A phase I clinical, pharmacologic, and biologic study of thrombopoietin and granulocyte colony-stimulating factor in children receiving ifosfamide, carboplatin, and etoposide chemotherapy for recurrent or refractory solid tumors: a Children's Oncology Group experience.

PURPOSE: Ifosfamide, carboplatin, and etoposide (ICE) are associated with grade III/IV dose-limiting thrombocytopenia. The Children's Oncology Group conducted a phase I dose escalation, pharmacokinetic, and biological study of recombinant human thrombopoietin (rhTPO) after ICE in children with recurrent/refractory solid tumors (CCG-09717) to assess the toxicity and maximum tolerated dose of rhTPO administered at 1.2, 2.4, or 3.6 microg/kg per dose. EXPERIMENTAL DESIGN: Children received ifosfamide 1,800 mg/m2 on days 0 to 4, carboplatin 400 mg/m2 on days 0 to 1, and etoposide 100 mg/m2 on days 0 to 4. rhTPO was administered i.v. on days +4, +6, +8, +10, and +12 at 1.2, 2.4, or 3.6 microg/kg per dose.RESULTS: rhTPO was well tolerated and maximum tolerated dose was not reached. Median time to platelet recovery > or =100,000/microL of rhTPO at 1.2, 2.4, and 3.6 microg/kg/d was 24 days (22-24 d), 25 days (23-29 d), and 22 days (16-37 d), respectively. Patients required a median of 2 days of platelet transfusions (0-7 days). Mean (+/- SD) rhTPO maximum serum concentrations were 63.3 +/- 9.7 and 89.3 +/- 15.7 ng/mL and terminal half-lives were 47 +/- 13 and 64 +/- 42 hours after 2.4 and 3.6 microg/kg/d, respectively. There was a significant increase in colony-forming unit megakaryocyte upon WBC count recovery. CONCLUSIONS: rhTPO was well tolerated. Time to hematologic recovery and median number of platelet transfusions seem to be improved compared with historical controls receiving ICE + granulocyte colony-stimulating factor (CCG-0894).     

Markers of past infection with simian virus 40 (SV40) and risk of incident non-Hodgkin lymphoma in a Maryland cohort.

Simian virus 40 (SV40) genome sequences have been detected in human non-Hodgkin lymphoma (NHL) tissues, and past infection with SV40 may be a risk factor for NHL. We conducted a population-based nested case-control study to investigate the association between serum antibodies to SV40 and incident NHL. Two research serum banks were established in Washington County, MD, with >45,000 volunteers contributing blood samples collected in 1974 and 1989. Incident cases of NHL diagnosed through 2002 (n = 170) were identified among participants by linkage to population-based cancer registries. Two controls were matched to each case (n = 340) on age, sex, and date of blood draw. Circulating immunoglobulin G antibodies to SV40 were measured using virus-like particle (VLP) ELISA. Positive samples were tested for cross-reactivity with JC virus (JCV) and BK virus (BKV) through competitive inhibition assays. Associations between SV40 antibody seropositivity and NHL were estimated using conditional logistic regression. Whereas SV40 antibodies were detected by VLP ELISA in 15% of cases and 10% of controls [matched odds ratio (OR), 1.97; 95% confidence interval (95% CI), 1.03-3.76], the SV40 reactivity of 85% of the SV40 antibody-positive sera was decreased by adsorption with BKV and/or JCV VLPs. Antibodies specific for SV40 (not cross-reactive) were identified in only 1.8% of cases and 1.6% of controls (OR, 1.51; 95% CI, 0.41-5.52). Our findings suggest that past infection with SV40 is not associated with an increased risk of developing NHL.     

Positive correlation of insulin-like growth factor-II with proliferating cell index in patients with colorectal neoplasia.

BACKGROUND: Insulin-like growth factor-II (IGF-II) stimulates cell proliferation and is considered a potential risk factor for colorectal cancer. Tumor levels of IGF-II seem to positively correlate with colorectal cancer cell proliferation. This investigation examined the association of circulating IGF-II to the proliferating cell index (PCI) of tumor and matched normal mucosa in patients with colorectal neoplasia. METHODS: Circulating IGF-II level (ng/mL) was determined in the peripheral blood plasma by ELISA. The proliferating cells in tumor or matched normal mucosa were immunohistochemically stained using the primary antibody against Ki-67. Computer image analysis was used and PCI was expressed as the percentage of Ki-67-positive cells/total counted cells. RESULTS: Sixty-four patients were evaluated; 45 had colorectal neoplasia (27 males/18 females; mean age, 66.8 +/- 11.8 years) and 19 had hyperplastic polyps (6 males and 13 females; mean age, 58.4 +/- 14.4 years). Among patients with colorectal neoplasia, blood IGF-II levels were positively correlated with PCI in the matched normal mucosa (r = 0.46, P < 0.05) but not in the tumor. In patients with hyperplastic polyps, blood IGF-II levels were not correlated with the PCI in the polyps. Blood IGF-II levels were higher in colorectal cancer patients with Dukes' C/D stage (P < 0.01) or with positive lymph nodes (P < 0.01). CONCLUSION: Circulating IGF-II positively correlated with PCI in normal colonic mucosa of patients with colorectal neoplasia, suggesting that IGF-II may have a role in initiating the carcinogenic pathway by stimulating cell proliferation. Blood IGF-II was increased in advanced colorectal cancer, indicating that it might enhance colorectal cancer progression and be a useful marker of poor prognosis.     

Fetal Hemoglobin in the Maternal Circulation – Contribution of Fetal Red Blood Cells

The major hemoglobin (Hb) during fetal life is fetal Hb (Hb F). It is mostly replaced by adult Hbs before birth and during the first year of life. In adults, where Hb F comprises <2.0% of the total Hb, it is not homogenously distributed among the red blood cells (RBCs) but is concentrated in a few RBCs, termed F-cells. Interestingly, for reasons that are unclear, Hb F increases in the maternal circulation during pregnancy. This increased Hb F could have two potential origins that are not mutually exclusive: A) maternal origin, due to inducing environment of Hb F in the maternal erythroid precursors; B) fetal origin, due to fetal cells crossing the placenta and entering the maternal circulation. The question we present herein is whether the observed increased Hb F in the maternal circulation during pregnancy is, at least partially, derived from the fetal origin. Peripheral blood was obtained from normal neonates (1–3 days old), adult men and pregnant and non pregnant women. The RBCs were stained for Hb F and carbonic anhydrase (CA) using a fetal cell count kit and analyzed by flow cytometry. Fetal and adult F-cells were distinguished by their expression of Hb F and CA. Fetal F-cells were Hb F⁺⁺/CA^?, while adult F-cells were Hb F⁺/CA⁺. Comparing pregnant and non pregnant women samples (n?=?10), we found six samples of pregnant women with 0.2–1.7% fetal cells, but none in the non pregnant group. These results support the possibility that at least part of the increase in Hb F during pregnancy is due to fetal cells entering the maternal circulation.     

CT-scan prediction of thyroid cartilage invasion for early laryngeal squamous cell carcinoma

Treatment choice for laryngeal cancer may be influenced by the diagnosis of thyroid cartilage invasion on preoperative computed tomography (CT). Our objective was to determine the predictive value of CT for thyroid cartilage invasion in early- to mid-stage laryngeal cancer. Retrospective study (1992–2008) of laryngeal squamous cell carcinoma treated with open partial laryngectomy and resection of at least part of the thyroid cartilage. Previous laser surgery, radiation therapy, chemotherapy and second primaries were excluded. CT prediction of thyroid cartilage invasion was determined by specialized radiologists. Tumor characteristics and pathologic thyroid cartilage invasion were compared to the radiologic assessment. 236 patients were treated by vertical (20 %), supracricoid (67 %) or supraglottic partial laryngectomy (13 %) for tumors staged cT1 (26 %), cT2 (55 %), and cT3 (19 %). The thyroid cartilage was invaded on pathology in 19 cases (8 %). CT’s sensitivity was 10.5 %, specificity 94 %, positive predictive value 13 %, and negative predictive value 92 %. CT correctly predicted thyroid cartilage invasion in only two cases for an overall accuracy of 87 %. Among the false-positive CT’s, tumors involving the anterior commissure were significantly over-represented (61.5 % vs. 27 %, p = .004). Tumors with decreased vocal fold (VF) mobility were significantly over-represented in the group of false-negatives (41 vs. 13 %, p = .0035). Preoperative CT was not effective in predicting thyroid cartilage invasion in these early- to mid-stage lesions, overestimating cartilage invasion for AC lesions and underestimating invasion for lesions with decreased VF mobility.