeschrittenen Mantelzell-Lymphom

Advanced stage mantle cell lymphoma (MCL) with a median survival of only three years and virtually no long-term survivors represents the lymphoma subtype with the poorest prognosis and remains incurable with conventional chemotherapy. Recently two randomized trials of the German Low Grade Lymphoma Study Group (GLSG) demonstrated the superiority of a combined immunochemotherapy with the anti-CD20 antibody rituximab in first-line therapy (R-CHOP) as well as in relapsed disease (R-FCM). In addition, in a trial of the European MCL Network, intensified-consolidation with high-dose radiochemotherapy followed by autologous stem cell transplantation significantly improved the progression-free survival in patients up to 65 years of age. However, the vast majority of patients with MCL will eventually relapse. Thus, new strategies such as allogenic transplantation after dose-reduced conditioning or novel molecular targeting agents (e. g. proteasome inhibitors or radiolabeled antibodies) are urgently warranted to further improve the long-term outcome of MCL.

Das angiozentrische T/NK-Zell-Lymphom - eine spezielle klinisch-pathologische Entität des letalen Mittelliniengranulomes: eine Fallbeschreibung

The term "midline granuloma syndrome" (MGS) is a clinical description of a broad spectrum of diseases, which are characterised by aggressive and progressive destruction of mucosa and adjacent structures of the midface and upper aerodigestive tract. After exclusion of granulomatous infections, rare granulomatous diseases and epithelial neoplasias, the differential diagnosis includes the following entities: Wegener's granulomatosis (WG), malignant lymphoma and idiopathic midline destructive disease (IMDD). Today there are doubts about the existence of IMDD. After exclusion of WG nearly all remaining cases presenting as MGS are peripheral sinonasal angiocentric T- and/or NK-cell lymphomas, which show a close association to Epstein-Barr virus infection and now are recognised as a special clinicopathological entity. The natural history of these lymphomas is characterised through a rapidly progressive course with a poor prognosis. A case of a 35-year-old male patient with an angiocentric nasal T/NK-cell lymphoma, which involved the left lacrimal cyst, the left maxillar and ethmoid sinus as well as the soft and hard palates, is presented. First clinical signs and symptoms were similar to chronic-recurrent sinusitis. For almost two years the patient was treated with systemic corticoids for suspected limited Wegener's granulomatosis. The patient underwent sinus surgery for pansinusitis three times. After development of midline destructive disease the diagnosis of angiocentric lymphoma was established. Soon after the diagnosis a combination high-dose radiochemotherapy was performed. The patient died only 3 months later because of multiorgan failure. Because of its poor prognosis the angiocentric nasal NK/T-cell lymphoma should included early into the differential diagnosis of the midline granuloma syndrome. Correct biopsy technic and in situ hybridization of EBV can be important for an early diagnosis. Therapy should be aggressive and consists of high-dose radiotherapy, which is most important to reach local tumor control, and combination chemotherapy, the use of which is presently in discussion.

High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: results of a phase II clinical trial

AbstractAdvanced stage follicular small cleaved and mixed cell lymphoma is characterized by relapse from remission and survival ranging from 6 to 12 years. Because young patients have the greatest compromise in longevity, the efficacy and toxicity of high-dose radiochemotherapy and bone marrow transplantation after conventional chemotherapy was evaluated in a prospective phase II clinical trial. Thirty-seven patients in a minimal disease state after conventional chemotherapy received fractionated total body irradiation and high-dose etoposide and cyclophosphamide, followed by purged autologous bone marrow. A reference sample of 188 patients of similar age, stage, and histology managed at this institution before 1988 was identified for comparison of patient characteristics and outcomes. Compared with reference patients, transplant recipients had a higher tumor burden at diagnosis. With a median follow-up of 6.5 years, the estimated 10-year survival after transplantation was 86%. There was a single lymphoma death yielding a 10-year disease-specific survival of 97%. There were 2 early transplant-related deaths and 2 late acute leukemia deaths. Ten patients relapsed, one with microscopic disease only. High tumor burden at diagnosis and incomplete response to chemotherapy adversely influenced survival in the reference but not in the transplanted patients. The estimated risk of death of 14% and relapse of 30% at 10 years in our transplanted follicular lymphoma patients, the majority of whom had high tumor burdens, compares favorably with our observations in appropriately matched reference patients.

Impaired plasma antioxidative defense and increased nontransferrin-bound iron during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation

To analyze the effects of radiochemotherapy on the pro-oxidative/antioxidative balance in plasma, we measured the total radical antioxidant parameter of plasma (TRAP) and single plasma antioxidants (uric acid, sulfhydryl groups, α-tocopherol, ubiquinone-10/total coenzyme-Q10 ratio, ascorbate, and bilirubin) every 12 h during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation (BMT). Nontransferrin-bound iron (NTBI) was monitored as a potential pro-oxidant. Plasma levels of polyunsaturated fatty acids (PUFA) were measured as substrates, and thiobarbituric acid–reactive substances (TBARS) were measured as products of lipid peroxidation. Allantoin was analyzed as the product of uric acid oxidation. Patients receiving busulfan, VP-16, and cyclophosphamide (BU/VP/CY) ( n = 8) were compared with those receiving total body irradiation in addition to VP-16 and cyclophosphamide (TBI/VP/CY) ( n = 8). TRAP values were within the normal range before therapy and decreased after BU/VP/CY by 37% ( p < .02) and after TBI/VP/CY by 39% ( p < .02). During TBI and after VP-16, a temporary increase in TRAP values occurred, which was not related to changes in individual antioxidants. In vitro experiments confirmed that VP-16 had an antioxidative effect. The concentration of uric acid declined in both groups and correlated with TRAP (BU/VP/CY: r = .80, p < .001; TBI/VP/CY: r = .84, p < .001). Levels of NTBI, which is normally not found in plasma, increased rapidly during conditioning therapy ( p < .02 in both groups) and correlated inversely with TRAP (weighted intraindividual Spearman rank correlation coefficient for both groups: NTBI and TRAP: r = −.59, p < .001) and PUFA (in the radiochemotherapy group: r = −.67, p < .001). Whereas PUFA declined ( p < .02 in both groups), TBARS increased ( p < .05 in both groups). Furthermore, an increase of allantoin and ubiquinone-10/total coenzyme-Q10 ratio in the BU/VP/CY group was found (allantoin: p < .02; ubiquinone-10/total coenzyme-Q10 ratio: p < .05). Antioxidants only partially recovered to baseline values until day 14 after BMT. Our findings indicate oxidative stress after high-dose radiochemotherapy and suggest a contribution of NTBI therein.

Myeloablative radiochemotherapy followed by reinfusion of purged autologous stem cells for Waldenström's macroglobulinaemia.

Waldenström's macroglobulinaemia (WM) is an incurable lymphoproliferative disorder. The purpose of this study was to investigate the role of autologous peripheral blood stem cell transplantation (ASCT) for the treatment of WM. Seven patients (untreated or after first-line therapy) with symptomatic WM underwent two or three cycles of Dexa-BEAM chemotherapy + G-CSF with stem cell harvesting and proceeded to total body irradiation and high-dose cyclophosphamide followed by reinfusion of ex-vivo B-cell-depleted stem cells. Engraftment was prompt, and procedure-related deaths did not occur. A strong reduction or normalization of BM infiltration and serum IgM levels occurred in all evaluable patients, but immunofixation electrophoresis revealed persistent paraproteinaemia in five of them. With 3-30 months of follow-up, all patients are alive without clinical or serological signs of disease progression. This pilot trial shows for the first time that high-dose radiochemotherapy with purged stem cells is effective and may improve the course of patients with WM. In the majority of cases, however, complete eradication of the disease does not appear to be possible with ASCT alone.

Engraftment in Nonobese Diabetic Severe Combined Immunodeficient Mice of Human CD34+ Cord Blood Cells After Ex Vivo Expansion: Evidence for the Amplification and Self-Renewal of Repopulating Stem Cells

AbstractUnderstanding the repopulating characteristics of human hematopoietic stem/progenitor cells is crucial for predicting their performance after transplant into patients receiving high-dose radiochemotherapy. We have previously reported that CD34+cord blood (CB) cells can be expanded in vitro for several months in serum containing culture conditions. The use of combinations of recombinant early acting growth factors and the absence of stroma was essential in determining this phenomenon. However, the effect of these manipulations on in vivo repopulating hematopoietic cells is not known. Recently, a new approach has been developed to establish an in vivo model for human primitive hematopoietic precursors by transplanting human hematopoietic cells into sublethally irradiated nonobese diabetic severe combined immunodeficient (NOD/SCID) mice. We have examined here the expansion of cells, CD34+ and CD34+38− subpopulations, colony-forming cells (CFC), long-term culture initiating cells (LTC-IC) and the maintenance or the expansion of SCID-repopulating cells (SRC) during stroma-free suspension cultures of human CD34+ CB cells for up to 12 weeks. Groups of sublethally irradiated NOD/SCID mice were injected with either 35,000, 20,000, and 10,000 unmanipulated CD34+ CB cells, which were cryopreserved at the start of cultures, or the cryopreserved cells expanded from 35,000, 20,000, or 10,000 CD34+ cells for 4, 8, and 12 weeks in the presence of a combination of early acting recombinant growth factors (flt 3/flk2 ligand [FL] + megakaryocyte growth and development factor [MGDF] ± stem cell factor [SCF] ± interleukin-6 [IL-6]). Mice that had been injected with ≥20,000 fresh or cryopreserved uncultured CD34+ cells did not show any sign or showed little engraftment in a limited number of animals. Conversely, cells that had been generated by the same number of initial CD34+ CB cells in 4 to 10 weeks of expansion cultures engrafted the vast majority of NOD/SCID mice. The level of engraftment, well above that usually observed when the same numbers of uncultured cells were injected in the same recipients (even in the presence of irradiated CD34− cells) suggested that primitive hematopoietic cells were maintained for up to 10 weeks of cultures. In addition, dilution experiments suggest that SRC are expanded more than 70-fold after 9 to 10 weeks of expansion. These results support and extend our previous findings that CD34+ CB stem cells (identified as LTC-IC) could indeed be grown and expanded in vitro for an extremely long period of time. Such information may be essential to design efficient stem cell expansion procedures for clinical use.

Engraftment in Nonobese Diabetic Severe Combined Immunodeficient Mice of Human CD34+ Cord Blood Cells After Ex Vivo Expansion: Evidence for the Amplification and Self-Renewal of Repopulating Stem Cells

Understanding the repopulating characteristics of human hematopoietic stem/progenitor cells is crucial for predicting their performance after transplant into patients receiving high-dose radiochemotherapy. We have previously reported that CD34+cord blood (CB) cells can be expanded in vitro for several months in serum containing culture conditions. The use of combinations of recombinant early acting growth factors and the absence of stroma was essential in determining this phenomenon. However, the effect of these manipulations on in vivo repopulating hematopoietic cells is not known. Recently, a new approach has been developed to establish an in vivo model for human primitive hematopoietic precursors by transplanting human hematopoietic cells into sublethally irradiated nonobese diabetic severe combined immunodeficient (NOD/SCID) mice. We have examined here the expansion of cells, CD34+ and CD34+38− subpopulations, colony-forming cells (CFC), long-term culture initiating cells (LTC-IC) and the maintenance or the expansion of SCID-repopulating cells (SRC) during stroma-free suspension cultures of human CD34+ CB cells for up to 12 weeks. Groups of sublethally irradiated NOD/SCID mice were injected with either 35,000, 20,000, and 10,000 unmanipulated CD34+ CB cells, which were cryopreserved at the start of cultures, or the cryopreserved cells expanded from 35,000, 20,000, or 10,000 CD34+ cells for 4, 8, and 12 weeks in the presence of a combination of early acting recombinant growth factors (flt 3/flk2 ligand [FL] + megakaryocyte growth and development factor [MGDF] ± stem cell factor [SCF] ± interleukin-6 [IL-6]). Mice that had been injected with ≥20,000 fresh or cryopreserved uncultured CD34+ cells did not show any sign or showed little engraftment in a limited number of animals. Conversely, cells that had been generated by the same number of initial CD34+ CB cells in 4 to 10 weeks of expansion cultures engrafted the vast majority of NOD/SCID mice. The level of engraftment, well above that usually observed when the same numbers of uncultured cells were injected in the same recipients (even in the presence of irradiated CD34− cells) suggested that primitive hematopoietic cells were maintained for up to 10 weeks of cultures. In addition, dilution experiments suggest that SRC are expanded more than 70-fold after 9 to 10 weeks of expansion. These results support and extend our previous findings that CD34+ CB stem cells (identified as LTC-IC) could indeed be grown and expanded in vitro for an extremely long period of time. Such information may be essential to design efficient stem cell expansion procedures for clinical use.