Sequential therapy combining clofarabine and T-cell-replete HLA-haploidentical haematopoietic SCT is feasible and shows efficacy in the treatment of refractory or relapsed aggressive lymphoma.

Prognosis is poor for patients with biologically aggressive Non-Hodgkin lymphoma (NHL), refractory to chemotherapy or relapsed after autologous transplantation, especially when no disease control before allogeneic transplantation is achieved. In 16 patients (median age 53, median prior regimes 5) with relapsed or refractory non-remission NHL, we analysed retrospectively the efficacy of a sequential therapy comprising clofarabine re-induction followed by a reduced-intensity conditioning with fludarabine, CY and melphalan, and T-cell-replete HLA-haploidentical transplantation. High-dose CY was utilized post-transplantation. All patients engrafted. Early response (day +30) was achieved in 94%. Treatment-related grade III-IV toxicity occurred in 56%, most commonly transient elevation of transaminases (36%), while there was a low incidence of infections (19% CMV reactivation, 19% invasive fungal infection) and GVHD (GVHD: acute III-IV: 6%; mild chronic: 25%). One-year non-relapse mortality was 19%. After a median follow-up of 21 months, estimated 1- and 2-year PFS was 56 and 50%, respectively, with 11 patients (69%) still alive after 2 years. In summary, sequential therapy is feasible and effective and provides an acceptable toxicity profile in high-risk non-remission NHL. Presumably, cytotoxic reinduction with clofarabine provides enough remission time for the graft-versus lymphoma effect of HLA-haploidentical transplantation to kick in, even in lymphomas that are otherwise chemo-refractory.

Surgical management of recurrent sinonasal mucosal melanoma: endoscopic or transfacial resection.

Sinonasal mucosal melanoma (SNMM) is associated with poor prognosis. Local recurrence is common and represents a major problem in the therapy. Wide resection surgery is usually applied. However, given the almost futile prognosis, optimal symptom control may be preferable to wide resection at all costs. The aim of our study was to analyze the outcome in patients with recurrent SNMM treated by transfacial radical surgery or by a less invasive endoscopically controlled approach. Patients with recurrent grade III or IV staged SNMM who presented to our ENT department between 2000 and 2010 were either treated by transfacial (n = 10) or endoscopically controlled surgery (n = 12). The patients' charts were reviewed for clinical symptoms, relapse-free time and survival time. Clinical symptoms improved after surgery. The morbidity after endoscopic surgery was significantly lower than after transfacial surgery. The chosen surgical technique did neither affect relapse-free nor survival time. When treating recurrent SNMM, the comparatively gentle and less mutilating endoscopic approach proved to be a sufficient surgical procedure, being not inferior to aggressive surgery with respect to recurrence and survival rate.

Mental distress and effort to engage an image-guided navigation system in the surgical training of endoscopic sinus surgery: a prospective, randomised clinical trial.

The use of image-guided navigation systems in the training of FESS is discussed controversy. Many experienced sinus surgeons report a better spatial orientation and an improved situational awareness intraoperatively. But many fear that the navigation system could be a disadvantage in the surgical training because of a higher mental demand and a possible loss of surgical skills. This clinical field study investigates mental and physical demands during transnasal surgery with and without the aid of a navigation system at an early stage in FESS training. Thirty-two endonasal sinus surgeries done by eight different trainee surgeons were included. After randomization, one side of each patient was operated by use of a navigation system, the other side without. During the whole surgery, the surgeons were connected to a biofeedback device measuring the heart rate, the heart rate variability, the respiratory frequency and the masticator EMG. Stress situations could be identified by an increase of the heart rate frequency and a decrease of the heart rate variability. The mental workload during a FESS procedure is high compared to the baseline before and after surgery. The mental workload level when using the navigation did not significantly differ from the side without using the navigation. Residents with more than 30 FESS procedures already done, showed a slightly decreased mental workload when using the navigation. An additional workload shift toward the navigation system could not be observed in any surgeon. Remarkable other stressors could be identified during this study: the behavior of the supervisor or the use of the 45° endoscope, other colleagues or students entering the theatre, poor vision due to bleeding and the preoperative waiting when measuring the baseline. The mental load of young surgeons in FESS surgery is tremendous. The application of a navigation system did not cause a higher mental workload or distress. The device showed a positive effort to engage for the trainees with more than 30 FESS procedures done. In this subgroup it even leads to decreased mental workload.

Specific stressors in endonasal skull base surgery with and without navigation.

The goal of modern organizational psychology is to recognize, anticipate and finally avoid stress situations. The aim of this study was to measure objectively the mental and physical demands during transnasal surgery with and without the aid of a navigation system. Forty endonasal surgeries (20 with and 20 without navigation, not blinded and not randomized) done by four different experienced rhinosurgeons (>250 FESS procedures done) were included. The heart rate, the heart rate variability, the respiratory frequency and the masseter tone were monitored as biometrical parameters by the surgeons during the whole surgery for the quantification of mental demand. Stress situations could be identified during the procedures by an increase in the heart rate and a decrease in the heart rate variability. Stress level in procedures with navigation did not significantly differ from procedures without navigation. Interestingly, in 10 % of the cases a navigation system would have been helpful, although the surgeon stated before the procedure that such a system would not be necessary. Other stressors could be identified like time pressure, students or colleagues speaking with the surgeon or chatting in the OR and system failure of medical devices, i.e. navigation, sinus drill, electrocautery or shaver. Surgical stressors blurred vision due to diffuse bleeding and drill out procedures in the sphenoid sinus. Calming situations were a quiet atmosphere in the OR (i.e. closed doors) and the participation of another experienced colleague, especially a neurosurgeon. Stress situations occur when complex medical devices like the navigation do not work. For their proper function it is important that the whole OR-team is trained with it. Unqualified or unmotivated OR personnel create stress for the surgeon and disharmony in the team, which then ends in inadequate behaviour.

Second haematopoietic SCT using HLA-haploidentical donors in patients with relapse of acute leukaemia after a first allogeneic transplantation.

Haploidentical haematopoietic SCT (HSCT) using T-cell-replete grafts and post-transplant high-dose CY has found increasing acceptance. Our purpose was to evaluate the feasibility and outcome of this strategy as second HSCT incorporating donor change for acute leukaemia relapse after a first allogeneic transplantation. The courses of 20 consecutive adults (median age 37 years, 12 male) with AML (n=14), ALL (n=5) and acute bi-phenotypic leukaemia (n=1) were analysed retrospectively. Conditioning consisted of fludarabine, CY and either melphalan or TBI or tresosulfan+/-etoposide. Engraftment was achieved in 17 (85%), and a second remission was induced in 15 patients (75%) on day +30. The rate of grade II-IV acute GvHD was 35%, while chronic GvHD occurred in five patients. Most commonly observed grade III-IV toxicities were mucositis (30%), hyperbilirubinemia (20%), elevation of transaminases (20%) and creatinine (20%), while invasive fungal infection affected 30%. One-year non-relapse mortality (NRM) was 36%. At a median follow-up of 17 months, estimated 1-year OS was 45%, and 1-year relapse-free survival was 33%. This strategy was feasible and allowed for successful engraftment with a moderate rate of toxicity. Early outcome and NRM are at least comparable with results after a second HSCT from HLA-matched donors without donor change at HSCT2.

Endoscopic sinus surgery training courses: benefit and problems - a multicentre evaluation to systematically improve surgical training.

BACKGROUND: The aim of this multicentre study was to systematically analyse the strengths and weaknesses in the surgical training for endoscopic sinus surgery (ESS) and identify measures that may improve training. METHODOLOGY: Using a structured questionnaire, 133 participants of ESS courses in seven centres in Germany, Switzerland and Australia were asked about their experiences during their dissection courses and how they perceived their course could be improved. RESULTS: Gaining confidence in handling of instruments and endoscopes was only a problem for participants with little experience in ESS. The majority of the participants, independent from their level of training, considered infundibulotomy and anterior ethmoidectomy as the easiest dissection steps, whilst surgery of the frontal sinus posed a considerable challenge for many surgeons even those with a higher level of training. Participants with and without ESS experience thought that emphasis on anatomy was the most important improvement that could be made during their surgical training. Virtually all participants stated that the course improved their anatomical knowledge, their surgical skills and their confidence when performing ESS. CONCLUSIONS: ESS dissection courses are considered beneficial by surgical trainees. Participants felt that more emphasis on sinus anatomy in conjunction with private study is essential to maximize their skills in surgical dissection. For beginners with ESS, an infundibulotomy and anterior ethmoidectomy were thought to be the best initial procedures to help develop endoscopic surgical skills.

Evaluation of an image-guided navigation system in the training of functional endoscopic sinus surgeons. A prospective, randomised clinical study.

INTRODUCTION: Many sinus surgeons report improved spatial orientation after using a navigation system. This study investigates the surgical, ergonomic and economic aspects of using a navigation system in training and teaching. MATERIALS AND METHODS: Eight rhino-surgeons in training and 32 patients with bilateral diseases of the paranasal sinus system were included. After randomisation, one patient`s side was operated on with a navigation system while the other side was operated on without navigation. It was monitored how often the surgeon used the navigation pointer and then changed the procedures. A standardised and validated interview recorded the cognitive load when using the navigation system and the application efficiency. RESULTS: The operations lasted on average 16 minutes longer with the navigation. Five paranasal sinuses could not be found in the control group without navigation. In only 10-13% of cases did the surgical procedure change after the use of the pointer. Most of the surgeons admitted that particular steps of the operation were more reliable and safer to carry out with the navigation system. The general trust in the system rose in proportion to intraoperative accuracy and repeated use. CONCLUSION: Overall, there was an overwhelming level of trust in the navigation system. Trainee sinus surgeons seeing their more experienced colleagues using a navigation device tend to overestimate the possibilities of the system and to underestimate the risks. The assistance system was used particularly effectively in the group of slightly more experienced surgeons. In this group, the additional expenditure of time was less and the navigation substantially contributed to reinforcing the anatomical sense of direction.

High antileukemic efficacy of an intermediate intensity conditioning regimen for allogeneic stem cell transplantation in patients with high-risk acute myeloid leukemia in first complete remission.

The goal of this analysis was to define the role of the moderate-intensity fludarabin Ara-C amsacrin (FLAMSA)-reduced intensity conditioning (RIC) regimen for patients with high-risk AML undergoing allogeneic SCT (alloSCT) in first CR1. High-risk was defined by (1) AML secondary to MDS or radio/chemotherapy, (2) unfavorable cytogenetics or (3) delayed response to induction chemotherapy. A total of 23 of 44 AML patients referred to the University of Munich for alloSCT in CR1 between 1999 and 2006 fulfilled these criteria and received FLAMSA chemotherapy, followed by RIC (4 Gy TBI/cyclophosphamide/ATG) for alloSCT. Twenty-two patients engrafted, one died in aplasia. Two-year cumulative incidences for relapse and nonrelapse mortality (NRM) were 4.6 and 22.5%, respectively. Four-year overall and leukemia-free survival was 72.7% (median follow-up among survivors: 35 months). The results of this high-risk cohort were compared to the outcome of 21 consecutive standard-risk patients <55 years, who had received standard, myeloablative sibling SCT in CR1 AML within the same center and time period. Survival and cumulative incidences of relapse and NRM were identical in both groups. In conclusion, the FLAMSA-RIC regimen produces long-term remission in a high proportion of patients with high-risk AML transplanted in CR1. In this cohort, FLAMSA-RIC showed equivalent antileukemic activity as compared to the standard protocols.

Combined treatment of metastatic breast cancer (MBC) by high-dose chemotherapy (HDCT) and bispecific antibodies: a pilot study.

UNLABELLED: This pilot study analyzed the efficacy and toxicity of high-dose chemotherapy (HDCT), autologous stem-cell transplantation (ASCT) and subsequent immunotherapy with T-cell reinfusion and trifunctional antibodies (trAbs) in chemotherapy-sensitive patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: After leukapheresis and cryopreservation of T-cells, patients received 2 cycles of induction chemotherapy ET (epirubicin/paclitaxel) and 1 cycle of El (epirubicin/ifosfamide), followed by G-CSF and stem-cell harvest. After a final cycle of ET, responders (CR/PR) underwent HDCT (thiotepa 600 mg/m2/melphalan 140-180 mg/m2) and ASCT. Once reconstitution was achieved, T-cells were reinfused, followed by application of trifunctional antibodies with specificities anti-EpCAM X anti-CD3 and anti-Her2/neu X anti-CD3. RESULTS: Thirty-three patients were recruited into the study and 19, who had responded to initial chemotherapy, underwent HDCT and ASCT (4 CR, 15 PR, OR = 57.6%; 95% CI: 40-75%). Two early deaths were observed (1 toxic, 1 early progression). T-cell reinfusion and trAbs were given to 17 patients. TrAbs treatment resulted in intermittent fever, chills and elevated liver enzymes, which were seen in all patients. The median overall survival was 27.7 months (range: 5.9-82.6+). Patients who received 3 trAbs doses showed a trend towards an improved overall survival (47.2 vs. 22.4 months, p = 0.08 log rank). CONCLUSION: This pilot study has shown the feasibility of combining HDCT with immunotherapy in MBC. Further investigation of this approach is indicated.

Reduced-intensity conditioning using TBI (8 Gy), fludarabine, cyclophosphamide and ATG in elderly CML patients provides excellent results especially when performed in the early course of the disease.

Allogeneic bone marrow or stem cell transplantation is a curative therapeutic option for chronic myelogenous leukemia. In order to decrease the toxicity of the procedure, the dosage of total body irradiation was reduced from 12 to 8 Gy and subsequently the dose of cyclophosphamide from 120 to 80 mg/kg. The purine analogue fludarabine, ATG, cyclosporine A and a short course of methotrexate were given for immune suppression. So far, 35 elderly CML patients with sibling and unrelated donors have been transplanted. Transplant-related mortality at day + 100 was 11%. After engraftment, all patients achieved a complete cytogenetic remission. Relapse occurred in 14% of the patients. The risk of relapse was significantly higher in those patients transplanted in second chronic or accelerated phase (P = 0.048). After a median follow-up of 30 months (range 12-62), 63% of the patients are alive. Those patients transplanted within the first year from diagnosis had an overall survival of 79% (P = 0.049), emphasizing the benefit of early transplantation. Stepwise reduction of conditioning intensity resulted in stable engraftment, low relapse rates and encouraging overall survival in this high-risk patient group.

Dose-dependent effects of in vivo antithymocyte globulin during conditioning for allogeneic bone marrow transplantation from unrelated donors in patients with chronic phase CML.

We conducted a dose-escalation study with antithymocyte globulin (ATG) in patients undergoing unrelated donor bone marrow transplantation (URD-BMT). This study analyzes the results for 97 patients with chronic myelogenous leukemia (CML) in first chronic phase. Median age was 36 years (16-51). In all, 40 patients were transplanted within 2 years after diagnosis and 57 later during disease. ATG-S (Fresenius) 20-120 mg/kg body weight (b.w.) was given prior to transplantation. A total of 31 patients received less than 60 mg/kg b.w. and 66 patients received 60 mg/kg b.w. or more. All patients except one were grafted with bone marrow, and graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A and methotrexate. Graft failure did occur in one patient. Grade II-IV acute GVHD developed in 56.7% and extensive chronic GVHD in 11.3% of the patients. The relapse rate was 13.4%. With a median follow-up of 5.8 years (1.5-12.1), 5-year disease-free and overall survival for all patients were 56 and 66%, and for patients transplanted within 2 years of diagnosis it was 72 and 82%. A lower dose of ATG was a significant risk factor for poor outcome. In summary, URD-BMT remains an excellent treatment option for patients with early phase CML, if a sufficient amount of ATG is included in the preparative regimen.

Prospective evaluation of neurological complications after allogeneic bone marrow transplantation.

OBJECTIVE: To determine the spectrum and frequency of neurologic sequelae after allogeneic bone marrow transplantation (BMT) and to define a risk profile of the patients. METHODS: A prospective follow-up of 71 allogeneic bone marrow recipients 14 +/- 3 months after transplantation. Patients underwent a neurologic examination, a neuropsychological test battery, and cranial MRI before and after BMT. RESULTS: A large proportion of patients (65%) developed sequelae after BMT. Acute complications of defined etiology occurred in 18% of the patients and led to death in 9% of the study population. A total of 47% of the patients developed new neurologic abnormalities of undefined origin that were mild and subacute and predominantly affected the peripheral nervous system. The cognitive and neuroradiologic outcome was favorable in a majority of these patients, but a small subgroup exhibited cognitive deterioration and white matter lesions. Risk factor analysis identified acute graft-versus-host disease (GvHD) and other variables partly related to GvHD such as long-lasting immunosuppression as the main predictors of sequelae after allogeneic BMT. The authors have established an association with various factors but, owing to the observational character of this study, conclusions about the etiology of the findings are unclear. CONCLUSION: Neurologic complications significantly contribute to the morbidity and mortality of patients receiving allogeneic BMT. Subclinical abnormalities, cognitive deficits, and white matter lesions detected 1 year after BMT in a subgroup of patients may be related to more extensive CNS changes observed after transplantation in an earlier retrospective study and may be associated with the risk factor chronic GvHD/immunosuppression.

[Dose-reduced conditioning before allogeneic stem cell transplantation: principles, clinical protocols and preliminary results]. / Dosisreduzierte Konditionierung vor allogener Stammzelltransplantation - Grundprinzipien, klinische Protokolle und erste Ergebnisse

BACKGROUND AND OBJECTIVE: In the treatment of leukemia by stem cell transplantation, the immunological effects of allogeneic T-lymphocytes presumably play a greater part than high-dosage total-body irradiation (TBI) and chemotherapy. Using this immunological effect, attempts are currently being made to reduce the dosage of pre-treatment that is toxic to stem cell, such as TBI, thereby making transplantation available for a larger group of patients at high risk for transplantation. This study presents preliminary results of three current studies of this approach. PATIENTS AND METHODS: Elderly patients with chronic myeloid leukemia (CML) have an increased transplantation risk. They were conditioned with TBI that was reduced stepwise (n = 27). Patients with advanced and refractory myeloid leukemia were treated with chemotherapy and dose-reduced TBI (FLAMSA protocol; n = 54). In patients with multiple myeloma, autologous transplantation with high-dose chemotherapy preceded allogeneic transplantation possible after dose-reduced conditioning (Tandem protocol; n = 6). RESULTS: All three protocols of TBI gave results that were not worse than those of previous studies. Relapse ocurred not more frequently in patients with CML. In patients with high-risk AML the FLAMSA protocol gave better results. Autologous-allogeneic tandem transplantation was well tolerated and led to a good response in all patients. CONCLUSION: Allogeneic transplantation after dose-reduced conditioning opens up new possibilities with respect to widening indications for transplantation and improving results in hematological diseases with previously unsatisfactory treatment.

[Allogeneic transplantation in malignant lymphoma]. / Allogene Transplantation maligner Lymphome.

INTRODUCTION: Allogeneic transplantation of bone marrow and peripheral blood stem cells is a frequently discussed therapeutic option in the treatment of malignant lymphoma. By analysing the results of our own transplant program in patients with advanced lymphoma we tried to evaluate indications for allogeneic transplantations. METHODS: Data from lymphoma patients treated at the Klinikum Grosshadern between 1985 and 2001 were analysed retrospectively. RESULTS: 56 patients were included. 24 patients had low grade Non-Hogdkin's lymphoma (NHL) (follicular lymphoma: n = 8, mantle cell lymphoma: n = 6) or chronic lymphocytic leukemia (CLL: n = 10), 16 patients had high grade NHL (immunoblastic/lymphoblastic: n = 5; large cell/diffuse: n = 5) and 8 patients suffered from Hodgkins's disease. Median age was 41 years, 34 patients were transplanted from an HLA-identical sibling, 19 from an HLA-id. unrelated donor and three from an HLA-mismatched related donor. 30 patients received bone marrow and 26 peripheral blood stem cells. 22 pat. were treated with an intensive 12 Gy TBI containing conditioning regimen, whereas 34 patients were treated with a dose-intensity reduced conditioning procedere. 25 patients are alive between 2 month and 15 years after transplantation. Overall survival after 2 years is 48 % for patients with low grade NHL (incl. CLL), 9.3 % for patients with high grade lymphoma and 25 % for patients with Hodgkin's disease. 1-year-transplant-related mortality (TRM) was 33.9 % in all patients. Dose-intensity-reduced conditioning was not able to reduce TRM. CONCLUSIONS: Allogeneic bone marrow or stem cell transplantation is able to induce long lasting complete remissions in patients with heavily pretreated malignant lymphoma. Results of allogeneic transplantation are encouraging in patients with follicular and other low grade lymphoma. However transplant-related toxicity is high. At present the impact of reducing the intensity of conditioning is not yet clear.