Abstract: RATIONALE: Global gene expression analysis provides a comprehensive molecular characterization of non-small cell lung cancer (NSCLC). OBJECTIVES: To evaluate the feasibility of integrating expression profiling into routine clinical work-up by including both surgical and minute bronchoscopic biopsies and to develop a robust prognostic gene expression signature. METHODS: Tissue samples from 41 chemotherapy-naive patients with NSCLC and 15 control patients with inflammatory lung diseases were obtained during routine clinical work-up and gene expression profiles were gained using an oligonucleotide array platform (NovaChip; 34'207 transcripts). Gene expression signatures were analyzed for correlation with histological and clinical parameters and validated on independent published data sets and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: Diagnostic signatures for adenocarcinoma and squamous cell carcinoma reached a sensitivity of 80%/80% and a specificity of 83%/94%, respectively, dependent on the proportion of tumor cells. Sixty-seven of the 100 most discriminating genes were validated with independent observations from the literature. A 13-gene metagene refined on four external data sets was built and validated on an independent data set. The metagene was a strong predictor of survival in our data set (hazard ratio = 7.7, 95% CI [2.8-21.2]) and in the independent data set (hazard ratio = 1.6, 95% CI [1.2-2.2]) and in both cases independent of the International Union against Cancer staging. Vascular endothelial growth factor-beta, one of the key prognostic genes, was further validated by immunohistochemistry on 508 independent tumor samples. CONCLUSIONS: Integration of functional genomics from small bronchoscopic biopsies allows molecular tumor classification and prediction of survival in NSCLC and might become a powerful adjunct for the daily clinical practice.
Abstract: INTRODUCTION: Anaemia during chemotherapy is often left untreated. Erythropoiesis-stimulating agents are frequently used to treat overt anaemia. Their prophylactic use, however, remains controversial and raises concerns about cost-effectiveness. Therefore, we assessed the efficacy of a dose-reduction schedule in anaemia prophylaxis. MATERIALS AND METHODS: The study included patients with untreated solid tumours about to receive platinum-based chemotherapy and had haemoglobin (Hb) levels >/=11 g/dL. Epoetin-alpha was administered at a dose level of 3 x 10,000 U weekly as soon as Hb descended to < 13 g/dL. Dose reductions to 3 x 4,000 U and 3 x 2,000 U weekly were planned in 4-week intervals if Hb stabilised in the range of 11-13 g/dL. Upon ascending to >/=13 g/dL, epoetin was discontinued. Iron supplements of 100 mg intravenous doses were given weekly. Of 37 patients who enrolled, 33 could be evaluated. RESULTS AND DISCUSSION: Their median Hb level was 13.7 (10.9-16.2) g/dL at baseline and descended to 11.0 (7.4-13.8) g/dL by the end of chemotherapy. Anaemia (Hb < 10 g/dL) was prevented in 24 patients (73%). The mean dose requirement for epoetin-alpha was 3 x 5,866 U per week per patient, representing a dose reduction of 41%. Treatment failed in nine patients (27%), in part due to epoetin-alpha resistance in four (12%) and blood transfusion in three (9%) patients. CONCLUSION: Dose reduction was as effective as fixed doses in anaemia prophylaxis but reduced the amount of prescribed epoetin substantially.
Abstract: BACKGROUND: Stage IIIB non-small-cell lung cancer (NSCLC) is usually thought to be unresectable, and is managed with chemotherapy with or without radiotherapy. However, selected patients might benefit from surgical resection after neoadjuvant chemotherapy and radiotherapy. The aim of this multicentre, phase II trial was to assess the efficacy and toxicity of a neoadjuvant chemotherapy and radiotherapy followed by surgery in patients with technically operable stage IIIB NSCLC. METHODS: Between September, 2001, and May, 2006, patients with pathologically proven and technically resectable stage IIIB NSCLC were sequentially treated with three cycles of neoadjuvant chemotherapy (cisplatin with docetaxel), immediately followed by accelerated concomitant boost radiotherapy (44 Gy in 22 fractions) and definitive surgery. The primary endpoint was event-free survival at 12 months. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030810. FINDINGS: 46 patients were enrolled, with a median age of 60 years (range 28-70). 13 (28%) patients had N3 disease, 36 (78%) had T4 disease. All patients received chemotherapy; 35 (76%) patients received radiotherapy. The main toxicities during chemotherapy were neutropenia (25 patients [54%] at grade 3 or 4) and febrile neutropenia (nine [20%]); the main toxicity after radiotherapy was oesophagitis (ten patients [29%]; nine grade 2, one grade 3). 35 patients (76%) underwent surgery, with pneumonectomy in 17 patients. A complete (R0) resection was achieved in 27 patients. Peri-operative complications occurred in 14 patients, including two deaths (30-day mortality 5.7%). Seven patients required a second surgical intervention. Pathological mediastinal downstaging was seen in 11 of the 28 patients who had lymph-node involvement at enrolment, a complete pathological response was seen in six patients. Event-free survival at 12 months was 54% (95% CI 39-67). After a median follow-up of 58 months, the median overall survival was 29 months (95% CI 16.1-NA), with survival at 1, 3, and 5 years of 67% (95% CI 52-79), 47% (32-61), and 40% (24-55). INTERPRETATION: A treatment strategy of neoadjuvant chemotherapy and radiotherapy followed by surgery is feasible in selected patients. Toxicity is considerable, but manageable. Survival compares favourably with historical results of combined treatment for less advanced stage IIIA disease. FUNDING: Swiss Group for Clinical Cancer Research (SAKK) and an unrestricted educational grant by Sanofi-Aventis (Switzerland).
Abstract: BACKGROUND: Gefitinib is active in patients with pretreated non-small-cell lung cancer (NSCLC). We evaluated the activity and toxicity of gefitinib first-line treatment in advanced NSCLC followed by chemotherapy at disease progression. PATIENTS AND METHODS: In all, 63 patients with chemotherapy-naive stage IIIB/IV NSCLC received gefitinib 250 mg/day. At disease progression, gefitinib was replaced by cisplatin 80 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1, 8 for up to six 3-week cycles. Primary end point was the disease stabilization rate (DSR) after 12 weeks of gefitinib. RESULTS: After 12 weeks of gefitinib, the DSR was 24% and the response rate (RR) was 8%. Median time to progression (TtP) was 2.5 months and median overall survival (OS) 11.5 months. Never smokers (n = 9) had a DSR of 56% and a median OS of 20.2 months; patients with epidermal growth factor receptor (EGFR) mutation (n = 4) had a DSR of 75% and the median OS was not reached after the follow-up of 21.6 months. In all, 41 patients received chemotherapy with an overall RR of 34%, DSR of 71% and median TtP of 6.7 months. CONCLUSIONS: First-line gefitinib monotherapy led to a DSR of 24% at 12 weeks in an unselected patients population. Never smokers and patients with EGFR mutations tend to have a better outcome; hence, further trials in selected patients are warranted.
Abstract: PURPOSE: Feasibility trial to test the toxicity and outcome of three cycles of induction chemotherapy followed by limited surgery in medically inoperable early stage NSCLC patients. PATIENTS AND METHODS: Thirteen patients with NSCLC (stages I-IIIB) with insufficient cardio-respiratory reserves for the oncologically required lung resection, received three cycles of induction chemotherapy with cisplatin (100mg/m(2)) and docetaxel (85mg/m(2)) followed by parenchyma-sparing lung surgery. Operability was evaluated with pulmonary function tests, perfusion scintigraphy and cardiopulmonary exercise testing. In selected patients coronary angiography or myocardial perfusion scintigraphy was performed. Rate of R0-resections was taken as primary outcome. RESULTS: Twelve of 13 patients received the three cycles of chemotherapy as planned. The main grade 3/4 hematological toxicity was neutropenia (62%), non-hematological toxicity was neutropenic fever (23%) and cough/dyspnea (31%). Complete, partial and stable responses to chemotherapy were seen in 1, 10 and 2 patients, respectively-the overall response rate was 85%. No patient had tumor progression. Eleven/13 (85% (CI 95% 54, 97) %) patients underwent surgery (4 lobectomies, 2 segmentectomies, and 5 wedge resections), all had a pathologically complete resection of the tumor. There was one postoperative death due to myocardial infarction. The median disease-free and overall survivals were 57(CI 95% 36-78) months and 66(CI 95% 40-92) months, with a median follow up time of 58 months. The 1-, 2- and 4-year OS was 85%, 85% and 67%, respectively. There were no significant changes in any lung function parameter compared to the preoperative assessment. The FEV(1) showed a trend for improved values after surgery. CONCLUSION: Induction chemotherapy in medically inoperable patients followed by parenchyma-sparing surgery is feasible and yields very promising results.
Abstract: BACKGROUND: TG4010 is a recombinant viral vector expressing both the tumor-associated antigen MUC1 and Interleukine-2. This vector is based on the modified virus of Ankara, a significantly attenuated strain of vaccinia virus. TG4010 has been designed to induce or amplify a cellular immune response directed against tumor cells expressing MUC1. METHODS: A multicenter, randomized phase II study has explored two schedules of the combination of TG4010 with first line chemotherapy in patients with stage IIIB/IV non-small cell lung cancer. In Arm 1, TG4010 was combined upfront with cisplatin (100 mg/m day 1) and vinorelbine (25 mg/m day 1 and day 8). In Arm 2, patients were treated with TG4010 monotherapy until disease progression, followed by TG4010 plus the same chemotherapy as in Arm1. Response rate was evaluated according to RECIST. Median time to progression and median overall survival were calculated according to the Kaplan-Meier method. RESULTS: Sixty-five patients were enrolled, 44 in Arm 1 and 21 in Arm 2, in accordance with the two stage Simon design of the statistical plan. In Arm 1, partial response was observed in 13 patients out of 37 evaluable patients (29.5% of the intent to treat population, 35.1% of the evaluable patients). In Arm 2, two patients experienced stable disease for more than 6 months with TG4010 alone (up to 211 days), in the subsequent combination with chemotherapy, one complete and one partial response were observed out of 14 evaluable patients. Arm 2 did not meet the criteria for moving forward to second stage. The median time to progression was 4.8 months for Arm 1. The median overall survival was 12.7 months for Arm 1 and 14.9 for Arm 2. One year survival rate was 53% for Arm 1 and 60% for Arm 2. TG4010 was well tolerated, mild to moderate injection site reactions, flu-like symptoms, and fatigue being the most frequent adverse reactions. A MUC1-specific cellular immune response was observed in lymphocyte samples from all responding patients evaluable for immunology. CONCLUSIONS: The combination of TG4010 with standard chemotherapy in advanced non-small cell lung cancer is feasible and shows encouraging results. A randomized study evaluating the addition of TG4010 to first line chemotherapy in this population is in progress.
Abstract: OBJECTIVE: To assess the characteristics of combination antiretroviral therapy (cART) administered concomitantly with chemotherapy and to establish prognostic determinants of patients with AIDS-related non-Hodgkin's lymphoma. METHODS: The study included 91 patients with AIDS-related non-Hodgkin's lymphoma from the Swiss HIV Cohort Study enrolled between January 1997 and October 2003, excluding lymphomas of the brain. We extracted AIDS-related non-Hodgkin's lymphoma- and HIV-specific variables at the time of lymphoma diagnosis as well as treatment changes over time from charts and from the Swiss HIV Cohort Study database. Cox regression analyses were performed to study predictors of overall and progression-free survival. RESULTS: During a median follow up of 1.6 years, 57 patients died or progressed. Thirty-five patients stopped chemotherapy prematurely (before the sixth cycle) usually due to disease progression; these patients had a shorter median survival than those who completed six or more cycles (14 versus 28 months). Interruptions of cART decreased from 35% before chemotherapy to 5% during chemotherapy. Factors associated with overall survival were CD4+ T-cell count (<100 cells/microl) (hazard ratio [HR] 2.95 [95% confidence interval (CI) 1.53-5.67], hepatitis C seropositivity (HR 2.39 [95% CI 1.01-5.67]), the international prognostic index score (HR 1.98-3.62 across categories) and Burkitt histological subtypes (HR 2.56 [95% CI 1.13-5.78]). CONCLUSIONS: Interruptions of cART were usually not induced by chemotherapy. The effect of cART interruptions on AIDS-related non-Hodgkin's lymphoma prognosis remains unclear, however, hepatitis C seropositivity emerged-as a predictor of death beyond the well-known international prognostic index score and CD4+ T-cell count.
Abstract: HISTORY AND PHYSICAL FINDINGS: A 34-year old man was referred because of persistent low-grade fever and a newly-diagnosed systolic murmur. He complained of atypical chest pain and dyspnoea on exertion for the past few weeks. STUDIES: Blood analysis revealed an elevated CRP level (67.7 mg/l) along with a hypochromic, microcytic anaemia (Hb 122 g/l). Transthoracic echocardiography showed an extracardiac tumour compressing the right ventricular outflow tract. Computed tomography (CT) localized the tumour in the anterior upper mediastinum. Subsequently, a biopsy was carried out and revealed a non-seminomatous germ-cell tumour. DIAGNOSIS, TREATMENT AND COURSE: The diagnosis having been made the patient received four cycles of chemotherapy according to the BEP-protocol (bleomycin-etoposide-cisplatin). The remaining tumour was then resected surgically. After additional cycles of chemotherapy two autologous stem cell transplantations were carried out. CONCLUSION: This patient presented initially with symptoms typical of endocarditis. However, the reason for his newly diagnosed systolic murmur and persistent fever was an extracardiac germ cell tumor compressing the right ventricular outflow tract.
Abstract: Epidermal growth factor receptor (EGFR) expression has been associated with clinical outcome in some studies of renal-cell carcinoma (RCC). We investigated the efficacy and safety of gefitinib (IRESSA), an EGFR tyrosine kinase inhibitor, in RCC patients. This phase II trial recruited 28 patients with advanced, metastatic, or relapsed RCC. Patients received oral gefitinib 500 mg/day. Objective responses (ORs) were assessed every 2 months according to RECIST. Baseline tumor biopsies were analyzed immunohistochemically for EGFR expression. At trial closure (March 2003), no ORs were seen but 14 patients (53.8%) had stable disease. At extended analysis (August 2004), median time to progression was 110 days (95% confidence interval [CI]: 55, 117); median overall survival was 303 days (95% CI 180, 444). Gefitinib was generally well tolerated. Skin rash and diarrhea were the most common drug-related adverse events (AEs) [54 and 39% of patients, respectively] and the most common drug-related grade 3/4 AEs (both 11%). The majority of tumor biopsies (91%) had > or =70% of tumor cells expressing membrane EGFR. Despite the lack of ORs in this study, disease control was observed in 53.8% of patients. Gefitinib was generally well tolerated and no unexpected drug-related AEs were observed.
Abstract: Vascular endothelial growth factor (VEGF) is a potent stimulant of angiogenesis. SU5416, is a small molecule tyrosine kinase inhibitor, and a potent inhibitor of VEGF-mediated Flk-1 receptor signaling. Intravenous agent SU5416 has shown evidence of biological activity against a variety of tumor types. The current intravenous dosing regimen is not optimal for long-term administration, which is needed for optimal efficacy. The aim of this study was to evaluate the safety profile and pharmacokinetics of a Nanocrystal Colloidal Dispersion (NCD) SU5416 formulation in humans. Patients with advanced and/or metastatic solid organ tumors were included in the trial; various SU5416 regimens were tested for tolerability, safety and were evaluated concerning pharmacokinetics. The results of this study indicate that induction of clearance after oral dosing of NCD SU5416 in humans occurs and is greater than following i.v. administration. It has been confirmed that SU5416 is a high clearance compound, also as an oral NCD formulation. The NCD formulation was well tolerated, but no effective drug serum levels could be achieved. These data help to understand the ADME (Absorption, Distribution, Metabolism, Excretion) properties of indoline chemical class compounds. The lessons learned should be applied in the development of next generation indoline anti-angiogenic and anti-tumor compounds.
Abstract: OBJECTIVE: In patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy, we compared survival in patients with treated central airway obstruction to those who did not have central airway obstruction. METHODS: One hundred forty-four patients with advanced and inoperable NSCLC were included. These consisted of 52 consecutive patients treated with therapeutic bronchoscopy plus chemotherapy with or without radiotherapy (group A) and 92 consecutive patients who did not have central airway obstruction treated with chemotherapy alone (group B). Chemotherapy consisted of cisplatin or carboplatin, and one third-generation chemotherapy agent. RESULTS: There was no significant difference in the survival of patients with and without central airway obstruction (p = 0.395). There was no influence of the histologic subtype on survival in both groups combined and also in each group separately. Median survival in patients belonging to group A was 8.4 months and those in group B was 8.2 months; 3-, 6-, and 12-month survival rates in patients in group A were 90%, 71%, and 40%, respectively, and those in group B were 82%, 63%, and 34%. CONCLUSION: Patients having advanced NSCLC with locally treated malignant central airway obstruction in combination with chemotherapy do not have a worse survival compared to those with advanced NSCLC without central airway obstruction. Therapeutic bronchoscopy should be offered to patients with NSCLC and central airway obstruction.
Abstract: The aim was to investigate the efficacy of neoadjuvant docetaxel-cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel-cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.
Abstract: The standard treatment for patients with aggressive B-cell lymphoma--particularly diffuse large-B-cell lymphoma [DLBCL)--is cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP) plus rituximab, a chimeric monoclonal antibody against the CD20 antigen. However, some patients are not fit enough to tolerate CHOP or they relapse after previous therapy with CHOP. Gemcitabine as a monotherapy is active and relatively non-toxic in the treatment of NHL. We investigated the toxicity and efficacy of a combination of gemcitabine with rituximab in a small series of elderly patients with high-grade B-cell lymphoma who had either a relapse after CHOP, or were medically unfit to tolerate CHOP as a first-line therapy. Gemcitabine was given at 1000 mg/m2/week x 3, q28 days; rituximab at 325 mg/m2/week x 4 in the first cycle, and on day 1 of all subsequent cycles. Seven patients have been treated. The median number of cycles given was 4. The major toxicity was haematologic: grade 3/4 leukocytopenia occurred in 4 patients, grade 3/4 thrombocytopenia in 3 patients. There were no episodes of clinically significant bleeding. One patient developed febrile neutropenia and died in the course of treatment; another patient developed non-Q-wave myocardial infarction possibly related to hydration pre-treatment to rituximab and erythrocyte transfusion. He recovered well after symptomatic therapy. In 7 patients, 2 complete and 3 partial remissions were achieved, with an estimated median time to progression of 12 months. This series of patients shows that the combination of gemcitabine and rituximab is feasible in this population not able to undergo standard poly-chemotherapy, shows promising activity, and merits further evaluation.
Abstract: Classical Hodgkin lymphoma (HL) is a rare complication after solid organ transplantation. We describe the first case of a patient developing CD20-positive HL after renal transplantation treated with the monoclonal antibody rituximab. Treatment with single agent rituximab led to partial remission. Subsequent combined modality treatment consisting of chemotherapy (adriamycin, bleomycin, vindesin and dacarbacin), immunotherapy (rituximab) and involved field irradiation achieved complete remission. Different therapeutic strategies in the treatment of patients developing lymphoproliferative disease - and particularly HL - after solid organ transplantation are discussed.
Abstract: STUDY OBJECTIVES: Prospective randomized trials (PRTs) have suggested that third-generation agents (eg, gemcitabine, the taxanes, and vinorelbine) improve the survival time of patients with non-small cell lung cancer (NSCLC). However, < 30% of unselected NSCLC patients fulfill the eligibility criteria of such trials. We analyzed the outcomes of all consecutive and unselected patients with inoperable NSCLC in a single institution to determine whether there was an improvement in survival over time, and if so, to identify the factors that were associated with improved survival. METHODS: A total of 230 documented patients with NSCLC at the Basel University Hospital treated after 1990 were analyzed retrospectively. Break points by year of treatment were determined using sequential Cox proportional hazards regression models and the Kaplan-Meier estimator. Multivariate analysis was used to determine which factors were associated with improved survival over time. RESULTS: A marked improvement of survival was found since the introduction of the third-generation agents in 1997. The 1-year (40% vs 19%, respectively) and 2-year survival rates (23% vs 5%, respectively, p < 0.0001) of patients in whom NSCLC had been diagnosed since 1997 were significantly better than those prior to 1997. The two cohorts did not differ significantly in sex, stage, performance status, weight loss, and lactate dehydrogenase levels. The improvement since 1997 was due to better best supportive care (p < 0.025), better first-line chemotherapy (median overall survival [OS] time (9.2 vs 6.9 months, respectively; p < 0.0016), and better second-line chemotherapy (p < 0.0001). Finally, patients who received therapy with platinum plus a third-generation drug had significantly better outcomes than those who received an older therapy regimen (median OS time, 9.3 vs 6.7 months, respectively; p < 0.027). CONCLUSIONS: A significant improvement of survival in patients with NSCLC was observed in the last decade. The results of PRTs for palliative treatment of NSCLC seem to be applicable to an unselected group of patients with NSCLC, and therapeutic nihilism in the palliative setting seems not to be justified.
Abstract: PURPOSE: To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. PATIENTS AND METHODS: Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m(2) intravenously (i.v.) day 1 with vitamin B(12), folic acid, and dexamethasone or docetaxel 75 mg/m(2) i.v. day 1 with dexamethasone every 21 days. The primary end point was overall survival. RESULTS: Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P =.105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia (40.2% v 5.3%; P <.001), febrile neutropenia (12.7% v 1.9%; P <.001), neutropenia with infections (3.3% v 0.0%; P =.004), hospitalizations for neutropenic fever (13.4% v 1.5%; P <.001), hospitalizations due to other drug related adverse events (10.5% v 6.4%; P =.092), use of granulocyte colony-stimulating factor support (19.2% v 2.6%, P <.001) and all grade alopecia (37.7% v 6.4%; P <.001) compared with patients receiving pemetrexed. CONCLUSION: Treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.
Abstract: PURPOSE: SAM486A is a new inhibitor of S-adenosyl-methionine-decarboxylase, a key enzyme for polyamine biosynthesis. It is more potent than the first generation S-adenosyl-methionine-decarboxylase inhibitor methylglyoxal bis-guanylhydrazone. This Phase IIa study reports the findings of SAM486A monotherapy in patients with refractory or relapsed non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Forty-one previously treated patients with either diffuse large cell, follicular, or peripheral T-cell NHL were treated i.v. with 100 mg/m(2) SAM486A as a daily 1-h infusion for 5 days repeated every 3 weeks. Treatment was continued for a total of eight cycles or until disease progression. RESULTS: Two patients, both with large B-cell lymphoma, showed a complete response at cycle 3 that was maintained for >or=13 and >or=28 months. Five patients had a partial response, and 3 had stable disease at last follow-up. The overall response rate (complete response plus partial response) was 18.9% for evaluable patients (7 patients). Anemia was the primary hematological toxicity and observed in 7 (17.1%) patients. Five patients experienced grade 3/4 anemia. Four patients (9.8%) experienced grade 3/4 febrile neutropenia and grade 3/4 thrombocytopenia, respectively. Nonhematological toxicities were mild to moderate in intensity. The most frequent side effects were nausea (39%), vomiting (22%), diarrhea (19.5%), asthenia (17.1%), abdominal pain (14.6%), and flushing (9.8%). CONCLUSION: SAM486A has a promising clinical activity in patients with poor prognosis NHL and manageable safety profile. To further define the role of SAM486A, in the treatment of NHL, additional studies are warranted.
Abstract: Merkel cell carcinomas (MCC) belong to the family of neuroendocrine tumors. In addition to other markers, they express somatostatin receptors. They are uncommon, highly malignant skin tumors with an aggressive clinical course. They develop in sun-exposed areas of the skin, mostly in elderly patients. In addition to frequent locoregional recurrences, there is a high incidence of distant metastases. Treatment is stage dependent and consists of operation and chemo- and/or radiotherapy, respectively. The advanced age of patients often impedes adequate therapy. (90)Y-DOTATOC is a novel radiolabeled somatostatin analogue containing the active octapeptide of somatostatin. It is very well tolerated and offers the option of treating somatostatin receptor-positive tumors by targeted radiotherapy. We report the case of an 83-year-old woman with recurrent MCC of the left cheek. The primary tumor and several relapses were treated with surgery and locoregional radiotherapy. After the 3rd relapse, she was treated 4 times with (90)Y-DOTATOC and two complete remissions were achieved. The fourth administration after the 2nd relapse was ineffective and conventional chemotherapy was started. There were no side effects of the (90)Y-DOTATOC. We conclude that due to its good tolerability, (90)Y-DOTATOC therapy should be evaluated further as a new therapy for somatostatin receptor-positive MCC.
Abstract: Toxic encephalopathy is a rarely described side effect of 5-fluorouracil which usually presents with cerebellar, neuropsychiatric, and focal neurological symptoms. Magnetic resonance imaging findings are described as patchy white matter alterations. We report the 1st case of capecitabine-induced toxic encephalopathy with epilepsy-like symptoms and diffuse white matter alterations on magnetic resonance imaging.
Abstract: In a phase II study, we assessed the toxicity and efficacy of daily low-dose cisplatin (6 mg/m2) and weekly vinorelbine (15 mg/m2) with concurrent thoracic irradiation (60 Gy) for locally advanced non-metastasized non-small-cell lung cancer. The overall response rate was 65%, complete response 12% and the median overall survival was 64 weeks.
Abstract: Vinorelbine intravenously (i.v.) demonstrated its efficacy and tolerability in advanced non-small cell lung cancer (NSCLC) patients, including elderly subjects. Since vinorelbine is now available as an oral formulation this phase II open study was designed to evaluate its activity and tolerability in advanced, elderly NSCLC patients. A total of 56 chemonaive patients were recruited from April 2001 through to March 2002. The dosage schedule, already tested in younger NSCLC patients, was 60 mg/m(2)once a week for three weeks (first cycle), followed by 80 mg/m(2) once a week until disease progression or development of unacceptable toxicity. A limited sampling scheme was used for performing pharmacokinetic analysis on 52 of 56 patients enrolled in the study. Treatment was well tolerated with grade 3/4 neutropenia in 11/17 patients (20/30%) and febrile neutropenia in 1 (2%). Six partial responses (11%) and 25 stable disease responses were recorded, with a disease control rate of 55%. Median overall survival was 8.2 months (95% Confidence Interval (CI) [6.2-11.3]). The clinical benefit response rate was 31% on 32 evaluable patients. Pharmacokinetic profiles appeared quite similar to the historical profiles recorded following i.v. administration. Oral vinorelbine appears to be a reasonable alternative to i.v. vinorelbine, both in terms of activity and tolerability, in advanced, elderly NSCLC patients.
Abstract: BACKGROUND: Some small cell lung carcinomas (SCLC) express neuro-endocrine markers, such as somatostatin receptors. Therefore, somatostatin analogues can be radio-labelled with 111Indium (Octreoscan) for diagnostic scintigraphy, or with 90Y-DOTATOC for therapeutic use. This is the first trial to assess the toxicity and efficacy of treatment with 90Y-DOTATOC in patients with Octreoscan positive SCLC. METHODS: Patients with SCLC after > or =first line chemotherapy received an Octreoscan scintigraphy and results were compared to CT scans. Patients with strong somatostatin-receptor expression were treated with 60 mCi/m2 90Y-DOTATOC i.v. every 3 weeks, for a total of three cycles. Major inclusion criteria were measurable tumour lesions, disease progression, normal creatinine clearance, PS < or = 2. RESULTS: Octreoscan scintigraphy identified 70% of all primary tumours, 87% of all mediastinal lesions, but only 26% of all extrathoracic tumour manifestations. Six patients were treated. Median number of 90Y-DOTATOC cycles was 2 (1-3). The only grade 3 toxicity was fatigue (n = 2) and dyspnea (n = 1). There were no severe renal or haematological toxicities. All six patients had tumour progression, median progression free survival (PFS) was 37.5 days (28-52) and median overall (OS) was 103.5 days (28-269). CONCLUSION: This is the first report of somatostatin-receptor targeted radiotherapy for SCLC in the literature. In contrast to well differentiated neuro-endocrine tumours, 90Y-DOTATOC seems to be inactive in SCLC.
Abstract: BACKGROUND: The MUC1 protein is a highly glycosylated mucin normally found at the apical surface of mucin-secreting epithelial cells in many types of tissues. MUC1 is expressed, but heavily underglycosylated, in different human tumors. TG4010 is a viral suspension of a recombinant vaccinia vector (MVA) containing DNA sequences coding for the human MUC1 antigen and interleukin-2 (IL-2). This product was developed for use as a vaccine in cancer patients whose tumors express the MUC1 antigen. The objective of the present study was to determine the safety of the product and to define the dose of TG4010 to be used in further clinical trials. MATERIALS AND METHODS: Thirteen patients with different solid tumors were treated by repeated intramuscular injection with increasing doses of TG4010 in two separate phase I studies, one in Europe (Basel-CR) and one in the United States (UCLA-RF): a total of 6 patients were treated at a dose of 5 x 10(6) pfu, 3 patients at 5 x 10(7) pfu, and 4 patients at 10(8) pfu. Safety, efficacy, and different immunological tests were the endpoints of the study. RESULTS: Tolerance of TG4010 was excellent, and side effects mainly consisted of injection site pain and influenza-like symptoms. There was no apparent detrimental effect of repeated injections of the vaccinia virus. Four of thirteen evaluable patients showed stabilization of their disease for 6 to 9 months. One lung cancer patient who was initially progressing after the first injections later showed a marked decrease in the size of his metastases that lasted for 14 months. Some T cell proliferative immune responses were seen in five patients. CONCLUSIONS: The administration of TG4010 was generally well tolerated in patients with metastatic tumors, and transient disease stabilization was observed in several patients, warranting further clinical studies with the product.
Abstract: PURPOSE: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non-small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. PATIENTS AND METHODS: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. RESULTS: Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0-1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P =.0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P =.0003) and complete resection (hazard ratio, 0.26; P =.0006) as strongly prognostic for increased survival. CONCLUSION: Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.
Abstract: The aim of this prospective phase II study was to evaluate the tumor response of neuroendocrine tumors to high-dose targeted irradiation with 7.4 GBq/m(2) of the radiolabeled somatostatin analog (90)Y-1,4,7,10-tetra-azacyclododecan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe-Tyr(3)-octreotide (DOTATOC). In addition, we investigated the clinical benefit of (90)Y-DOTATOC regarding the malignant carcinoid syndrome and tumor-associated pain. METHODS: Thirty-nine patients (mean age, 55 y) with progressive neuroendocrine gastroenteropancreatic and bronchial tumors were included. The treatment consisted of 4 equal intravenous injections of a total of 7.4 GBq/m(2) (90)Y-DOTATOC, administered at intervals of 6 wk. After each treatment cycle, a standardized clinical benefit assessment using the National Cancer Institute grading criteria (NCI-CTC) was performed. RESULTS: The objective response rate according to World Health Organization (WHO) criteria was 23%. For endocrine pancreatic tumors (13 patients), the objective response rate was 38%. Complete remissions were found in 5% (2/39), partial remissions in 18% (7/39), stable disease in 69% (27/39), and progressive disease in 8% (3/39). A significant reduction of clinical symptoms could be found in 83% of patients with diarrhea, in 46% of patients with flush, in 63% of patients with wheezing, and in 75% of patients with pellagra. The overall clinical benefit was 63%. All responses (both clinical benefit and WHO response) were ongoing for the duration of follow-up (median, 6 mo; range, 2-12 mo). Side effects were grade 3 or 4 (NCI-CTC) lymphocytopenia in 23%, grade 3 anemia in 3%, and grade 2 renal insufficiency in 3%. CONCLUSION: High-dose targeted radiotherapy with 7.4 GBq/m(2) (90)Y-DOTATOC is a well-tolerated treatment for neuroendocrine tumors, with remarkable clinical benefit and objective response.
Abstract: PURPOSE: The aim of this phase II study was to evaluate the tumour response of neuroendocrine tumours to targeted irradiation with the radiolabelled somatostatin analogue 90Y-DOTATOC. In addition, the palliative effect of 90Y-DOTATOC treatment on the malignant carcinoid syndrome and tumour-associated pain was investigated. PATIENTS AND METHODS: Forty-one patients (mean age 53 years) with neuroendocrine gastroenteropancreatic and bronchial tumours were included. Eighty-two percent of the patients had therapy resistant and progressive disease. The treatment consisted of four intravenous injections of a total of 6000 MBq/m2 90Y-DOTATOC, administered at intervals of six weeks. RESULTS: The overall response rate was 24%. For endocrine pancreatic tumours it was 36%. Complete remissions (CR) were found in 2% (1 of 41), partial remissions (PR) in 22% (9 of 41), minor response in 12% (5 of 41), stable disease (SD) in 49% (20 of 41) and progressive disease (PD) in 15% (6 of 41). The median follow up was 15 months (range 1 month to 36 months). The median duration of response has not been reached at 26 months. The two-year survival time was 76 +/- 16%. Eighty-three percent of the patients suffering from the malignant carcinoid syndrome achieved a significant reduction of symptoms. The treatment was well tolerated. A reduction of pain score was observed in all patients (5 of 41) with morphine dependent tumour-associated pain. Side effects included grade III (NCIGC) pancytopenia in 5%, and vomiting shortly after injection in 23%. No grade III-IV renal toxicity was observed. CONCLUSION: Targeted radiotherapy with 90Y-DOTATOC is a novel, well-tolerated treatment for neuroendocrine tumours with a remarkable objective response rate, survival time, and symptomatic response.
Abstract: AIM: Differentiated thyroid carcinomas (DTC) and medullary thyroid carcinomas (MTC) overexpress somatostatin receptor subtypes (sstr). The aim of this pilot study was to evaluate the tumour response of thyroid carcinomas to targeted irradiation with the radiolabelled somatostatin analogue [90Y]-1,4,7,10-tetra-azacyclododecan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe1-Tyr3-octreotide ([90Y]-DOTA-D-Phe1-Tyr3-octreotide, or 90Y-DOTATOC) which has a high affinity to subtype 2 and a low affinity to subtype 5. It shows no affinity to sstr1, sstr3 and sstr4. PATIENTS AND METHODS: Twenty patients (mean age 58 years; 50% female, 50% male) with thyroid cancer were included (medullary thyroid cancer (MTC), 12 patients; differentiated thyroid cancer (DTC), seven patients; papillar carcinoma (PC), four patients; follicular carcinoma (FC), three patients; anaplastic carcinoma (AC), one patient). All patients had been therapy resistant and had progressive disease before 90Y-DOTATOC therapy. The dose applied was between totals of 1700 MBq x m(-2) to 7400 MBq x m(-2) 90Y-DOTATOC, administered in one to four injections at intervals of 6 weeks. In the case of tumour progression under therapy, treatment was terminated. RESULTS: The overall antitumour effect (objective response and stable disease) was 35%; in MTC 42%, in DTC 29%, and in AC 0%. The objective overall response rate was 0%. A stable disease was achieved in 35% (7/20), and progressive disease was found in 65% (13/20). The median time to progression was 8 months, with a median follow-up of 15 months. The treatment was very well tolerated. There were no grade III/IV haematological or renal toxicities. CONCLUSION: Targeted radiotherapy using 90Y-DOTATOC is able to stop tumour progression in a small number of patients and therefore may be an alternative treatment option for resistant disease. More significant tumour responses in thyroid and medullary thyroid cancer may be obtained by using radiopeptides with pan-somatostatin characteristics.
Abstract: Sixty-one consecutive patients with locally advanced inoperable non-small-cell lung cancer were treated with chemoradiation with 60 Gy and concomitant daily low-dose cisplatin (6 mg/m(2)) in a single uninterrupted course. Toxicity was mild, 80% of patients were treated as outpatients. The median survival of 70 weeks compares favorably to the literature.
Abstract: The predictive value of daily C-reactive protein (CRP) monitoring to distinguish causes of fever in neutropenic patients was studied retrospectively. A total of 143 fever episodes during 113 consecutive hospitalizations were studied in 71 patients who had been referred for chemotherapy or haemopoietic stem cell transplantation (HSCT). There were, on average, 1.3 fever episodes per hospital stay, attributed to: infection (55, 27 invasive bacterial, 5 fungal, 3 viral and 20 probable infections); acute graft vs host disease (GvHD) (20); drugs (22); transfusions (7); and not attributable (39). 130 (91%) fever episodes were accompanied by a rise in CRP, 6 (4%) episodes were fatal. Maximal CRP levels (CRPmax) and maximal temperature (Tmax) were higher in invasive bacterial infections than in aGvHD and higher in aGvHD than in drug- or transfusion-related fever (p < 0.0001). Temperature and CRP rose in parallel. A total of 16 patients developed grade II-IV aGvHD by day 11 (9-21) (median, range) after allogeneic HSCT. Acute GvHD was preceded by fever for 3 d (1-7), and by CRP increase for 5 d (0-15) (p < 0.0001). CRP monitoring may be useful to distinguish between causes of fever. Very high CRP levels tend to be associated with invasive bacterial infections. CRP is not an early warning sign. An increase in CRP and fever may precede other clinical manifestations of aGvHD.
Abstract: Induction of pleurodesis offers benefit for patients with metastatic tumors and symptomatic malignant pleural effusions, but the best method for achieving this is still unknown. In this prospective, randomized comparison of two well-established pleurodesis procedures, 36 patients with malignant pleural effusions, expanded lungs after drainage, and expected survival of > 1 mo received either bleomycin instillation (60E) via a small-bore thoracostomy tube or thoracoscopic talc poudrage (5 g) under local anesthesia. Efficacy, safety, and cost could be evaluated for 32 treatments (17 bleomycin, 15 talc) in 31 patients. Recurrence rates of effusion with bleomycin and talc poudrage after 30 d were 41% and 13% (p = 0.12), respectively, those after 90 d were 59% and 13%, respectively (p = 0.01), and those after 180 d were 65% and 13% (p = 0.005), respectively. Neither procedure showed any major adverse effect, and both were equally well tolerated. Cost estimation favored thoracoscopic talc poudrage, both for the initial hospitalization and with regard to recurrences. In conclusion, thoracoscopic talc pleurodesis under local anesthesia is superior to bleomycin instillation for pleurodesis in cases of malignant pleural effusion.
Abstract: The potential of recombinant human (rh)Flt3 ligand (FL), alone or in combination with other recombinant growth factors, to mobilize peripheral blood precursor cells (PBPCs) was examined in an animal model. Adult outbred New Zealand White rabbits received subcutaneous injections daily for 14 days in a standardized protocol; whole blood cell counts and colony-forming unit-granulocyte/macrophage (CFU-GM) colonies were measured 3 times weekly during the injection period and for an additional observation period of 14 days. Two animals in each group were treated as follows: 200 or 500 microg/kg FL, 10 microg/kg granulocyte colony-stimulating factor (G-CSF), 10 or 75 microg/kg stem cell factor (SCF), 10 microg/kg G-CSF + 500 microg/kg FL, 10 microg/kg G-CSF + 75 microg/kg SCF + 500 microg/kg FL. Both G-CSF and FL induced a sustained and dose-dependent increase in the leukocyte count to a maximum of 5-fold. They were additive in combination, leading to a tenfold increase in white blood cell counts. No consistent pattern was observed for platelet counts or red blood cells. No toxic side effects were seen. Both G-CSF and FL mobilized CFU-GM in a dose-dependent fashion to a 59-fold increase for G-CSF and 116-fold for FL. Maximum mobilization occurred on day 4 with G-CSF and on day 11 with FL. G-CSF + FL in combination acted synergistically, inducing a 503-fold increase of CFU-GM over baseline. The addition of SCF to this combination did not alter leukocyte counts or CFU-GM mobilization. Our results indicate that FL is a potent and safe agent for the mobilization of PB-PCs and is synergistic with G-CSF.
Abstract: Cytokine receptors activate multiple signal transduction pathways, resulting in the induction of specific target genes. We have recently identified a hematopoietic cell-specific immediate-early gene, DUB-1, that encodes a growth-regulatory deubiquitinating enzyme. The DUB-1 gene contains a 112-bp enhancer element that is specifically induced by the beta c subunit of the interleukin-3 (IL-3) receptor. To investigate the mechanism of DUB-1 induction, we examined the effects of dominant-negative forms of JAK kinases, STAT transcription factors, and Raf-1 in transient transfection assays. In Ba/F3 cells, IL-3 induced a dose-dependent activation of DUB-1-luciferase (luc) and GAS-luc reporter constructs. A dominant-negative form of JAK2 (truncated at amino acid 829) inhibited the induction of DUB-1-luc and GAS-luc by IL-3. A dominant-negative form of STAT5 (truncated at amino acid 650) inhibited the induction of GAS-luc but not DUB-1-luc. A dominant-negative form of Raf-1 inhibited the induction of DUB-1-luc but had no effect on the induction of GAS-luc by IL-3. The requirement for JAK2 in the stimulation of the DUB-1 enhancer was further supported by the suppression of DUB-1 induction in Ba/F3 cells stably expressing the dominant-negative JAK2 polypeptide. We hypothesize that IL-3 activates a JAK2/Raf-1 signaling pathway that is required for DUB-1 induction and is independent of STAT5.
Abstract: Ectopic expression of the erythropoietin receptor (EpoR) in the interleukin-3 (IL-3)-dependent cell line Ba/F3 results in growth and partial erythroid differentiation in Epo. In contrast, introduction and activation of the interleukin-5 receptor (IL-5R) or of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) results in proliferation only. As this effect is specific to the EpoR, the role of its extracellular or cytoplasmic domain in differentiation was tested after construction of two chimeric receptors. One receptor contained the extracellular domain of EpoR fused to the endodomain of IL-3R beta-chain (E/beta), while the other contained the EpoR cytoplasmic region fused to the extracellular domain of GM-CSFR alpha-chain (GMER). Surprisingly, both receptors induced differentiation ruling out a strict specificity of the extracellular or cytoplasmic region of EpoR in this process. Instead the ability to signal differentiation correlated with structural features shared by the EpoR, GMER, and E/beta receptors. Dimerization of all three receptors results in the pairing of two signal transducing chains in the cytoplasm, in contrast to the mitogenic receptors IL-3R, IL-5R, GM-CSFR, which assemble as alphabeta heterodimers. Two new chimeric receptors that fulfilled the structural requirement exemplified by EpoR, but lacked any part of EpoR, were designed to consolidate this model. They consisted of the ectodomains of the GMR-alpha and IL-5R alpha, respectively, fused to the endodomain of IL-3R beta-chain. Both receptors were as effective as EpoR in signaling differentiation in response to their cognate ligand. Another property of receptors fulfilling these structural requirements is that they cause a marked delay in signal transducers and activators of transcription 5 (STAT5) activation on ligand stimulation. Taken together our studies show that structural assembly of receptors dictates their potential to signal erythroid differentiation in Ba/F3 cells, that differentiation can take place in the absence of Epo and that a delay in STAT5 activation is highly predictive of this process.
Abstract: A 39-year-old patient with severe aplastic anemia (AA), resistant to therapy, received recombinant human IL-3 (rhIL-3) on a phase I/II trial. During treatment she developed disseminated skin lesions, suggestive of vasculitis, and severe progressive peripheral neuropathy culminating in complete paralysis. She died 25 days after beginning treatment from profuse bleeding. On autopsy, evidence of vascular leaks with widespread bleeding and extensive hemorrhagic involvement of peripheral nerves was found. An additional feature was massive reactive erythrophagocytosis in lymph nodes, spleen and bone marrow. The coincidence between rhIL-3 administration and the dramatic events suggest a causal relation. As a possible pathogenic mechanism, an rhIL-3 induced excessive stimulation of macrophages and production of secondary cytokines such as tumor necrosis factor (TNF) is suggested. TNF is considered as a major factor in the development of both a vascular leak and reactive erythrophagocytosis. This case report can be regarded as an example of the possible unusual pathologic phenomena we may expect to see in the near future with increasing use of growth factors.
Abstract: Cytokines regulate cell growth and differentiation by inducing the expression of specific target genes. We have recently isolated a cytokine-inducible, immediate-early cDNA, DUB-1, that encodes a deubiquitinating enzyme. The DUB-1 mRNA was specifically induced by the receptors for interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-5, suggesting a role for the beta common (betac subunit known to be shared by these receptors. In order to identify the mechanism of cytokine induction, we isolated a murine genomic clone for DUB-1 containing a functional promoter region. The DUB-1 gene contains two exons, and the nucleotide sequence of its coding region is identical to the sequence of DUB-1 cDNA. Various regions of the 5' flanking region of the DUB-1 gene were assayed for cytokine-inducible activity. An enhancer region that retains the beta c-specific inducible activity of the DUB-1 gene was identified. Enhancer activity was localized to a 112-bp fragment located 1.4 kb upstream from the ATG start codon. Gel mobility shift assays revealed two specific protein complexes that bound to this minimal enhancer region. One complex was induced by betac signaling, while the other was noninducible. Finally, the membrane-proximal region of human betac was required for DUB-1 induction. In conclusion, DUB-1 is the first example of an immediate-early gene that is induced by a specific subunit of a cytokine receptor. Further analysis of the DUB-1 enhancer element may reveal specific determinants of a betac-specific signaling pathway.
Abstract: Mobilized peripheral blood precursor cells (PBPC) are used with increasing frequency to restore autologous hematopoiesis following high-dose radio-chemotherapy. The success of this method has aroused interest in the use of mobilized PBPC for allogeneic transplants. This approach would eliminate the need for marrow aspiration and general anesthesia. In this project we tested the feasibility of allogeneic histoincompatible PBPC transplants in rabbits. Adult outbred Red Burgundy rabbits were used as donors, histoincompatible New Zealand White rabbits of the opposite sex as recipients. One individual donor was used for one individual recipient. Conditioning consisted of 10 Gy total body irradiation (TBI). Donor animals were pre-treated with recombinant human granulocyte colony-stimulating factor (rh G-CSF) given s.c. at 10 micrograms/kg daily. Three schedules of PBPC collection and reinfusion were tested in 3 groups of animals, each consisting of 5 donor recipient pairs: (A) PBPC were collected either on days -2, -1 and 0, and infused at once after TBI on day 0; (B) collected and infused on days 0, +2, +4, +7, +9, and +11; (C) collected on 3 consecutive days, cryopreserved for 1 month and infused on day 0 followed by 3 fresh donations on days +4, +8 and +11. The median amount of blood processed from donor animals was 470 ml (312-602) containing about 10 x 10(8) (5-71 x 10(8)) nucleated cells. Recipient animals received a median of 2.7 x 10(8) cells/kg equivalent to 9.6 x 10(4) colony-forming units granulocyte-macrophages (CFU-GM)/kg (data derived from Group C of the animals).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The goal of this prospective randomized single-center study was the comparison of safety and efficacy of high-dose oral/intravenous fluconazole (400 mg daily) (group A) with oral nystatin plus miconazole inhalations (group B) in the prevention of fungal infections on a hemato-oncological isolation Ward. Of 157 patients admitted to the isolation ward during the study period only 90 (57%) were eligible for randomization; 22 (14%) had a fungal infection at admission. Of the 90 randomized patients, 89 were evaluable, 43 in group A and 46 in group B. The age, sex, diagnosis, planned therapy and risk factors for fungal infections at admission as well as the duration of neutropenia were in the same proportions in both groups. Oral thrush and mucocutaneous candidiasis were prevented in all patients of both groups, and 29 patients (32%: 17 in group A, 12 in group B) were discharged after successful prophylaxis (NS). Empiric amphotericin B was given according to predetermined criteria to 45 patients (51%: 23 group A, 22 group B; NS). Fluconazole significantly delayed the time before the start of intravenous amphotericin B. It was begun after a median of 10 days (0-45 days, range) of neutropenia below 0.5 x 10(9) granulocytes/l in group A and 7.5 days (0-26, range) in group B (P < 0.05). The duration of successful prophylaxis was significantly longer in group A (26 days median) than in group B (21 days, median) (P < 0.05). Systematic fungal infection was documented in 3 patients (1 group A, 2 group B; NS).
Abstract: We report the case of a 70-year-old patient with B-cell chronic lymphocytic leukemia. During therapy with the new purine analog 2-chloro-deoxyadenosine (2-CDA) the patient developed Pneumocystis carinii pneumonia (PCP). Although the mechanism of action of 2-CDA suggests the incidence of opportunistic infections and therefore pneumocystis pneumonia, this is the first case of PCP among 140 patients of the Swiss study of 2-CDA. The mechanism of action of 2-CDA is described and the occurrence of PCP among patients without acquired immunodeficiency syndrome is discussed.
Abstract: The murine interleukin-3 receptor beta-chain genes, IL-3R beta IL-3 and IL-3R beta c, encode the signal transducing chains of the high affinity receptors for IL-3 and IL-3, GM-CSF and IL-5 respectively. Little is known about the regulation of their expression. To enable the study of the promotors of IL-3R beta IL-3 and IL-3R beta c, we have characterized their respective 5' untranslated regions using a modified 5' RACE protocol. Four classes of alternatively spliced transcripts were isolated that initiate in a 400 nt region upstream from a previously reported start site(1). The initially reported partial IL-3R beta IL-3 clone belongs to the first class of transcripts(2). The second class starts in the middle of an intron as defined by the first class. The 3rd and 4th class establish 2 novel splice donor sites. These results were confirmed by RNAse-protection assay. The complex organization as evident from our data establishes an experimental framework for future experiments aimed at the study of the promoters for the murine IL-3R beta genes.
Abstract: After organ transplantation, life-long immunosuppression is mandatory to prevent rejection. This is not the case after allogeneic bone marrow transplantation (BMT). The mechanisms of tolerance are little understood and there is little data about the required duration of immunosuppression. In a retrospective study we analyzed the use of cyclosporine A (CyA) treatment in all BMT patients who where transplanted in Basel from 1979 to 1991. 243 patients with a median age of 26 (2-49) years received CyA to prevent graft-versus-host-disease (GvHD) and rejection. 206 patients had leukemia, 26 severe aplastic anemia and 10 a lymphoproliferative disorder. All were treated according to a common CyA regimen with initial parenteral administration followed by oral treatment for a year; after 1988 treatment duration was reduced to 6 months. Drug dosage was adjusted according to clinical symptoms, plasma levels and toxicity. At relapse of the original disease CyA was always withdrawn. Three months after BMT 96% were still on CyA. After 6 months 79%, after 1 year 61%, after 2 years 29%, after 3 years 18%, after 4 years 15%, after 5 years 8% and after 8 years 2% of patients were still taking CyA. All 20 patients who are still alive 10 years after BMT are off CyA. CyA was administered parenterally for a median of 31 (5-147) days. Oral treatment started at day 25 (4-28). The oral dose was reduced 5 (1-20) times, increased once (1-75) and finally discontinued after a median time lapse of 1 year (14d-8y).(ABSTRACT TRUNCATED AT 250 WORDS)
