Validation of the Decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial.

BACKGROUND: The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase III trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy. PATIENTS AND METHODS: A clinical-grade whole-transcriptome assay was carried out on radical prostatectomy samples obtained from patients enrolled in Swiss Group for Clinical Cancer Research (SAKK) 09/10, a phase III trial of 350 men with biochemical recurrence after radical prostatectomy randomized to 64 Gy versus 70 Gy without concurrent hormonal therapy or pelvic nodal RT. A prespecified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, postradical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks. RESULTS: The analytic cohort of 226 patients was representative of the overall trial, with a median follow-up of 6.3 years (interquartile range 6.1-7.2 years). The GC (high versus low-intermediate) was independently associated with biochemical progression [subdistribution hazard ratio (sHR) 2.26, 95% confidence interval (CI) 1.42-3.60; P < 0.001], clinical progression (HR 2.29, 95% CI 1.32-3.98; P = 0.003), and use of hormone therapy (sHR 2.99, 95% CI 1.55-5.76; P = 0.001). GC high patients had a 5-year freedom from biochemical progression of 45% versus 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower versus higher GC scores. CONCLUSIONS: This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. These data confirm the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting.

A cost-effectiveness analysis of consolidation immunotherapy with durvalumab in stage III NSCLC responding to definitive radiochemotherapy in Switzerland.

BACKGROUND: Consolidation immunotherapy with the programmed death ligand 1 (PD-L1) inhibitor durvalumab improves survival in patients with stage III non-small-cell lung cancer responding to radiochemotherapy. The aim of this study was to assess the cost-effectiveness of durvalumab in Switzerland based on the most recent PACIFIC survival follow-up. MATERIALS AND METHODS: We constructed a Markov model based on the 3-year follow-up data of the PACIFIC trial and compared consolidation durvalumab with observation. We used published utility values and assessed costs for treatment strategies from the perspective of the Swiss health care payers. Cost-effectiveness was tested both in the intention-to-treat population of the PACIFIC trial unselected for PD-L1 tumor expression and in patients with PD-L1-expressing tumors (≥1%). RESULTS: In the unselected/PD-L1-positive patients, durvalumab showed an incremental effectiveness of 0.76/1.18 quality-adjusted life year (QALY) and incremental costs of Swiss Francs (CHF) 67 239/78 177, resulting in incremental cost-effectiveness ratios of CHF 88 703/66 131 per QALY gained, respectively. The most influential factors for the incremental cost-effectiveness ratio were the utility before first progression, costs for durvalumab, and the hazard ratio for overall survival under durvalumab versus observation. The cost-effectiveness of durvalumab was better than CHF 100 000 per QALY gained in 75% of the simulations in probabilistic sensitivity analysis. CONCLUSION: Assuming a willingness-to-pay threshold of CHF 100 000 per QALY gained, consolidation durvalumab is likely to be cost-effective both in patients with inoperable stage III non-small-cell lung cancer (NSCLC) unselected for PD-L1 status and in patients with PD-L1-expressing tumors in Switzerland.

Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08).

Background: This open-label, phase III trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma. Patients and methods: Patients were randomly assigned (1 : 1) to two cycles of chemotherapy (docetaxel 75 mg/m2, cisplatin 75 mg/m2) followed by chemoradiation (45 Gy, docetaxel 20 mg/m2 and cisplatin 25 mg/m2, weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m2 weekly and adjuvant cetuximab 500 mg/m2 fortnightly for 3 months. The primary end point was progression-free survival (PFS). Results: In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years [95% confidence interval (CI), 2.0 to not reached] with cetuximab and 2.0 years (95% CI, 1.5-2.8) with control [hazard ratio (HR), 0.79; 95% CI, 0.58-1.07; P = 0.13]. Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2-4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52-1.01; P = 0.055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31-0.90; P = 0.017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64-1.59, P = 0.97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings. Conclusion: Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma. Clinical trial information: NCT01107639.

Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial.

Background: The addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT â†’ TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population. Patients and methods: ARTE was a 2 : 1 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40 Gy in 15 fractions) with bevacizumab (10 mg/kg×14 days) (arm A, N = 50) or without bevacizumab (arm B, N = 25) in patients with newly diagnosed glioblastoma aged ≥65 years. The primary objective was to obtain evidence for prolongation of median OS by the addition of bevacizumab to RT. Response was assessed by RANO criteria. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Exploratory studies included molecular subtyping by 450k whole methylome and gene expression analyses. Results: Median PFS was longer in arm A than in arm B (7.6 and 4.8 months, P = 0.003), but OS was similar (12.1 and 12.2 months, P = 0.77). Clinical deterioration was delayed and more patients came off steroids in arm A. Prolonged PFS in arm A was confined to tumors with the receptor tyrosine kinase (RTK) I methylation subtype (HR 0.25, P = 0.014) and proneural gene expression (HR 0.29, P = 0.025). In a Cox model of OS controlling for established prognostic factors, associations with more favorable outcome were identified for age <70 years (HR 0.52, P = 0.018) and Karnofsky performance score 90%-100% (HR 0.51, P = 0.026). Including molecular subtypes into that model identified an association of the RTK II gene methylation subtype with inferior OS (HR 1.73, P = 0.076). Conclusion: Efficacy outcomes and exploratory analyses of ARTE do not support the hypothesis that the addition of bevacizumab to RT generally prolongs survival in elderly glioblastoma patients. Molecular biomarkers may identify patients with preferential benefit from bevacizumab. Clinical trial registration number: NCT01443676.

Patterns of care in recurrent glioblastoma in Switzerland: a multicentre national approach based on diagnostic nodes.

Despite moderate improvements in outcome of glioblastoma after first-line treatment with chemoradiation recent clinical trials failed to improve the prognosis of recurrent glioblastoma. In the absence of a standard of care we aimed to investigate institutional treatment strategies to identify similarities and differences in the pattern of care for recurrent glioblastoma. We investigated re-treatment criteria and therapeutic pathways for recurrent glioblastoma of eight neuro-oncology centres in Switzerland having an established multidisciplinary tumour-board conference. Decision algorithms, differences and consensus were analysed using the objective consensus methodology. A total of 16 different treatment recommendations were identified based on combinations of eight different decision criteria. The set of criteria implemented as well as the set of treatments offered was different in each centre. For specific situations, up to 6 different treatment recommendations were provided by the eight centres. The only wide-range consensus identified was to offer best supportive care to unfit patients. A majority recommendation was identified for non-operable large early recurrence with unmethylated MGMT promoter status in the fit patients: here bevacizumab was offered. In fit patients with late recurrent non-operable MGMT promoter methylated glioblastoma temozolomide was recommended by most. No other majority recommendations were present. In the absence of strong evidence we identified few consensus recommendations in the treatment of recurrent glioblastoma. This contrasts the limited availability of single drugs and treatment modalities. Clinical situations of greatest heterogeneity may be suitable to be addressed in clinical trials and second opinion referrals are likely to yield diverging recommendations.

Erectile function following brachytherapy, external beam radiotherapy, or radical prostatectomy in prostate cancer patients.

BACKGROUND AND PURPOSE: For localized prostate cancer, treatment options include external beam radiotherapy (EBRT), radical prostatectomy (RP), and brachytherapy (BT). Erectile dysfunction (ED) is a common side-effect. Our aim was to evaluate penile erectile function (EF) before and after BT, EBRT, or RP using a validated self-administered quality-of-life survey from a prospective registry. MATERIAL AND METHODS: Analysis included 478 patients undergoing RP (n = 252), EBRT (n = 91), and BT (n = 135) with at least 1 year of follow-up and EF documented using IIEF-5 scores at baseline, 6 weeks, 6 months, 1 year, and annually thereafter. RESULTS: Differences among treatments were most pronounced among patients with no or mild initial ED (IIEF-5 ≥ 17). Overall, corrected for baseline EF and age, BT was associated with higher IIEF-5 scores than RP (+ 7.8 IIEF-5 score) or EBRT (+ 3.1 IIEF-5 score). EBRT was associated with better IIEF-5 scores than RP (+ 4.7 IIEF-5 score). In patients undergoing EBRT or RP with bilateral nerve sparing (NS), recovery of EF was observed and during follow-up, the differences to BT were not statistically significant. Overall age had a negative impact on EF preservation (corrected for baseline IIEF). CONCLUSION: In our series, EF was adversely affected by each treatment modality. Considered overall, BT provided the best EF preservation in comparison to EBRT or RP.

Measurements of isocenter path characteristics of the gantry rotation axis with a smartphone application.

PURPOSE: For stereotactic radiosurgery, the AAPM Report No. 54 [AAPM Task Group 42 (AAPM, 1995)] requires the overall stability of the isocenter (couch, gantry, and collimator) to be within a 1 mm radius. In reality, a rotating system has no rigid axis and thus no isocenter point which is fixed in space. As a consequence, the isocenter concept is reviewed here. It is the aim to develop a measurement method following the revised definitions. METHODS: The mechanical isocenter is defined here by the point which rotates on the shortest path in the room coordinate system. The path is labeled as "isocenter path." Its center of gravity is assumed to be the mechanical isocenter. Following this definition, an image-based and radiation-free measurement method was developed. Multiple marker pairs in a plane perpendicular to the assumed gantry rotation axis of a linear accelerator are imaged with a smartphone application from several rotation angles. Each marker pair represents an independent measuring system. The room coordinates of the isocenter path and the mechanical isocenter are calculated based on the marker coordinates. The presented measurement method is by this means strictly focused on the mechanical isocenter. RESULTS: The measurement result is available virtually immediately following completion of measurement. When 12 independent measurement systems are evaluated, the standard deviations of the isocenter path points and mechanical isocenter coordinates are 0.02 and 0.002 mm, respectively. CONCLUSIONS: The measurement is highly accurate, time efficient, and simple to adapt. It is therefore suitable for regular checks of the mechanical isocenter characteristics of the gantry and collimator rotation axis. When the isocenter path is reproducible and its extent is in the range of the needed geometrical accuracy, it should be taken into account in the planning process. This is especially true for stereotactic treatments and radiosurgery.

Taxane-containing induction chemotherapy followed by definitive chemoradiotherapy. Outcome in patients with locally advanced head and neck cancer.

BACKGROUND: Induction chemotherapy followed by definitive chemoradiotherapy is an intensified treatment approach for locally advanced squamous cell carcinoma of the head and neck (HNSCC) that might be associated with high rates of toxicity. MATERIALS AND METHODS: The data of 40 consecutive patients who underwent induction chemotherapy with docetaxel-containing regimens followed by intensity-modulated radiotherapy (IMRT) and concomitant systemic therapy for unresectable locally advanced HNSCC were retrospectively analyzed. Primary objectives were RT-related acute and late toxicity. Secondary objectives were response to induction chemotherapy, locoregional recurrence-free survival (LRRFS), overall survival (OS), and influencing factors for LRRFS and OS. RESULTS: The median follow-up for surviving patients was 21 months (range, 2-53 months). Patients received a median of three cycles of induction chemotherapy followed by IMRT to 72 Gy. Three patients died during induction chemotherapy and one during chemoradiotherapy. Acute RT-related toxicity was of grade 3 and 4 in 72 and 3 % of patients, respectively, mainly dysphagia and dermatitis. Late RT-related toxicity was mainly xerostomia and bone/cartilage necrosis and was of grade 3 and 4 in 15 % of patients. One- and 2-year LRRFS and OS were 72 and 49 % and 77 and 71 %, respectively. CONCLUSION: Induction chemotherapy followed by chemoradiotherapy using IMRT was associated with a high rate of severe acute and late RT-related toxicities in this selected patient cohort. Four patients were lost because of fatal complications. Induction chemotherapy did not compromise the delivery of full-dose RT; however, the use of three cycles of concomitant cisplatin was impaired.

[Castration-resistant prostate cancer: surgical and radio-oncological therapeutic options]. / Kastrationsresistentes Prostatakarzinom : Chirurgische und strahlentherapeutische Therapieoptionen.

Treatment of patients suffering from castration-resistant prostate cancer is a challenge for the attending physician. Due to the polysymptomatic nature of this disease, multidisciplinary cooperation (urology, radiation oncology, medical oncology, palliative care, orthopaedics, neurosurgery) is the centre of attention. Different surgical and radio-oncological therapeutic options are available based on different stages of this disease. Optimizing quality of life should always be the focus of attention in these patients.

Topological methods for the comparison of structures using LDR-brachytherapy of the prostate as an example.

The dose coverage of low dose rate (LDR)-brachytherapy for localized prostate cancer is monitored 4-6 weeks after intervention by contouring the prostate on computed tomography and/or magnetic resonance imaging sets. Dose parameters for the prostate (V100, D90 and D80) provide information on the treatment quality. Those depend strongly on the delineation of the prostate contours. We therefore systematically investigated the contouring process for 21 patients with five examiners. The prostate structures were compared with one another using topological procedures based on Boolean algebra. The coincidence number C(V) measures the agreement between a set of structures. The mutual coincidence C(i, j) measures the agreement between two structures i and j, and the mean coincidence C(i) compares a selected structure i with the remaining structures in a set. All coincidence parameters have a value of 1 for complete coincidence of contouring and 0 for complete absence. The five patients with the lowest C(V) values were discussed, and rules for contouring the prostate have been formulated. The contouring and assessment were repeated after 3 months for the same five patients. All coincidence parameters have been improved after instruction. This shows objectively that training resulted in more consistent contouring across examiners.

Tumour hypoxia: impact on biology, prognosis and treatment of solid malignant tumours.

Tumour hypoxia is a major constraint for radiotherapy and many types of chemotherapy. A variety of different pathogenetic mechanisms contribute to the development of hypoxia in solid tumours. Hypoxia is associated with unfavourable prognosis, regardless of the treatment modality applied. Two different effects have been considered to explain the deleterious effects of hypoxia on the outcome of tumour patients. The first aspect encompasses the direct interference of hypoxia with antineoplastic treatment modalities. The efficacy of ionizing radiation, but also of a variety of cytotoxic drugs and cytokines rely directly on adequate oxygen tensions. The second aspect concerns the effects of hypoxia on the biology of tumour and stromal cells. Hypoxia is related to malignant progression, increased invasion, angiogenesis and an increased risk of metastasis formation. Possibly, hypoxia is furthermore a stressor which selects cells with increased resistance to apoptosis and thereby indirectly contributes to treatment resistance. This article reviews in brief the specific pathophysiology of tumour oxygenation and its implications for prognosis, tumour treatment and biology.

Fibronectin and laminin increase resistance to ionizing radiation and the cytotoxic drug Ukrain in human tumour and normal cells in vitro.

PURPOSE: Cell-extracellular matrix (ECM) interactions are thought to mediate drug and radiation resistance. Dependence of cell survival, beta1-integrin expression and cell cycling on the ECM proteins and beta1-integrin ligands fibronectin (FN) and laminin (LA) were examined in malignant and normal cells exposed to the cytotoxic drug Ukrain plus/minus irradiation. MATERIALS AND METHODS: Human A549 lung cancer and MDAMB231 (MDA231) breast cancer cells and normal fibroblasts (HSF1) grown on FN, LA, bovine serum albumin (BSA) or polystyrene were treated with Ukrain (1 microg ml(-1), 24 h) plus/minus irradiation (2-8 Gy) and the effects studied using colony formation assays, flow cytometry (beta1-integrin, DNA analysis) and adhesion assays. RESULTS: FN and LA reduced the cytotoxic effect of single Ukrain treatment compared with polystyrene and BSA. FN and LA also abolished Ukrain-dependent radiosensitization in A549 cells and decreased the radiosensitivity of MDA231 and HSF1 cells. Single Ukrain exposure on polystyrene significantly reduced beta1-integrin expression and promoted G2-phase accumulation of A549 cells. In contrast, Ukrain-treated MDA231 and HSF1 cells showed elevated beta1-integrin expression and no Ukrain-specific cell cycle effect. Under Ukrain-radiation exposure, irradiation, FN or LA abolished Ukrain-mediated reduction of beta1-integrin expression and G2-phase accumulation in A549 cells, whereas in MDA231 cells and fibroblasts beta1-integrin expression and cell cycle distribution were stabilized. Cell adhesion to FN or LA was significantly impaired (A549) or improved (MDA231, HSF1) upon Ukrain treatment. CONCLUSIONS: The data corroborate the findings of other groups that cell adhesion-mediated resistance to either single or combined drug and radiation exposure is tightly correlated to specific ECM proteins. By demonstrating a strong modulatory impact of FN and LA on the radiosensitivity-modifying activity of the drug Ukrain, the set findings are also highly important for the assessment of drug and radiation effects within in vitro cytotoxicity studies. The data give the first mechanistic insights into specific FN- and LA-modulated cellular resistance mechanisms as well as into the important role for beta1-integrins using the unique cytotoxic and radiosensitivity-modifying drug Ukrain.

Primary central nervous system (CNS) lymphoma in immunocompetent patients.

Primary CNS lymphoma (PCNSL) has been increasing in incidence among both immunocompetent and immunocompromised patients. Today there is no uniform approach to the treatment of this disease. Whole brain irradiation (WBI) has been standard treatment, resulting in complete remission in the majority of patients, but with most patients relapsing and dying of their disease within 2 years after treatment. The addition of chemotherapy to WBI appears to prolong survival for patients younger than 60 years with median survival reaching a plateau at approximately 40 months. The issue of the best treatment for older patients remains controversial. Prospective studies will be needed, as it is impossible to draw conclusions from the nonrandomized small series published so far. This is because the prognostic variables of age and performance status to date have affected outcome more than therapy. In this review, some of the questions regarding the management of PCNSL are addressed. Since the role of radiotherapy remains unclear, we designed a new randomized multicenter study (G-PCNSL-SG-1 trial) to investigate the optimal timing of WBI after high-dose methotrexate (HD-MTX) chemotherapy.

[Massive Gorham-Stout osteolysis of the temporal bone and the craniocervical transition]. / Massive Osteolyse Gorham-Stout des Felsenbeines und des kraniozervikalen Uberganges.

Massive osteolysis Gorham-Stout is a rare, benign but locally aggressive angiomatosis which results in destruction and resorption of bone. The etiology and pathogenesis are undefined. The occurrence of the disease in the skull base is uncommon. A 54-year-old female presented with isolated, one-sided surditas. Eight years before the patient underwent surgery and radiation therapy for treatment of hypopharyngeal cancer. A transtemporal biopsy was taken and a highly vascularized, cystic lesion with destruction of the right occipital and temporal bone and the atlas was found. Histopathology showed thin-walled capillaries with flattened endothelial lining cells. After exclusion of malignant and infectious components the diagnosis of Gorham's disease was established. Review of the literature suggests radiation therapy as the method of choice for stopping the disease's progress. The aim of this case report is to emphasize the Gorham-Stout-Syndrome as a rare differential diagnosis for skull base lesions.

Ukrain, an alkaloid thiophosphoric acid derivative of Chelidonium majus L. protects human fibroblasts but not human tumour cells in vitro against ionizing radiation.

PURPOSE: Ukrain, an alkaloid thiophosphoric acid derivative of Chelidonium majus L., has demonstrated a promising impact on chemotherapy in a variety of malignancies. The effects of the drug on cell survival, alteration of the cell cycle and induction of apoptosis were examined without and in combination with ionizing radiation (IR). The TP53 status of the cell lines used was also investigated. MATERIALS AND METHODS: Exponentially growing human tumour cell lines MDA-MB-231 (breast), PA-TU-8902 (pancreas), CCL-221 (colorectal), U-138MG (glioblastoma), and human skin and lung fibroblastic cells, HSF1, HSF2 and CCD32-LU were studied by colony assay, flow cytometry (cell-cycle, annexin-V staining for apoptosis) and Western blotting. Ukrain was used in concentrations from 0.1 to 50 microg ml(-1) for 1, 3 and 24 h and radiation as single doses of 1-10Gy. Combined drug-radiation exposure employed 1 microg ml(-1) Ukrain for 24h plus 2-8 Gy. RESULTS: Ukrain cytotoxicity was time- and dose-dependent. The combination of Ukrain plus IR gave enhanced toxicity in CCL-221 and U-138MG cells, but not in MDA-MB-231 and PA-TU-8902 cells. Most strikingly, a radioprotective effect was found in normal human skin and lung fibroblasts. Flow-cytometry analyses supported the differential and cell line-specific cytotoxicity of Ukrain. CCL-221 and U-138MG cells accumulated in G2 after 24-h Ukrain treatment, whereas no alterations were detected in the other tumour cells and normal fibroblasts tested. Western blotting of TP53 demonstrated non-functional overexpression in all tumour cell lines without affecting p21. HSF1 presented wild-type TP53 and a p21 response after IR. Flowcytometric analyses of annexin-V staining showed no induction of apoptosis after Ukrain treatment in comparison with untreated controls. CONCLUSIONS: Differential effects of Ukrain in modulating radiation toxicity of human cancer cell lines and its protective effect in normal human fibroblasts suggest that this alkaloid may have potential properties for clinical radiochemotherapy.

Activity of extracranial metastases as a prognostic factor influencing survival after radiosurgery of brain metastases.

Information about prognostic factors influencing survival have been only occasionally reported in studies on the use of radiosurgery in the treatment of patients with brain metastasis. To answer the question of whether activity of extracranial metastases is an independent prognostic factor influencing survival in radiosurgery of brain metastases, a review of the literature was performed. Fourteen studies were identified in the English language literature that dealt with this topic. Only three studies showed borderline insignificance of the influence of activity of extracranial metastases when analysed by univariate methods. When multivariate analysis was used to test for the independent influence of this factor on survival, of nine studies that used that statistical approach eight showed that it is an independent prognosticator influencing survival, most often being the strongest one. This review of literature supports the view that the "activity of extracranial metastases" is an independent prognostic factor influencing survival of these patients as documented in published reports. However, prospective randomised trials are necessary to definitely establish the independent influence of this prognostic factor.

Time- and dose-limiting erysipeloid rash confined to areas of lymphedema following treatment with gemcitabine--a report of three cases.

Gemcitabine is a deoxycytidine analog with broad antitumor activity. Its main toxicities include myelosuppression, flu-like symptoms, bronchospasms and mild skin rash. We report three cases, in which the patients developed time- and dose-limiting erysipeloid skin reactions confined to areas of impaired lymphatic drainage after application of gemcitabine. Three patients with metastatic tumors (breast cancer, endometrial cancer and non-small cell lung cancer) received weekly infusions of gemcitabine (1000 mg/m2). All patients suffered from lymphedema of different origin and developed an erysipeloid erythema 40-48 h after chemotherapy within their preexisting lymphedema. Genuine erysipela was ruled out by laboratory tests and clinical observation. The skin reaction was repeatedly observed and faded after 14 days without specific treatment. Although the pathogenesis of the observed reaction is unclear, it is suspected that the skin symptoms were caused by gemcitabine or its metabolites. Gemcitabine is usually metabolized fast and excreted renally. In areas with impaired lymphatic drainage pharmakocinetics might be altered: inactivation happens slower and the drug might accumulate in the s.c. and cutaneous tissue, thus increasing local toxicity. Clinical judgement and biochemical parameters can help to tell apart genuine erysipela and the erysipeloid reaction.

Hypoxia-induced tumour cell migration in an in vivo chicken model.

To investigate the relationship between hypoxia, neovascularisation and tumour cell spread, experiments on the area vasculosa of the early chick embryo under different oxygen concentrations were performed in vivo. Human glioblastoma cells (U-138MG) were inoculated onto the area vasculosa and the fertilised eggs were incubated under conditions of normoxia or hypoxia. For evaluation, we performed in vivo video-microscopy of the area vasculosa and determination of microvessel density (MVD), as well as a histological examination of the fixed specimen. Under hypoxia, MVD was significantly increased compared to normoxic conditions. Only under hypoxic conditions was tumour cell spread found outside the main tumour mass and within the vessels, at times followed by the subsequent development of secondary tumour cell bulks on the area vasculosa. These data lead to the conclusion that hypoxia can stimulate tumour cell migration in this in vivo model.

Interaction of paclitaxel (Taxol) and irradiation. In-vitro differences between tumor and fibroblastic cells.

AIM: Optimal dose and schedule of paclitaxel in combined drug-irradiation treatment could not be determined for most of tumors yet. The aim of this study was to compare in vitro cytotoxicity and radiosensitizing abilities as a function of single paclitaxel (Taxol) exposure in tumor and fibroblastic cells using different drug incubation irradiation intervals. MATERIAL AND METHOD: A lung-carcinoma (SK-LU-1), glioblastoma (U-138 MG) and rodent fibroblast cell line (HyB14FAF28) were used. The clonogenic assay was applied for survival investigation. alpha beta-values were calculated using the linear-quadratic model (log S = -alpha D - beta D2). Cytotoxicity of Taxol was examined at 0 to 50 microM. Combined Taxol-radiotherapy exposure was accomplished with 10 microM Taxol plus 10 Gy irradiation (RT) following after a 1-hour and 9-hour interval. For controls cells were exposed to Cremophor EL/ethanol (CEL/eth) and a phosphate buffered saline (PBS). RESULTS: Single Taxol exposure (10 microM) resulted in 0.54/0.50/0.84 (3-hours incubation) and 0.094/0.48/0.82 (15-hours incubation) survival of SK-LU-1, U-138 MG and HyB14FAF28 cells, respectively. Taxol concentrations from 2 to 50 microM only had cytotoxic effect in tumor cells. Single dose RT (10 Gy) led to cell survival of 0.0006/0.006/0.03. The diluent CEL/eth also showed cytotoxic activity. Taxol plus RT led to cell survival of 0.00025/0.0014/0.042 (1 hour) and 0.0004/0.0019/0.04 (9 hours) without significant difference between chosen time intervals. alpha beta-values showed great variation lacking evidence for definite radiosensitization. alpha increase after Taxol and alpha decrease after CEL/eth exposure were detected. CONCLUSIONS: The data presented demonstrate a potential beneficial effect, described as co-operation, by combining Taxol and RT in human tumor cells and rodent fibroblasts. High intrinsic alpha components of the tumor cells as well as CEL/eth's antagonizing actions could be likely to disturb and influence paclitaxel's abilities leading to radiosensitization.