Circulating growth factor levels are associated with tumorigenesis in neurofibromatosis type 1.

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by systemic development of neurofibromas. Early clinical diagnosis can be ambiguous, and genetic diagnosis can be prohibitively difficult. Dysregulation of a number of growth factors has been suggested to be a mechanism of pathogenesis. This study was performed to assess the contribution of circulating growth factors for diffuse tumorigenesis and the diagnostic value of circulating growth factor identification in serum. EXPERIMENTAL DESIGN: The growth stimulation of neurofibroma-derived cells by serum from NF1 patients was tested, and serum growth factor levels in a cohort of NF1 patients (n = 39) between the ages of 7 and 70 years were analyzed. RESULTS: Concentrations of midkine (MK) and stem cell factor, but not epidermal growth factor, were substantially increased in serum of NF1 patients when compared with healthy controls. Within the NF1 group, MK levels increased dramatically at puberty from an average of 0.79 ng/mL in patients <18 years to 1.18 ng/mL in patients >18 years old. Stem cell factor and MK concentrations above a defined threshold in serum of NF1 patients are of diagnostic benefit for 96% of patients in the cohort tested. Furthermore, serum from NF1 patients enhanced proliferation of human neurofibroma-derived primary Schwann cells and endothelial cells substantially better than normal serum. CONCLUSIONS: Enhanced circulating growth factor levels contribute to diffuse tumorigenesis in NF1 and may provide the basis for molecular diagnosis.     

Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma: associations with presenting features, serum interleukin 10 levels, and clinical outcome.

PURPOSE: EBV-latent membrane protein-1 (LMP-1) is often expressed in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin's lymphoma (cHL), but its clinical significance is controversial. We correlated LMP-1 with presenting features, including serum interleukin 10 levels and clinical outcome. EXPERIMENTAL DESIGN: Patients were eligible if they had biopsy-proven cHL, were untreated, HIV-1 negative, and had available archival tissue. LMP-1 expression was determined by immunohistochemistry. RESULTS: We identified 577 patients with cHL with a median age of 30 years, 55% of whom were male. LMP-1 was expressed in HRS cells of 124 patients (21%) and was detected in 78 of 461 (17%) patients with nodular sclerosis compared with 44 of 112 (39%) with mixed cellularity (P < 0.001 by Fisher's exact test). Patients with tumors with LMP-1-positive HRS cells had higher serum interleukin 10 levels (P = 0.009 by Mann-Whitney test). For the 303 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalent regimens, the 5-year failure-free survival (FFS) for those with LMP-1-positive tumors was 74% compared with 81% for those with LMP-1-negative tumors (P = 0.23, by log-rank test). Overall survival (OS) at 5 years for patients with LMP-1-positive tumors was 90 versus 91% for patients with LMP-1-negative tumors (P = 0.8 by log-rank test). Expression of LMP-1 was not associated with different FFS and OS in patients treated with other regimens or with radiotherapy alone. CONCLUSIONS: LMP-1 was expressed by HRS cells in 21% of cHL and correlated with mixed cellularity type and higher serum interleukin 10 levels. The presence of LMP-1 was not associated with FFS or OS in uniformly treated patients.     

Endometrial volume change during spontaneous menstrual cycles: volumetry by transvaginal three-dimensional ultrasound

Objective: At present, only limited data are available on endometrial volume during the menstrual cycle. Most of these studies deal with animal models and use magnetic resonance imaging for volume measuring. The application of three-dimensional ultrasound in endometrial volume estimation is the subject of this study.Setting: Patients visiting the outpatient unit of the division of endocrinology and reproductive medicine of a university hospital.Patient(s): Twenty patients with a history of a normal menstrual cycle were selected.Intervention(s): Ultrasound examinations were performed during a single menstrual cycle in addition to routine laboratory tests.Main Outcome Measure(s): Uterus-endometrial volume ratio.Result(s): Data from 18 patients could be evaluated. In 81 examinations the endometrium volume could be determined. Mean endometrial volume measured by three-dimensional ultrasound was 1.23 cm'. Mean uterus volume was 48.93 cm3. The change of the uterus-endometrial volume ratio showed a good correlation with the day of menstrual cycle. Quadratic regression analysis of volume and cycle length was R² = 0.432.Conclusion(s): Three-dimensional ultrasound allows assessment of volume data of the female internal genitalia. In this study changes of the endometrial volume in menstrual cycles were measured. Additional studies are required to give information on the clinical impact of this new technique of endometrial volume estimation.     

Influence of intratumoral basic fibroblast growth factor concentration on survival in ovarian cancer patients

Since basic fibroblast growth factor (bFGF) is considered as a potent mitogen that stimulates the growth of ovarian cancer cells, we evaluated the role of bFGF as a prognostic marker in patients with epithelial ovarian cancer. bFGF was quantified from the tumor cytoplasm of 76 patients with FIGO stage I–III ovarian cancer by a human FGF basic immunoassay (R&D Systems). After a mean follow-up period of 42 months, 50 patients were found to be free of tumor while 26 patients had died of the disease. The median bFGF concentration was 352.9 pg/mg (range 27.4–26 600 pg/mg). After dichotomization cytoplasmic expression of bFGF was found to be low in 44 tumors (≤500 pg/mg) and high in 32 tumors (>500 pg/mg). The probability of overall survival was 38.8 and 58.5% in the low bFGF and high bFGF groups, respectively (log-rank P=0.0066). In multivariate analysis, residual tumor after initial surgery and bFGF, but not histologic grade or stage of the disease, independently influenced the overall survival probability. Furthermore, tumors with high cytoplasmic expression of bFGF revealed a much greater stromal content. Therefore, we hypothesize that bFGF may induce a fibroblastic response which causes tumors with a high bFGF to be less aggressive than those with less stromal tissue.     

The T393C polymorphism of the G alpha s gene (GNAS1) is a novel prognostic marker in bladder cancer.

The G protein G(alpha)s pathway is linked to proapoptotic signaling in cancer cell lines. To assess the role of the GNAS1 locus encoding G(alpha)s as a genetic factor for disease progression of transitional cell carcinoma (TCC) of the bladder, we genotyped the synonymous T393C polymorphism in 254 patients with TCC (minor allele frequency: 0.43) to examine a potential association between genotypes and disease progression. Using Kaplan-Meier estimates to calculate 5-year probabilities of follow-up, we could show that progression-free survival, metastasis-free survival, and cancer-specific survival was significantly increased in TT genotypes (56%, 84%, 82%) compared with CC genotypes (35%, 53%, 58%). In multivariate Cox proportional hazard analysis, the T393C polymorphism was an independent prognostic factor for clinical outcome. Homozygous CC patients were at highest risk for progression [odds ratio (OR), 1.94; P = 0.020], metastasis (OR, 3.49; P = 0.005), and tumor-related death (OR, 2.49; P = 0.031) compared with TT genotypes. Heterozygous patients had an intermediate risk compatible with a gene-dose effect. Real-time PCR analysis of urothelial tumor tissue as well as adipose and heart tissue revealed that G(alpha)s mRNA expression was highest in TT genotypes, indicating a proapoptotic effect in these genotypes. In conclusion, the GNAS1 T393C status associated with differential G(alpha)s mRNA expression is a novel independent prognostic marker for clinical outcome supporting a functional role of G(alpha)s in bladder cancer progression.     

Treatment of refractory Hodgkin's lymphoma patients with an iodine-131-labeled murine anti-CD30 monoclonal antibody.

PURPOSE: Hodgkin's lymphoma (HL) has been demonstrated to be a good target for immunotherapy since lymphocyte activation markers such as CD30 are expressed in high numbers on the malignant cells. Thus, we developed a new radioimmunoconjugate consisting of the murine anti-CD30 monoclonal antibody (MAb) Ki-4 labeled with iodine-131 ((131)I). PATIENTS AND METHODS: The biodistribution of (131)I-Ki-4 was assessed via dosimetry after preinfusion of 5 mg native Ki-4 followed by 250 to 300 MBq (131)I-labeled Ki-4. Whole-body scintigraphy was performed 1 hour, 24 hours, 48 hours, 72 hours, and 6 days after the infusion. Dosimetry was calculated using the programs NucliDose ICON-IDL (version 5.0.2; Siemens, Erlanger, Germany) and MIRDOSE (version 3.1; Oak Ridge National Laboratories; Oak Ridge, TN). The therapeutic dose was given on day 8 after preinfusion of unlabeled Ki-4. RESULTS: We treated 22 patients with relapsed or refractory CD30-positive HL. Preinfusion of 5 mg native Ki-4 was sufficient to bind the soluble CD30. Imaging demonstrated localization of involved areas measuring 5 cm in diameter or more in four patients and 2.5 cm in one patient. Patients received total body doses of 0.035 Gy to 0.99 Gy. Acute toxicity was mild with grade 1 fatigue in 19 of 22 assessable patients. Seven patients experienced grade 4 degrees hematotoxicity 4 to 8 weeks after treatment. Response included one complete remission, five partial remissions, and three minor responses. CONCLUSION: Treatment with (131)I-Ki-4 is effective but can be associated with severe hematotoxicity.     

Phase I trial of a monoclonal antibody specific for alphavbeta3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion.

At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the alpha(v)beta(3) integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the alpha(v)beta(3) integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at alpha(v)beta(3) could be investigated in the treatment of human malignancies. The current phase I dose escalation study evaluated the safety of MEDI-522, a monoclonal antibody specific for the alpha(v)beta(3) integrin, in patients with advanced malignancies. Twenty-five patients with a variety of metastatic solid tumors were treated with MEDI-522 on a weekly basis with doses ranging from 2 to 10 mg/kg/wk. Adverse events were assessed weekly; pharmacokinetic studies were done; and radiographic staging was done every 8 weeks. In addition, dynamic computed tomography imaging was done at baseline and at 8 weeks in patients with suitable target lesions amenable to analysis, to potentially identify the effect of MEDI-522 on tumor perfusion. Treatment was well tolerated, and a maximum tolerated dose was not identified by traditional dose-limiting toxicities. The major adverse events observed were grade 1 and 2 infusion-related reactions (fever, rigors, flushing, injection site reactions, and tachycardia), low-grade constitutional and gastrointestinal symptoms (fatigue, myalgias, and nausea), and asymptomatic hypophosphatemia. Dynamic computed tomography imaging suggested a possible effect on tumor perfusion with an increase in contrast mean transit time from baseline to the 8-week evaluation with increasing doses of MEDI-522. No complete or partial responses were observed. Three patients with metastatic renal cell cancer experienced prolonged stable disease (34 weeks, >1 and >2 years) on treatment. With this weekly schedule of administration, and in the doses studied, MEDI-522 seems to be without significant toxicity, may have effects on tumor perfusion, and may have clinical activity in renal cell cancer. These findings suggest the MEDI-522 could be further investigated as an antiangiogenic agent for the treatment of cancer.     

Disseminated Bartonella henselae disease mimicking Langerhans’ cell histiocytosis

Bartonella henselae, the causative agent of cat‐scratch disease, has been recognized to be responsible for a broad range of clinical syndromes. We report the case of a patient with disseminated B. henselae infection mimicking Langerhans cell histiocytosis at presentation and its successful management with neurosurgery, prolonged antibacterial therapy, and observation.