Optimization of rituximab for the treatment of DLBCL (I): dose-dense rituximab in the DENSE-R-CHOP-14 trial of the DSHNHL.

BACKGROUND: To improve outcome of elderly patients with diffuse large B-cell lymphoma, dose-dense rituximab was evaluated in the prospective DENSE-R-CHOP-14 trial. PATIENTS AND METHODS: Rituximab (375 mg/m(2)) was given on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85, and 99 together with six CHOP-14 cycles. Results were to be compared with patients who had received the same chemotherapy in combination with eight 2-week applications of rituximab in RICOVER-60. RESULTS: One hundred twenty-four patients are assessable. Dose-dense rituximab resulted in considerably higher serum levels during the first 50 days of treatment, but rituximab exposure time was not prolonged. Grade 3 and 4 infections were exceptionally high in the first 20 patients without anti-infective prophylaxis, but decreased after introduction of prophylaxis with aciclovir and cotrimoxazole in the remaining 104 patients (from 13% to 6% per cycle and from 35% to 18% per patient; P = 0.007 and P = 0.125, respectively). Patients with international prognostic index = 3-5 had higher complete response/complete response unconfirmed rates (82% versus 68%; P = 0.033) than in the respective RICOVER-60 population, but this did not translate into better long-term outcome, even though male hazard was decreased (event-free survival: from 1.5 to 1.1; progression-free survival: from 1.7 to 1.1; overall survival: from 1.4 to 1.0). CONCLUSIONS: Dose-dense rituximab achieved higher rituximab serum levels, but was not more effective than eight 2-week applications in the historical control population, even though minor improvements in poor-prognosis and male patients cannot be excluded. The increased, though manageable toxicity, precludes its use in routine practice. Our results strongly support anti-infective prophylaxis with aciclovir and cotrimoxazole for all patients receiving R-CHOP.

Comparison and modelling of pegylated or unpegylated G-CSF schedules in CHOP-14 regimen of elderly patients with aggressive B-cell lymphoma.

Bi-weekly (R)-CHOP therapy is one of the standard treatmentS for elderly patients with aggressive B-cell lymphoma, but it is only feasible with supportive G-CSF treatment. In the trials of the DSHNHL, either unpegylated G-CSF was given daily over 7 or 10 days or pegylated G-CSF was applied at day 4 of each cycle. These schedules were planned on the basis of simulations of a biomathematical pharmacokinetic/pharmacodynamic model. By analysing the observed data, we investigated whether our model predictions were correct and whether even better schedules can be proposed. We used data on 249 matched patients of two prospective trials, RICOVER-60 and PEGFILGRASTIM. The three G-CSF-schedules showed similar outcomes regarding leukocytopenia, infections and days in hospital, with pegylated G-CSF having slightly but not significantly better scores in all three endpoints. Regarding pegylated G-CSF, the best timing is predicted to be any day between days 4 and 7. With respect to unpegylated G-CSF, the starting day is less important, but it should be continued until the end of each cycle.The three G-CSF-schedules are interchangeable in (R)-CHOP-14 for elderly patients with aggressive B-cell lymphoma. Our model correctly predicts time courses of leukocytes. Further model predictions are presented, which can be tested in subsequent clinical trials.

Randomized comparison of pegfilgrastim day 4 versus day 2 for the prevention of chemotherapy-induced leukocytopenia.

BACKGROUND: To study the effects of deferring pegfilgrastim until day 4 on the reduction of chemotherapy-induced leukocytopenia. PATIENTS AND METHODS: Patients of age 61-80 years with aggressive lymphoma were randomly assigned to receive 6 mg pegfilgrastim on day 2 or 4 of a 2-week chemotherapy regimen (R-CHOP-14). RESULTS: Two hundred and ninety-two and 313 chemotherapy cycles were evaluable in 103 patients. Post-nadir pegfilgrastim serum levels were higher after day 4 than after day 2 application. This was associated with an attenuated leukocyte nadir after day 4 pegfilgrastim and there were fewer days with leukocytes <2 × 10(3)/mm(3) compared with day 2 pegfilgrastim. Grade 3 and 4 leukocytopenias (70% versus 43.3%; P < 0.001) and grade 4-only leukocytopenias (47% versus 20.5%; P < 0.001) were more frequent after day 2 pegfilgrastim. There were more chemotherapy cycles with grade 3 and 4 infections after day 2 than day 4 pegfilgrastim (9.4% versus 6.0%; P = 0.118). Interventional antibiotics were given more often after day 2 than after day 4 pegfilgrastim (30.7% versus 21.9% of cycles; P = 0.008). There were five deaths during leukocytopenia after day 2 and none after day 4 pegfilgrastim (P = 0.027). CONCLUSIONS: Administration of pegfilgrastim on day 4 was more effective in reducing severe leukocytopenias and resulted in fewer deaths during leukocytopenia. Pegfilgrastim should be given on day 4 to better exploit its myeloprotective potential.

[Treatment of diffuse large B-cell lymphoma]. / Behandlung diffus-grosszelliger B-Zell-Lymphome.

Diffuse large B-cell lymphoma represent 40% of all lymphoma. The development of dose-dense chemotherapeutic regimens and the application of the monoclonal CD20 antibody rituximab improve the prognosis significantly. Evaluation of clinical risk factors (age, stage, LDH, ECOG performance status, number of extranodal involvement) at initial diagnosis are the most important approaches for risk stratification that allows risk adapted modifications of the standard R-CHOP regimen.

Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: I. A randomized dose escalation and feasibility study with bi- and tri-weekly regimens.

BACKGROUND: To determine the maximum tolerated dose of a bi- and tri-weekly combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone plus etoposide (CHOEP) regimen without stem-cell support. PATIENTS AND METHODS: Randomized phase I/II multicenter four-level (cyclophosphamide: 1000-1200-1400-1600 mg/m2; doxorubicin: 55-60-65-70 mg/m2; etoposide: 375-450-525-600 mg/m2) dose escalation study with CHOEP-14 and CHOEP-21 in young patients (18-60 years) with newly diagnosed aggressive non-Hodgkin's lymphoma. Dose-limiting toxicity was defined as thrombocytopenia <80,000/mm3 and leukocytopenia <2500/mm3 on days 16 (CHOEP-14) and 23 (CHOEP-21) or prolonged (>4 days) leukocytopenia (<1000/mm3) or thrombocytopenia (<20,000/mm3). RESULTS: One hundred and thirty-nine patients (high-CHOEP-14: 47, high-CHOEP-21: 92) were randomly allocated to the study. Maximal tolerated dose was level 2 for CHOEP-14 and level 4 for CHOEP-21. With a less favorable profile of patients in CHOEP-14, 4-year event-free survival was 47.9% after high-CHOEP-14 and 66.2% after high-CHOEP-21, 4-year overall survival 62.1% after high-CHOEP-14 and 73.4% after high-CHOEP-21, respectively. CONCLUSION: Significant dose escalations of CHOEP are possible with granulocyte colony-stimulating factor support, with different chemotherapy models favoring the maximally escalated bi- or tri-weekly regimen, respectively. Because a higher total dose can be achieved with six cycles of the tri-weekly compared with the biweekly regimen, CHOEP-21 at dose escalation level 3 was chosen for a nationwide randomized comparison with baseline CHOEP-21 in a subsequent phase III trial.

Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: II. Results of the randomized high-CHOEP trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL).

BACKGROUND: The addition of etoposide to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone [etoposide to combination chemotherapy with cyclophosphamide, vincristine and prednisone (CHOEP)] improved outcome of young patients with good-prognosis aggressive lymphoma. To improve results further, the maximal dose-escalated version of CHOEP-21 tolerable without stem-cell support (high CHOEP: cyclophosphamide 1400 mg/m2, doxorubicin 65 mg/m2, vincristine 2 mg, etoposide 175 mg/m2 x3, prednisone 100 mg x5) was compared with CHOEP-21. PATIENTS AND METHODS: Intention-to-treat analysis of 389 young (18-60 years) patients with good-prognosis (age-adjusted International Prognostic Index = 0, 1) aggressive lymphoma randomized to CHOEP-21 (n = 194) or high CHOEP (n = 195). RESULTS: There was no difference in 3-year event-free (64% versus 67%; P = 0.734) or overall survival (83% versus 87%; P = 0.849). Neither low-risk nor low-intermediate risk patients benefited from high CHOEP. High CHOEP was more toxic than CHOEP-21 (grades 3 and 4 leukocytopenia 100% versus 87.2%, P < 0.001; thrombocytopenia 80.8% versus 9.6%, P < 0.001; infections 35% versus 11%, P < 0.001; therapy-associated deaths 3.1% versus 0%, P = 0.03). CONCLUSION: Dose-escalated CHOEP-21 does not provide clinical benefit for young patients with good-prognosis aggressive lymphomas. Since differences between chemotherapy regimens are compressed by the addition of rituximab, the results of this trial have bearing on strategies aiming to improve outcome of good-prognosis aggressive lymphomas in the rituximab era.

[Treatment of aggressive lymphomas]. / Therapie grosszelliger Lymphome.

The age-adjusted International Prognostic Index (IPI) allows the definition of clinically relevant subgroups in younger patients (< or = 60 years) with aggressive lymphomas. Six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone-21 (CHOP-21) with rituximab (R-CHOP-21) achieved an event free survival after 3 years of > 90% in patients with a very good prognosis (IPI 0, without bulk). In contrast, in patients from the less favourable groups (all IPI 1, IPI 0 with bulk only), the same therapy resulted in an event-free survival at 3 years of less than 80%. This requires improvement. Young patients with a worse risk profile have a survival probability of 60% after 5 years. Dose dense therapeutic regimens and autologous stem cell transplantation are being applied to this patient group in clinical trials. For patients > 60 years, the advantage of combined immunochemotherapy has been clearly documented. For patients > 60 years from all IPI groups, the best results have so far been achieved with six courses of R-CHOP-14 followed by two additional applications of rituximab.

[Soft-tissue coverage of the hand using the posterior interosseous artery flap]. / Defektdeckung an der Hand mit der A. interossea posterior-Lappenplastik.

UNLABELLED: Significant trauma, severe bacterial infections and tumour resections of the hand are often complicated by primary or secondary soft-tissue defects. The Posterior Interosseous Artery Flap (PIA), described by Zancolli and Angrigiani in 1985 offers one possibility for soft-tissue coverage. In this abstract, we present the results of 35 patients who were treated with distally based PIA flap reconstructions during the years 1998 to 2003. 24 patients were available for one-year follow-up and beyond. RESULTS: Long-term follow-up demonstrates excellent colour and texture match with reliable soft-tissue coverage. Two of the 33 flaps were lost because of ischemic necrosis. The incidence of distal local ischemia was predictable when the flaps were extended to the level of the PIP joint or beyond. CONCLUSION: The PIA flap affords a very durable and aesthetic option for soft-tissue coverage of the dorsum of the hand. The flap donor site can usually be closed primarily with little to no morbidity. In comparison to other local and distally based flaps such as the radial forearm flap, major blood vessels are spared. In summary, the PIA flap should be considered as a reliable and judicious alternative to free microvascular transfer procedures for soft-tissue defects of the hand proximal to the level of the PIP joint.

Expression of cancer testis genes in human brain tumors.

Cancer-testis (CT) genes are expressed in a variety of human cancers but not in normal tissues, except for testis tissue, and represent promising targets for immunotherapeutic and gene therapeutic approaches. Because little is known about their composite expression in human brain tumors, we investigated the expression of seven CT genes (MAGE-3, NY-ESO-1, HOM-MEL-40/SSX-2, SSX-1, SSX-4,HOM-TES-14/SCP-1, and HOM-TES-85) in 88 human brain tumor specimens. Meningiomas expressed only HOM-TES-14/SCP-1 (18% of meningiomas were HOM-TES-14/SCP-1 positive) and did not express any other CT genes. One ependymoma was negative for all CT genes tested. SSX-4 was the only CT gene expressed in oligodendrogliomas (2 of 5 cases), and it was also expressed in oligoastrocytomas (3 of 4 cases) and astrocytomas (10 of 37 cases). Astrocytomas were most frequently positive for HOM-TES-14/SCP-1 (40%) and SSX-4 (27%), followed by HOM-TES-85 (13%), SSX-2 (11%), and MAGE-3 (7%). Whereas MAGE-3 was detected only in grade IV astrocytomas, the expression of the other CT genes showed no clear correlation with histological grade. Of 39 astrocytomas, 60% expressed at least one CT gene, 21% expressed two CT genes, and 8% coexpressed three CT genes of the seven CT genes investigated. We conclude that a majority of oligoastrocytomas and astrocytomas might be amenable to specific immunotherapeutic interventions. However, the identification of additional tu-mor-specific antigens with a frequent expression in gliomas is warranted to allow for the development of widely applicable polyvalent glioma vaccines.

Exploitation of the antibody repertoire of cancer patients for the identification of human tumor antigens.

The screening of tumor-derived expression libraries for antigens which are recognized by high titered IgG antibodies present in autologous sera of the cancer patients by SEREX (serological identification of antigens by recombinant expression cloning) allows for the systematic identification of antigens in human cancers. SEREX has led to the definition of a plentitude of new tumor antigens in many different tumor entities. The majority of the antigens are encoded by hitherto unknown genes and can be grouped into different classes of antigens. The abundance of serologically defined human tumor antigens is not only of relevance for tumor biology and serodiagnosis of cancer, but also facilitates the identification of proteins recognized by tumor specific T lymphocytes, thus providing a molecular basis for polyvalent peptide-based and gene-therapeutic vaccine strategies in a wide variety of human neoplasms.

Identification of a meiosis-specific protein as a member of the class of cancer/testis antigens.

Little is known about the function of human cancer/testis antigens (CTAs), such as MAGE, BAGE, GAGE, HOM-MEL-40, and NY-ESO-1, the expression of which is restricted to human malignancies and testis. When screening a cDNA expression library enriched for testis-specific representative long transcripts for reactivity with high-titered IgG antibodies from the serum of a patient with renal cell carcinoma, one repeatedly detected antigen, designated HOM-TES-14, turned out to be encoded by the synaptonemal complex protein 1 (SCP-1) gene. SCP-1 is known to be selectively expressed during the meiotic prophase of spermatocytes and is involved in the pairing of homologous chromosomes, an essential step for the generation of haploid cells in meiosis I. Investigation of a broad spectrum of normal and malignant tissues revealed expression of SCP-1 transcripts and antigen selectively in a variety of neoplastic tissues and tumor cell lines. Immunofluorescence microscopy analysis with specific antiserum showed a cell cycle phase-independent nuclear expression of SCP-1 protein in cancer cells. SCP-1 differs from other members of the class of CTA by its localization on chromosome 1 and its frequent expression in malignant gliomas, breast, renal cell, and ovarian cancer. The aberrant expression of SCP-1 in tumors might contribute to their genomic instability and suggests that the functional role of other CTA might also relate to meiosis.

Expression of SSX genes in human tumors.

The HOM-MEL-40 antigen which is encoded by the SSX-2 gene was originally detected as a tumor antigen recognized by autologous IgG antibodies in a melanoma patient. Expression analysis demonstrated that SSX-2 is a member of the recently described cancer/testis antigen (CTA) class as it is expressed in a variety of different human neoplasms, but not in normal tissues with the exception of testis and a weak expression in the thyroid. Further studies demonstrated that SSX-2 belongs to a gene family consisting of at least 5 homologous genes. We now report the analysis of the expression of all 5 SSX genes in 325 specimens of human neoplasms from various histological origins, using reverse transcription polymerase chain reaction (RT-PCR). SSX-1, -2, and -4 were found to be expressed in 8%, 15% and 15%, of the tumors, respectively, while the expression of the SSX-5 gene was rare (7/325), and SSX-3 expression was not detected. For defined tumor types, expression of at least one of the SSX family members was most frequently observed in head and neck cancer (75%), followed by ovarian cancer (50%), malignant melanoma (43%), lymphoma (36%), colorectal cancer (27%) and breast cancer (23%), while leukemias and the few cases of leiomyosarcomas, seminomas and thyroid cancers were found not to express any SSX gene.

Relationship between supranormal circulatory values, time delays, and outcome in severely traumatized patients.

OBJECTIVE: To describe the temporal patterns of hemodynamics and oxygen transport in survivors and nonsurvivors of severe trauma in relation to time delays, mortality, and morbidity. DESIGN: Prospective, empiric analysis. SETTING: University-run, inner city county hospital with a Level I trauma center. PATIENTS: A series of 90 consecutively monitored, severely ill trauma patients. METHODS: We followed 90 patients from admission through their hospital course, and divided the study group into patients with estimated blood loss of < or = 3000 mL and those patients with an estimated blood loss of < 3000 mL. For each patient, vital signs were recorded in the Emergency Department, operating room, recovery room, and surgical ICU. Hemodynamic and oxygen transport variables were measured at least every 12 hrs for 96 hrs postadmission. Final outcome and complications were recorded. RESULTS: In the first 24 hrs, the values of 60 survivors were significantly higher than the values of 30 nonsurvivors for mean cardiac index (4.52 +/- 1.45 vs. 3.80 +/- 1.20 L/min/m2; p < .05), oxygen delivery (670 +/- 230 vs. 540 +/- 200 mL/min/m2; p < .01), and oxygen consumption (166 +/- 48 vs. 134 +/- 47 mL/min/m2; p < .01). Thirteen (50%) of 26 patients who never attained mean survivors' values (defined as the mean survivors' values listed above) died. Also, 12 (57%) of 21 patients who took > 24 hrs to attain these values died. In contrast, only five (12%) of 43 patients who reached mean survivors' values in < or = 24 hrs died. Thirty-five of 90 patients lost < 3000 mL of blood; 17 of these 35 patients failed to reach survivors' values within 24 hrs, and 12 (71%) patients died. However, of 18 patients with an estimated blood loss of > 3000 mL, who reached survivors' values in < or = 24 hrs, only two (12%) died. The patients reaching survivors' values in < or = 24 hrs, > 24 hrs, or not at all had similar Injury Severity Scores (28 +/- 13, 26 +/- 13, and 26 +/- 12, respectively) and Trauma Scores (12 +/- 3, 13 +/- 3, and 12 +/- 3, respectively). Only six (12%) of 43 patients reaching survivors' values in < or = 24 hrs developed adult respiratory distress syndrome (ARDS), while 27 (57%) of 47 patients showed these values in > 24 hrs or never developed ARDS. CONCLUSIONS: Reaching supranormal circulatory values, especially within 24 hrs of injury, may improve survival and reduce the frequency of shock-related organ failure in severely traumatized patients.