Filamentation of a relativistic proton bunch in plasma.

We show in experiments that a long, underdense, relativistic proton bunch propagating in plasma undergoes the oblique instability, which we observe as filamentation. We determine a threshold value for the ratio between the bunch transverse size and plasma skin depth for the instability to occur. At the threshold, the outcome of the experiment alternates between filamentation and self-modulation instability (evidenced by longitudinal modulation into microbunches). Time-resolved images of the bunch density distribution reveal that filamentation grows to an observable level late along the bunch, confirming the spatiotemporal nature of the instability. We provide a rough estimate of the amplitude of the magnetic field generated in the plasma by the instability and show that the associated magnetic energy increases with plasma density.

Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL).

BACKGROUND: Bevacizumab, the anti-vascular endothelial growth factor agent, provides clinical benefit when combined with platinum-based chemotherapy in first-line advanced non-small-cell lung cancer. We report the final overall survival (OS) analysis from the phase III AVAiL trial. PATIENTS AND METHODS: Patients (n = 1043) received cisplatin 80 mg/m(2) and gemcitabine 1250 mg/m(2) for up to six cycles plus bevacizumab 7.5 mg/kg (n = 345), bevacizumab 15 mg/kg (n = 351) or placebo (n = 347) every 3 weeks until progression. Primary end point was progression-free survival (PFS); OS was a secondary end point. RESULTS: Significant PFS prolongation with bevacizumab compared with placebo was maintained with longer follow-up {hazard ratio (HR) [95% confidence interval (CI)] 0.75 (0.64-0.87), P = 0.0003 and 0.85 (0.73-1.00), P = 0.0456} for the 7.5 and 15 mg/kg groups, respectively. Median OS was >13 months in all treatment groups; nevertheless, OS was not significantly increased with bevacizumab [HR (95% CI) 0.93 (0.78-1.11), P = 0.420 and 1.03 (0.86-1.23), P = 0.761] for the 7.5 and 15 mg/kg groups, respectively, versus placebo. Most patients ( approximately 62%) received multiple lines of poststudy treatment. Updated safety results are consistent with those previously reported. CONCLUSIONS: Final analysis of AVAiL confirms the efficacy of bevacizumab when combined with cisplatin-gemcitabine. The PFS benefit did not translate into a significant OS benefit, possibly due to high use of efficacious second-line therapies.

Phase II and pharmacologic study of weekly oral paclitaxel plus cyclosporine in patients with advanced non-small-cell lung cancer.

PURPOSE: A phase II study was performed to assess the efficacy and toxicity of oral cyclosporine (CsA) plus paclitaxel in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive or previously treated patients (one regimen) with measurable disease and World Health Organization performance status

Antifungal prophylaxis with itraconazole in neutropenic patients with acute leukaemia.

The efficacy of antifungal prophylaxis with itraconazole capsules and its serum concentrations were evaluated in patients intensively treated for acute leukaemia. A consecutive group of patients without systemic antifungal prophylaxis (January 1993 to August 1994, period 1) was compared with another consecutive group of patients (period 2) who received itraconazole capsules (September 1994 to April 1995 400 mg/day, from May 1995 onwards 600 mg/day). All patients admitted with acute leukaemia and standard or high-dose chemotherapy were included into the study. Clinical endpoint was mortality from proven fungal infection. Seventy-six patients and 148 courses of cytotoxic chemotherapy were analysed in the control group as well as 47 patients and 112 treatment courses in the intervention group. Antifungal prophylaxis led to a significant decrease of mortality from invasive fungal infections (8.8%-0.9%, P = 0.005). The median trough concentration of itraconazole of all measurements was 520 ng/ml (range 230-793) in patients who received 400 mg/day and 760 ng/ml (370-1200) in patients receiving a dosage of 600 mg/day (P = 0.002). These findings suggest that itraconazole is an effective drug for antifungal prophylaxis but also that a considerable number of patients do not reach the desired trough levels (>500 ng/ml) with itraconazole capsules.

Oral idarubicin, dexamethasone and vincristine (VID) in the treatment of multiple myeloma.

In order to replace the central venous line necessary for continuous infusion of vincristine and doxorubicin with high-dose dexamethasone (VAD) and to avoid hospitalization, we evaluated the efficacy and toxicity of oral idarubicin, vincristine and dexamethasone (VID) in patients with multiple myeloma. Vincristine (1.6 mg/m2, max 2 mg) was given as a bolus injection on day 1. Idarubicin was given in capsules 10 mg/m2/day for days 1-4 with an intraindividual dose escalation, 40 mg dexamethasone were given on days 1-4, 9-12, 17-20. Treatment cycles were repeated every 28 days. At this interim analysis, 53 patients have been entered into the ongoing trial; 46 patients are evaluable for toxicity. The median age was 60 years (interquartile range, 52-65). 46% were primary or secondary refractory, 20% had previously been treated with VAD and 30% had previously untreated disease, 4% had two or more relapses. Four patients died within 2 months from entry and were considered as early deaths (8.7%). 45% of the 42 patients evaluable for efficacy achieved a partial remission and 26% a minor remission. The median reduction of the M-component was 43% (interquartile range, 25-64%). VID is an effective and convenient alternative to VAD even in relapsed or refractory patients.

Clinical significance of serum S100 in metastatic malignant melanoma.

The clinical significance of serum S100 was assessed in comparison to neuron-specific enolase (NSE) in 126 patients with malignant melanoma: 80 patients with clinical stage I/II, 23 patients with stage III and 23 patients with stage IV according to the criteria of the American Joint Committee on Cancer (AJCC). Using cut-off values of 0.15 microgram/l for S100 and 12.5 micrograms/l for NSE, the sensitivity was found to be 1.3% (1/80) for S100 and 8.75% (7/80) for NSE in patients with stage I/II, 8.7% (2/23) for S100 and 13% (8/23) for NSE in patients with stage III, and 73.9% (17/23) for S100 and 34.8% (8/23) for NSE in patients with stage IV disease (P < 0.05). In 6 patients with stage III/IV tumours, serial measurement of serum S100 and NSE was performed. A rise of serum S100 indicated progression of the disease; a decline indicated response to treatment. Our preliminary results support the value of serum S100 as an adjunct to the clinical staging and monitoring of metastatic malignant melanoma.

Clinical significance of serum S100 in metastatic malignant melanoma.

The clinical significance of serum S100 was assessed in comparison to neuron-specific enolase (NSE) in 126 patients with malignant melanoma: 80 patients with clinical stage I/II, 23 patients with stage III and 23 patients with stage IV according to the criteria of the American Joint Committee on Cancer (AJCC). Using cut-off values of 0.15 micrograms/l for S100 and 12.5 micrograms/l for NSE, the sensitivity was found to be 1.3% (1/80) for S100 and 8.75% (7/80) for NSE in patients with stage I/II, 8.7% (2/23) for S100 and 13% (8/23) for NSE in patients with stage III, and 73.9% (17/23) for S100 and 34.8% (8/23) for NSE in patients with stage IV disease (P < 0.05). In 6 patients with stage III/IV tumours, serial measurement of serum S100 and NSE was performed. A rise of serum S100 indicated progression of the disease; a decline indicated response to treatment. Our preliminary results support the value of serum S100 as an adjunct to the clinical staging and monitoring of metastatic malignant melanoma.

Reduced-dose cladribine (2-CdA) plus mitoxantrone is effective in the treatment of mantle-cell and low-grade non-Hodgkin's lymphoma.

Cladribine (2-chlorodeoxyadenosine) (2-CdA) has been shown to be effective in mantle-cell (MCL) and low-grade lymphomas (lgNHL). The aim of this multicentre study was to evaluate the rate and duration of remissions and to examine the toxicity of the combination of reduced-dose 2-CdA and mitoxantrone (CdM) in MCL and lgNHL as first-line therapy or for patients in their relapse. A total of 285 courses, median of five courses per patient, were administered to 62 evaluable patients (42 previously untreated, 20 relapsed) with 5 mg/m(2) 2-CdA per day given as an intermittent 2-h infusion over 3 consecutive days combined with 8 mg/m(2) mitoxantrone on days 1 and 2 for the untreated patients or 12 mg/m(2) mitoxantrone on day 1 for patients in their first relapse for a maximum of six cycles every four weeks. 32 follicular, 18 MCL, 9 lymphoplasmacytoid, 2 marginal zone and 1 unclassified low-grade B-cell lymphoma were involved in the study. 56 of the 62 patients responded to CdM resulting in an overall response rate of 90% (95% confidence interval (CI), 80-96%) with a complete remission (CR) rate of 44% (95% CI, 31-57%) and a median duration of remission of 25 months (range 6-42+). The overall survival rate at 48 months was 80%. For 42 previously untreated patients, the overall response rate was 88% (95% CI, 74-96%) with a CR rate of 38% (95% CI, 24-54%), whereas the response rate for the group of 20 previously treated patients was similar with a 95% overall response (95% CI, 75-100%) and a CR rate of 55% (95% CI, 32-77%). In MCL, CdM showed a high activity, achieving a response rate of 100% (95% CI, 81-100%) with a CR rate of 44% and a median duration of remission of 24 months (range 6-35+). Myelosuppression was the major toxicity with 23% grade 3 granulocytopenia and 50% grade 4. Thrombocytopenia was less commonly observed, with only 8% grades 3 and 4. These results demonstrate that the combination of reduced-dose 2-CdA and mitoxantrone is a highly active regimen in the treatment of low-grade lymphomas, and in particular of MCL.

Are children born to young mothers at increased risk of maltreatment?

Previous case-control or cross-sectional studies have provided conflicting results about whether children of teenage mothers are at increased risk of maltreatment compared with children of older mothers. This study is the first to examine this question using a longitudinal, cohort design and the first to address important methodologic issues such as detection bias. Subjects were 219 consecutive index children born to inner-city women who were 18 years or younger and 219 sociodemographically similar comparison children born to women 19 years or older. Data were collected by reviewing the medical records of each child through the fifth birthday. Three outcomes were examined: maltreatment, poor growth, and a change in the child's primary caretaker. Maltreatment was ascertained by having two experts, one of whom was blind to the group status, review each injury documented in the records. Predefined criteria were used to distinguish unintentional injuries from maltreatment (abuse, neglect, or sexual abuse). Maltreatment occurred more frequently in the children of young mothers (12.8%) than in the comparison group (6.4%) (risk ratio [RR] = 2.00; 95% confidence interval [CI] = 1.17, 3.64). Poor growth, defined by growth criteria, occurred in 6.9% of the index group and in 4.1% of comparison children (RR = 1.67; 95% CI = 0.75, 3.73). A change in the child's primary caretaker, either because of placement in foster care or because the mother left the home, occurred in 12.8% of the index group and in 3.2% in comparison children (RR = 4.00; 95% CI = 1.80, 8.87).(ABSTRACT TRUNCATED AT 250 WORDS)

Philadelphia chromosome-negative acute hematopoietic malignancy: ultrastructural, cytochemical and immunocytochemical evidence of mast cell and basophil differentiation.

We describe a patient with fever and multiple osteolytic bone lesions accompanied by hypercalcemia, a duodenal ulcer, anemia, and thrombocytopenia. Bone marrow showed a dense infiltration by abnormal cells characterized by small basophil granula, erythrophagocytosis and nuclear atypia. These cells were positive for toluidine blue and partly for myeloperoxidase and chloroacetate esterase, expressed myeloid differentiation markers, and exhibited multiple numerical and structural chromosome aberrations. Molecular genetic analysis showed no breakpoint cluster region rearrangement. Electron microscopy demonstrated granula both of basophil and mast cell type. Concluding, in this patient an acute hematopoietic malignancy with many features of malignant mastocytosis but also with signs of a basophil differentiation. This is further support for a hematopoietic stem cell origin of human mast cells.

Diagnostic significance of carcinoembryonic antigen in the differential diagnosis of malignant mesothelioma.

The histologic and cytologic distinction of malignant mesothelioma from carcinomas metastatic to the pleura or peritoneum is often problematic. For this reason immunologic methods are being increasingly used as diagnostic adjuncts. This review summarizes 40 studies on the expression of carcinoembryonic antigen in mesotheliomas and in lung and other carcinomas involving the pleura or peritoneum. Carcinoembryonic antigen was identified immunohistochemically in 11% of mesotheliomas and in 84% of carcinomas examined and immunocytochemically (in serous effusions) in 4% and 58%, respectively. In serum and in pleural or ascitic fluid, significantly elevated levels of carcinoembryonic antigen are commonly associated with (lung) carcinomas but rarely with mesotheliomas. Thus, together with identification of the antigen in serum, pleural fluid, or ascitic fluid, immunohistochemical and immunocytochemical techniques for detecting carcinoembryonic antigen provide a valuable aid for distinguishing malignant mesothelioma from metastatic carcinomas.

Tumour associated antigens in diagnosis of serous effusions.

The use of tumour associated antigens in the diagnosis of serous effusions was studied in 76 patients with benign and 200 patients with malignant disease. Tissue polypeptide antigen (TPA), alpha fetoprotein, and CA 125 were found to be of little value. At cut off points of 3 ng/ml, 10 U/ml, and 30 U/ml, respectively, carcinoembryonic antigen (CEA), biliary glycoprotein I (BGP I), and CA 19-9 discriminated between benign and malignant serous effusions with a sensitivity of between 24% and 67%. The immunocytochemical staining for these markers resulted in malignant cells being detected in 18% to 33% of cases. Various combinations of conventional cytological examination, effusion fluid tumour marker determination, and immunocytochemical analysis identified malignant cells in serous effusions in up to 72% of cases; conventional cytology alone detected tumour cells in only 30%.

A case of malignant mastocytosis with near-haploid, near-diploid, and polyploid cells in the bone marrow.

Chromosome analysis in bone marrow cells of a 41-year-old woman with malignant mastocytosis (MM) revealed near-haploid (59%), near-diploid (36%), and polyploid (5%) cells. Near-haploid cells had a mode of 25 chromosomes with variable disomy and nullisomy of particular chromosomes. Disomy for chromosome 19 and chromosome 20 were most common. A 17p+ marker was observed in all cells. Other structural chromosomal changes were dicentrics, ring chromosomes, translocations, and double minutes. The modal chromosome number in near-diploid cells was 46 with a range of 41-52. The majority of cells with 46 chromosomes were pseudodiploid and only a few had a normal female karyotype. As in near-haploid cells, various structural chromosomal changes were found. The 17p+ marker was also present in occasional cells suggesting a relationship between the two tumor cell populations. Chromosome numbers in polyploid cells ranged from 70 to about 600. Identical copies of dicentrics or markers were identified in some cells.

Value of human chorionic gonadotropin compared to CEA in discriminating benign from malignant effusions.

Human chorionic gonadotropin (HCG) is expressed in germ cell tumors and urothelial, breast, lung and colon cancers. The aim of the study was to investigate if the determination of HCG in comparison with CEA is able to discriminate between malignant and benign effusions. Effusion and partially serum samples of 61 patients with benign (g.i., heart/kidney isnuff.) and 116 patients with malignant diseases (g.i., gynec., lung, misc., CUP) were investigated. HCG was specifically determined by an IRMA using 2 monoclonal antibodies, CEA by a conventional double Ab RIA. Cytological staining was preformed using the Pappenheim-method on cytospin preparations. Significant differences (p < 0.001) were found for HCG between benign and malignant ascitic effusions with the best discrimination at 5 IU/l (ROC) and an overall sensitivity of 31.3% (spec. vs benign eff. 93.4%) increasing in subgroups from hematol. (5.8%) < misc. (31.3%) < gynec. (32.1%) < g.i. (36%) < lung (38.1%) to CUP (50%). CEA also showed significant differences between benign and malignant total and ascitic effusions, and weaker for the pleural subgroup (cutoff 9 ng/ml) with a total sensitivity of 44.6% (sp = 100%) increasing from misc. (30.8%) < lung (47.1%) < CUP (50%) < gynec. (60%) < g.i. (60.9%). Comparative cytology and TM determinations increased the positiverate of cytology (45.2%) to 58.3% for either cytology or HCG positive cases, or to 61.6% for either cytology or CEA positive cases. For the combined determination of cytologoy and HCG and CEA, the overall TM positive rate for 33 cytology-pos. cases was 78.8%, but in 40 cytology-negative cases 37.5% for TM positive cases. In conclusion HCG is useful in ascitic > pleural effusions with high specificity (90% at 5 IU/l) but low sensitivity of 31% increasing in g.i., lung and gynecologic cases, CEA a more general TM with higher sensitivity of 45% increasing in g.i., gynecologic and lung cases (sp. 100% at 9 ng/ml) both adding significantly to cytology-negative effusions.

A summer vacation from diabetes: evidence from a clinical trial.

PURPOSE: This study examined the metabolic trend and factors associated with an unexpected rise in HbA1c levels during the summer, with a return to baseline when school resumed, in 40 intensively treated adolescents with type 1 diabetes. METHODS: Psychosocial data were collected using a variety of diabetes evaluation instruments. HbA1c was measured monthly. RESULTS: HbA1c values increased by a mean of .73% from May to July and decreased by a mean of .75% from August to October. Lack of consistency in summer routines compared with school days was associated with a worsening in metabolic control during the summer months. Other factors associated with the summer increase in HbA1c included lower guidance scores on the Diabetes Family Behavior Scale, and higher impact and worry scores on the Diabetes Quality of Life for Youth Scale. CONCLUSIONS: Interviews suggested that teenagers need to take a vacation from intensive diabetes care during the summer.

Factors associated with vaginal yeast infections in HIV-positive women.

To better understand factors associated with symptomatic and asymptomatic vulvovaginal candidiasis, including the role of immune compromise and patient self-report, a cross-sectional analysis of factors associated with the isolation of yeast from vaginal swabs and clinical diagnosis of Candida vaginitis (CV) among 184 HIV-infected women was conducted. Sixty-four (35%) of the women had vaginal swabs positive for yeast. Nineteen (10%) women met the case definition for CV. In a logistic regression model, only CD4 < or = 100 cells/mm3 was predictive of CV (adds ratio = 4.5; 95% confidence interval = 1.0, 20; p = .05). The predictive value of patient self-report of CV was only 12%. This study demonstrates that all HIV-infected women should receive a regular and thorough gynecologic evaluation, regardless of self-reported symptoms. HIV-infected women will benefit from education about prevention and treatment of CV, and women whose CD4 counts are low may wish to consider prophylaxis for CV.

Identification of carcinoma cells in ascitic and pleural fluid. Comparison of four panepithelial antigens with carcinoembryonic antigen.

The cell membrane antigens epithelial membrane antigen (EMA), epithelial glycoprotein 34, (egp34), BW-495 and tumor-associated antigen 72 (TAG-72) are present in most benign and malignant epithelial cells and can be demonstrated with the help of monoclonal antibodies. In a study on the identification of carcinoma cells in samples of ascitic and pleural fluid involving 170 patients, we compared the value of immunocytochemical labeling of these antigens with that of immunocytochemical demonstration of carcinoembryonic antigen (CEA). Antibodies to EMA and egp34 occasionally also reacted with reactively proliferating mesothelial cells in benign conditions and thus appear to be inappropriate for diagnostic use. Cells positive for BW-495, TAG-72 and CEA, however, have never been found in benign conditions; the specificity of these antigens thus permits their use in diagnosis. Antigen-expressing cells were found in 85% (BW-495), 62% (TAG-72) and 60% (CEA) of cytologically positive samples from carcinoma patients. Similarly, positive reactions for BW-495, TAG-72 and CEA were observed in, respectively, 36%, 29% and 34% of cytologically negative or suspicious samples. BW-495 thus appears to be a suitable marker for the demonstration of carcinoma cells in samples of pleural and ascitic fluid and to have a higher degree of sensitivity than does either TAG-72 or CEA.

Possible role of FDG-PET in the early prediction of therapy outcome in liver metastases of colorectal cancer.

Nonresectable colorectal cancer metastases in the liver respond to chemotherapy in 20-25% only. Early identification of nonresponders might allow the use of other regimens. In a limited feasibility study, it should be determined whether (a) a single high-dose chemotherapy application has an early effect on glucose-utilization, detectable and quantitatable by noninvasive positron emission tomography using [18F]-Fluoro-deoxyglucose (FDG-PET) and (b) assess its value as a predictor of the final therapeutic outcome. A total of 10 patients with documented nonresectable liver metastases of a colorectal cancer were studied by FDG-PET, prior and 72 h after a single infusion of 5-Fluorouracil and Folinic acid (5-FU/FA). Glucose utilization was quantitated by determination of standard-uptake values and correlated with final therapy outcome following completion of the anticipated therapy cycle. Patients were followed up for at least 6 months. All metastases responding to therapy (n = 6) exerted a statistically significant decrease of FDG uptake (-22+/-10%), metastases (n = 2) showing a short-term effect (duration of tumor reduction <3 months) had a slightly diminished, and progressing metastases (n = 3) an enhanced FDG uptake (13+/-17%). Our preliminary data indicate that acute changes of glucose utilization-as detected by FDG-PET-following a single application of chemotherapy, seems to be indicative for the final therapeutic outcome, at least in liver metastases of colorectal cancer.

[Expression of transforming growth factor beta-3 (TGF-beta-3) on reactive and malignant cells in ascites and pleural effusion]. / Expression von Transforming-growth-factor-beta-3 (TGF-beta-3) auf reaktiven und malignen Zellen in Aszites und Pleuraergüssen.

PATIENTS AND METHOD: The expression of TGF-beta-3 was examined in 64 patients with reactive and malignant effusion by immunocytochemistry. RESULT: In about half of the patients with malignant effusions (especially breast cancer, gastric cancer, and carcinomas of unknown primary) TGF-beta positive tumor cells could be detected. We could show here for the first time that reactive mesothelial cells could also express TGF-beta. Lymphatic cells were negative in all cases. TGF-beta-3 bioactivity could also be detected in the effusions studied. In our group of patients with far advanced cancer, the expression of TGF-beta had no clear-cut clinical or prognostic correlate. However, the expression of TGF-beta on tumor cells should be interpreted as a marker of tumor progression, taking into account the fibrogenic, angiogenic and immunosuppressive properties of TGF-beta. CONCLUSION: Further research is necessary to answer the question if the 3 isoforms of TGF-beta are coordinately expressed and to elucidate the involvement of this cytokine in tumor progression and metastasis.