Early autologous and allogeneic peripheral blood stem cell transplantation for adult patients with acute B and T cell precursor neoplasms: a 12-year single center experience.

Adult acute lymphoblastic leukemia/lymphoma (ALL/LBL) is a rare and heterogeneous malignancy characterized by uncontrolled proliferation of B or T cell precursor cells. Here, we retrospectively analyzed the outcome of early autologous stem cell transplantation in standard-risk patients in first complete remission (n=24) and of allogeneic transplantation in high and highest risk, and relapsed/refractory patients (n=35). The 10-year overall survival after autologous transplantation was 45%. The 10-year overall survival after allogeneic transplantation was 58%. The cumulative incidence of relapse was 29% after allogeneic and 67% after autologous transplantation. The cumulative incidence of non-relapse mortality was 0% after autologous and 12% after allogeneic transplantation. This retrospective single center analysis in a limited number of standard-risk patients clearly demonstrates that early autologous transplantation in first complete remission leads to an acceptable long-term outcome with a short overall treatment duration of less than 6 months compared with more than 2 years with conventional chemotherapy. More sensitive and standardized methods to detect minimal residual disease (MRD) will further help to identify those patients more accurately who are most likely to benefit from such a short and intensive treatment strategy (i.e., MRD negative standard-risk patients) or those who require early targeted therapy (e.g., blinatumomab) in case of MRD positivity. Early allogeneic transplantation results in long-term survival/cure in nearly two-thirds of all high and highest risk, and relapsed/refractory patients.

Effects of paclitaxel and docetaxel on EGFR-expressing human carcinoma cells under normoxic versus hypoxic conditions in vitro.

Human malignant tumors, such as non-small lung, breast, ovarian, head and neck, prostate, stomach and colorectal cancers express a number of growth factor receptors (e.g. EGFR or EGFR family members) that are regulated by tumor hypoxia and contribute to tumor growth and failure of cytotoxic therapy. Paclitaxel and docetaxel are indispensable substances in the treatment of these tumors. Despite the active clinical use of taxanes, little is known about their cytotoxic activity under hypoxia. The aim of the present work was to compare the cytotoxic effect of taxanes, paclitaxel and docetaxel on the EGFR-expressing carcinoma cell lines A431, MDA-MB-231 and NCI-H358 under normoxic and hypoxic conditions. The two taxanes caused different cell cycle distribution and varying aneuploid cell formation under hypoxia. EGFR-overexpressing carcinoma cells showed hypoxia to severely affect the cytotoxicity of paclitaxel, whereas docetaxel preserved its tumor cell-killing activity even at lowest concentrations (0.5 nM), as was observed for both taxanes under normoxia.

Conformal proton radiation treatment for retroperitoneal neuroblastoma: introduction of a novel technique.

BACKGROUND: Postoperative irradiation for locoregionally advanced neuroblastoma requires coverage of the paraspinal retroperitoneum. The proximity of both kidneys and the liver, and a more complex target configuration, can pose a dosimetric challenge for conventional X-ray treatment and intraoperative irradiation. We utilized proton radiation therapy (PRT) to reduce dose to uninvolved kidneys, liver, intestine, and spinal cord. PROCEDURE: A 4-year-old male underwent PRT for neuroblastoma of the right adrenal gland, following chemotherapy and delayed surgical resection. Clinical target volume (CTV), boost volume, and normal structures were outlined on the 3D treatment planning CT scan. The patient received 25.2 CGE (cobalt Gray equivalent) to the CTV and 34.2 CGE to the boost region, using 1.8 CGE per fraction, five treatments per week. Dose-volume histograms (DVHs) were obtained for target and nontarget structures. RESULTS: The 95% isodose volume enclosed CTV and boost volumes. The dose to 50% of the ipsilateral kidney, with tumor involvement of the medial renal surface, was < or = 16 CGE (47% of prescribed total dose). Doses to 50% and 20% of the contralateral kidney in close proximity to deep left-side, paraspinal soft tissue involvement were restricted to 1 CGE and 10 CGE, respectively. Eighty percent of the liver received 27 CGE (80% of prescribed dose). Using a patch technique, unique to charged particle therapy, the spinal cord was almost completely spared during boost volume irradiation. CONCLUSIONS: PRT can achieve excellent dose conformity for advanced retroperitoneal, paraspinal lesions, while respecting normal tissue tolerance levels.

A simple and non-invasive vacuum mouthpiece-based head fixation system for high precision radiotherapy.

PURPOSE: To demonstrate why conventional non-invasive mouthpiece-based fixation has not achieved the expected accuracy and to suggest a solution of the problem. PATIENTS AND METHODS: The Vogele Bale Hohner (VBH) head holder is a non-invasive vacuum mouthpiece-based head fixation system. Feasibility and repositioning accuracy were evaluated by portal image analysis in 12 patients with cranial tumors intended for stereotactic procedures, fixated with the newest version (VBH HeadFix-ARC). RESULTS: Portal image analysis (8 patients evaluated in 2-D, 4 patients in 3-D) showed that even in routine external beam radiation therapy, treatment can be applied to within a mean 2-D and 3-D accuracy of under 2 mm (SD 0.92 mm and 1.2 mm, respectively) with cost and repositioning time per patient and patient comfort comparable to that of common thermoplastic masks. CONCLUSION: These preliminary results show that high repositioning accuracy does not rule out simple and quick application and patient comfort. Paramount, however, is tensionless repositioning via the vacuum mouthpiece.

Comparison of standard and individually planned infradiaphragmatic fields in irradiation of retroperitoneal lymph nodes.

PURPOSE: In prophylactic irradiation of infradiaphragmatic lymphatic nodes (LN), the width of the paraaortic and pelvic field is given by a line joining the tips of the transverse processes of the 11th thoracic to the 4th lumbar vertebrae. Then the field boundary follows a straight line to the most lateral point of the acetabulum seen on the simulation film. Another method of setting the field border is to project the lateral contours of the large abdominal vessels from T(1)-weighted coronal MR images of the abdomen onto the simulator radiographs and add a 2-cm margin along the so delineated vessels. In our study, we compared both methods as to full enclosure of paraaortic and pelvic lymphatics or nodal miss. MATERIAL AND METHODS: Abdominal CT scans of 81 patients with involvement of paraaortic lymph node regions with LN sizes not exceeding 2.5 cm were examined. The distance from the center of the appropriate vertebra to the center of the most lateral lymph node was referred to the transverse process as well as to the outside contour of the aorta on the left and the vena cava on the right side. Respectively, the LN were measured referenced to the iliac vessels from the 5th lumbar through to the 2nd sacral vertebra. At the level of the hip joint the distance was measured from the midline as determined by a line through the center of the sacrum, perpendicular to a line connecting center of both femoral heads. RESULTS: Our measurements showed that lymph nodes do occur (1) lateral to the transverse processes of the thoracic and lumbar vertebrae as well as (2) outside the 2-cm safety margin from the lateral contour of the large abdominal vessels. CONCLUSION: These data clearly show that the traditional fields for radiation of infradiaphragmatic lymphatic nodes have not been large enough to enclose almost all retroperitoneal and pelvic lymph nodes with certainty. We recommend an expansion of the fields.

Proton radiation therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique.

PURPOSE: Following adequate therapy, excellent long-term survival rates can be achieved for patients with optic pathway gliomas. Therefore, avoidance of treatment-related functional long-term sequelae is of utmost importance. Optimized sparing of normal tissue is of primary concern in the development of new treatment modalities. The present study compares proton radiation therapy (PRT) with a three-dimensional (3D)-planned multiport photon and a lateral beam photon technique for localized and extensive optic pathway tumors. METHODS AND MATERIALS: Between February 1992 and November 1997, seven children with optic pathway gliomas underwent PRT. For this study, we computed proton, 3D photon, and lateral photon plans based on the same CT data sets, and using the same treatment planning software for all plans. Radiation exposure for normal tissue and discrete organs at risk was quantified based on dose-volume histograms. RESULTS: Gross tumor volume (GTV) ranged from 3.9 cm3 to 127.2 cm3. Conformity index (relation of encompassing isodose to GTV volume) was 2.3 for protons, 2.9 for 3D photons, and 7.3 for lateral photons. The relative increase of normal tissue (NT) encompassed at several isodose levels in relation to NT encompassed by the 95% proton isodose volume was computed. Relative NT volume of proton plan isodoses at the 95%, 90%, 80%, 50%, and 25% isodose level increased from 1 to 1.6, 2.8, 6.4, to a maximum of 13.3. Relative volumes for 3D photons were 1.6, 2.4, 3.8, 11.5, and 34.8. Lateral plan relative values were 6, 8.3, 11.5, 19.2, and 26.8. Analysis for small (<20 cm3) and larger (> 80 cm3) tumors showed that protons encompassed the smallest volumes of NT at all isodose levels. Comparable conformity and high-dose gradient were achieved for proton and 3D photon plans in small tumors. However, with increasing tumor volume and complexity, differences became larger. At the 50% isodose level, 3D photons were superior to lateral photons for small tumors; this advantage was equalized for larger tumors. At the lowest isodose level, 3D photons encompassed the highest amount of NT. Analysis of organs at risk showed that PRT reduced doses to the contralateral optic nerve by 47% and 77% compared to 3D photons and lateral photons, respectively. Reductions were also seen for the chiasm (11% and 16%) and pituitary gland (13% and 16%), with differences at clinically relevant tolerance levels. Furthermore, reduced dose exposure of both temporal lobes (sparing 39% and 54%) and frontal lobes was achieved with PRT. CONCLUSION: PRT offered a high degree of conformity to target volumes and steep dose gradients, thus leading to substantial normal tissue sparing in high- and low-dose areas. It is expected that this will result in decreased long-term toxicity in the maturing child. Advantages of proton versus 3D photon plans became increasingly apparent with increasing target size and tumor complexity. Even in small tumors, conformity of 3D photon irradiation came at the expense of a larger amount of NT receiving moderate to low radiation doses. Lateral photons resulted in inferior dose distribution with high radiation exposure of clinically relevant normal tissues.

[Standard versus individually planned irradiation field in radiotherapy of infradiaphragmatic lymph node sites]. / Standard- versus individuell geplantes Bestrahlungsfeld bei Radiotherapie infradiaphragmaler Lymphknotenstationen.

PURPOSE: In prophylactic irradiation of infradiaphragmatic lymphatic nodes, the width of the paraaortic and pelvic field is given by a line joining the tips of the transverse processes of the 11th thoracic to the 4th lumbar vertebra from where the field boundary follows a straight line to the most lateral point of the acetabulum as seen in simulation film. Another way to build the field border is to project the lateral contours of the large abdominal vessels from T1-weighted coronal MR images of the abdomen on the simulator radiographs and add a 2-cm margin along the vessels delineated. In our study, we compared both methods as to full enclosure of paraaortic and pelvic lymphatics or nodal miss. MATERIAL AND METHODS: Abdominal CT scans of 81 patients with involvement of paraaortic lymph node regions were examined with maximum lymph node sizes of 2.5 cm. The distance from the center of the appropriate vertebra to the lateral lymph node contour referring to the transverse process as well as to the outside contour of the aorta on the left and the vena cava on the right side, respectively, the iliac vessels were measured from T12 through S1. At the level of the hip joint the measurement point was given by the caput femoris. RESULTS: Our measurement prove that 10% of the lymph nodes were found lateral from the transverse processes of the thoracic and lumbar vertebras and 12% outside the 2-cm safety margin from the lateral contour of the large abdominal vessels. CONCLUSION: Our data show, that the customary fields for infradiaphragmatic lymphatic nodes have so far not been able to enclose all retroperitoneal and pelvic lymph nodes with certainty.

Repositioning accuracy: comparison of a noninvasive head holder with thermoplastic mask for fractionated radiotherapy and a case report.

PURPOSE: To compare accuracy, clinical feasibility, and subjective patient impression between a noninvasive head holder (Vogele Bale Hohner [VBH]; Wellhoefer Dosimetry, Schwarzenbruck, Germany) developed at the University of Innsbruck and the thermoplastic mask fixation system for use in fractionated external radiotherapy. We present a case report of an actual patient fixated in the VBH head holder during radiation therapy. MATERIALS AND METHODS: The VBH head holder consists of an individualized vacuum dental cast connected to a head plate via two hydraulic arms allowing noninvasive, reproducible head fixation of even uncooperative patients. Accuracy was tested and compared with that of the thermoplastic mask using the Phillips EasyGuide navigation system on five volunteers. Specific external registration points served as landmarks and their positions were compared after each repositioning. System and operator inaccuracy were also taken into account. The times taken for production and repositioning of the respective fixation devices were compared, and subjective impressions were noted. RESULTS: Mean VBH head holder repositioning accuracy was 1.02 mm while that of the thermoplastic mask was 3.05 mm. 69% of mask repositionings showed a deviation > 2 mm and 41% > 3 mm (as opposed to 8% and 1% respectively for the VBH head holder) Those points located farthest away from the respective plane of fixation showed the largest deviations. Both production and repositioning times were similar between the systems; depending upon the patient, the VBH head holder was generally better tolerated than the mask system. CONCLUSION: Due to its significantly better repositioning accuracy compared to that of the thermoplastic mask, the VBH head holder is especially suited for external radiation requiring precise repositioning due to critical tissues in immediate surrounding of the area to be irradiated.

Clinical value of fructose 1,6 bisphosphatase in monitoring renal proximal tubular injury.

The usefulness of the gluconeogenic key enzyme fructose 1,6 bisphosphatase (FBPase), which is localized exclusively in the proximal nephron segment, as a marker compound to monitor injury of the proximal nephron segment during nephrotoxic therapy, was tested in a collective model of male patients treated for testicular cancer. These patients with normal kidney function were submitted to therapy with the nephrotoxic chemotherapeutics carboplatinum and a combination of cisplatinum, etoposide, bleomycin and ifosfamide. The release of FBPase activities into the urine was monitored during the initial two treatments over a period of eight days. The urinary enzyme activities measured were compared to the excretion of the "proximal tubular injury markers" N-acetyl-beta-D-glucosaminidase (NAG) and alpha 1-microglobulin (alpha 1m). The presence of glomerular damage was determined by measurement of urinary excretion rates of albumin (ALB) and IgG. In addition, protein excretion patterns following chemotherapy were monitored. The combined administration of cisplatin, etoposide and ifosfamide resulted in a pronounced proximal tubular injury as shown by the release of FBPase into the urine. This is substantiated by simultaneously increased excretion rates for NAG and alpha 1m. Proximal tubular toxicity was found to be less severe when cisplatin was combined with etoposide and bleomycin and was nearly absent following carboplatinum monotherapy. Carboplatinum only affected glomerular function and resulted in an elevated ALB and IgG excretion. From this model investigation it can be delineated that determination of urinary FBPase activities ensures a sensitive and reliable identification of proximal nephron damage.