Maternal diet and infant leukemia: the DNA topoisomerase II inhibitor hypothesis: a report from the children's oncology group.

BACKGROUND: The MLL 11q23 translocation arises in utero and is present in 75% of infant leukemias. That MLL+ acute myeloid leukemia (AML) can arise following chemotherapy with DNA topoisomerase II (DNAt2) inhibitors suggests that these substances, which also occur naturally in foods, may contribute toward infant leukemia. We hypothesized that maternal consumption of dietary DNAt2 inhibitors during pregnancy would increase the risk of infant leukemia, particularly AML(MLL+). METHODS: This Children's Oncology Group case-control study consisted of 240 incident cases of infant acute leukemia [AML and acute lymphoblastic leukemia (ALL)] diagnosed during 1996 to 2002 and 255 random digit dialed controls. Maternal diet during pregnancy was determined through a food frequency questionnaire. An index of specific foods identified a priori to contain DNAt2 inhibitors as well as vegetables and fruits were created and analyzed using unconditional logistic regression. RESULTS: There was little evidence of an association between the specific DNAt2 index and leukemia overall and by subtype. An exception was AML(MLL+); odds ratios (95% confidence intervals) comparing the second to fourth quartiles to the first were 1.9 (0.5-7.0), 2.1 (0.6-7.7), and 3.2 (0.9-11.9), respectively (P for trend = 0.10). For the vegetable and fruit index, there were significant or near-significant inverse linear trends for all leukemias combined, ALL(MLL+), and AML(MLL-). CONCLUSION: Overall, maternal consumption of fresh vegetables and fruits during pregnancy was associated with a decreased risk of infant leukemia, particularly MLL+. However, for AML(MLL+) cases, maternal consumption of specific DNAt2 inhibitors seemed to increase risk. Although based on small numbers, these data provide some support for distinct etiologic pathways in infant leukemia.     

Fibrinolytic system after laparoscopic cholecystectomy

BACKGROUND: Deep-vein thrombosis (DVT) and pulmonary embolism (PE) are the most important causes of morbility and mortality in patients submitted to surgical intervention: some peculiar factors of laparoscopic surgery can modify their risk. The aim of this study is to evaluate possible variations of the fibrinolytic system after cholecystectomy. METHODS: Eighteen patients affected by symptomatic and non-complicated gallstones have been included in this study. They were divided into two groups of nine patients each: the first group was submitted to laparoscopic cholecystectomy (LC) and the second to open cholecystectomy (OC). Antitrombin III (ATIII), fibrinogen degradation products (FDP), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI) have been evaluated preoperatively and 6, 12, 24 and 48 hours after the operation. RESULTS: The levels of ATIII did not present significantly variations. The FDP in both groups were significantly increased 48 hours after open cholecystectomy. Levels of PAI instead were increased in comparison to the basal values at 6, 12, 24, 48 hours with p < 0.05; p < 0.01 and p < 0.05 respectively in patients submitted to OC, in the LC group no variations were observed; a comparison between the groups showed a significant modification (p < 0.05) only at the 12th hour. CONCLUSIONS: The early mobilization of patients in the postoperative course and the lower invasion of LC can oppose the prothrombotic effect in the lower limbs.     

Pharmacological evidence for a presynaptic action of venoms from Bothrops insularis (jararaca ilhoa) and Bothrops neuwiedi (jararaca pintada).

Whereas the presynaptic action of Crotalus durissus terrificus venom is well-established, Bothrops venoms have historically been considered to have only postsynaptic and muscular effects. However, some studies have also suggested a presynaptic action for these venoms. In this work, we used chick biventer cervicis preparations to compare the presynaptic actions of two Bothrops venoms (B. insularis and B. neuwiedi) with that of C. d. terrificus venom. At 10 microg/ml, all venoms produced irreversible blockade of the twitch tension responses, with no reduction in acetylcholine (ACh)-induced contractures and only a slight decrease in potassium induced-contractures. The times (in min) required to produce 50% neuromuscular blockade (C. d. terrificus: 16.3+/-0.7, n = 8; B. insularis: 30.0+/-1.9, n = 5; B. neuwiedi: 42.0+/-2.0, n = 8; mean +/- SEM) were significantly different among the venoms (p < 0.01). Lowering the temperature at which the experiments were done (from 37 to 24 degrees C) prevented neuromuscular blockade by the three venoms, indicating that enzyme activity may be involved in this response. At concentrations capable of causing complete neuromuscular blockade, creatine kinase release remained close to levels seen in control preparations incubated with Krebs solution alone (500-1200 IU/l). Commercial crotalic antivenom, but not bothropic antivenom, protected against the neuromuscular blockade caused by B. insularis and B. neuwiedi venoms. These observations indicate that bothropic venoms may contain components which act presynaptically in a manner similar to C. d. terrificus venom, and that at low venom concentrations a direct action on skeletal muscle does not contribute to this presynaptic neurotoxicity.     

In vitro metabolism of MK-0767 [(+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)-phenyl] methyl]benzamide], a peroxisome proliferator-activated receptor alpha/gamma agonist. II. Identification of metabolites by liquid chromatography-tandem mass spectrometry.

The in vitro metabolism of MK-0767 [(+/-)-5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxy-N-[[(4-trifluoromethyl)-phenyl] methyl]benzamide], a novel 2,4-thiazolidinedione (TZD)-containing peroxisome proliferator-activated receptor alpha/gamma agonist, was studied in rat, dog, monkey, and human liver microsomes and hepatocytes, as well as in recombinant human CYP3A4-containing microsomes. Twenty-two metabolites (some at trace levels) were detected by liquid chromatography-tandem mass spectrometry analysis. All appeared to be phase I metabolites except for a glucuronide conjugate of a hydroxylated metabolite that was detected at trace levels. A constant neutral loss scan experiment performed on a triple quadrupole mass spectrometer proved to be very useful for resolving the metabolites from endogenous compounds. It was observed that the initial site of metabolism of MK-0767 was at the TZD ring leading to two major metabolites, namely the 5-hydroxy-TZD metabolite (M24) and the mercapto metabolite (M22). The latter was formed via the cleavage of the TZD ring with the elimination of the carbonyl adjacent to the sulfur atom. The structure of M24 was established by accurate mass measurements and NMR analysis. This hydroxy-TZD metabolite might represent an important precursor for a group of metabolites formed by TZD ring opening and subsequent loss of the sulfur moiety. The mercapto metabolite, on the other hand, is probably the key precursor for the TZD ring-opened metabolites with retention of the sulfur, even though the detailed mechanism of the ring scission remains to be characterized. From these studies, it was concluded that the TZD ring was the major site of metabolism of MK-0767. All the metabolites produced in vitro from human preparations were detected in the corresponding preparations from the nonclinical species.     

The successful use of alemtuzumab for treatment of steroid‐refractory acute graft‐versus‐host disease in pediatric patients

SR‐aGVHD remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Alemtuzumab has been used with success in adult patients but has not been studied in the pediatric setting. To estimate the effectiveness of alemtuzumab for the treatment of SR‐aGVHD in pediatric patients, we retrospectively reviewed the charts of 19 patients (median age 4 yr, range 0.5–28 years) with grades II (n = 3), III (n = 10), or IV (n = 6) SR‐aGVHD who received alemtuzumab treatment. Patients received a median dose of 0.9 mg/kg alemtuzumab (range 0.3–2 mg/kg) divided over 2–6 days. Eighty‐nine percent of patients received additional courses. A complete response, defined as GVHD of grade 0 at four wk following the first alemtuzumab course, was observed in nine patients (47%). A partial response, defined as an improvement in grade after four wk, was observed in five patients (26%). There was no response in five patients (26%). The overall response rate at four wk was 73%. Infectious complications included bacteremia (47%), presumed or documented fungal infections (21%), adenovirus viremia (52%), EBV viremia (36%), and CMV viremia (36%). We conclude that alemtuzumab is effective for SR‐aGVHD in pediatric patients with a tolerable spectrum of complications.     

Heparanase expression increases throughout the endometrial hyperplasia-cancer sequence.

OBJECTIVE: To assess the expression of heparanase in the different stages leading to endometrial cancer. METHODS: The 38 examined specimens included adenocarcinoma, hyperplasia, and normal endometrium specimens. Heparanase, estrogen, and progesterone receptor expressions were analyzed immunohistochemically and the intensity was scored. RESULTS: Secretory normal endometrium and simple hyperplasia specimens expressed the lowest mean values of expression (1.00 and 0.63, respectively); the complex hyperplasia specimens and G2 endometrioid adenocarcinoma showed the highest values of expression (2.33 and 2.71, respectively). A linear trend (P=0.005) of heparanase expression was observed when comparing the normal endometrium and simple hyperplasia group with the complex hyperplasia+G1 carcinoma group and the G2+G3 carcinoma group. Evaluation of atrophic and inactive endometrium compared with papillary serous carcinomas yielded no significant differences. We found no significant correlation between heparanase expression and estrogen receptor or progesterone receptor expression. CONCLUSION: Heparanase expression was tightly regulated in endometrial tumorigenesis.     

Cyclodextrins: Their Future in Drug Formulation and Delivery

Pharmaceutical Research - Since their discovery, cyclodextrins and their ability to form inclusion complexes have fascinated chemists, formulators and recently, entrepreneurs. This mini-review has...     

Distant muscular (gluteus maximus muscle) metastasis from laryngeal squamous cell carcinoma

Clinical evidence of non-lymphatic distant metastasis has been reported in approximately 10% of cases of head and neck squamous cell carcinoma (HNSCC). The lungs are the commonest site of distant metastasis of HNSCC, followed by the bones, liver and skin. A 65-year-old male underwent supraglottic laryngectomy and left modified neck dissection for a carcinoma of the laryngeal surface of the epiglottis extending to both false cords. Eight months later the patient underwent right radical modified neck dissection for hypodermal metastatic disease involving the underlying (sternocleidomastoid) muscle. Thirty-two months later, surgical excision of a lesion in the right gluteus maximus muscle was performed. Histological study diagnosed a muscular metastasis with the same morphological aspect as the laryngeal carcinoma. The patient showed no evidence of cervical or distant recurrence at follow-up after 13 months. Although skeletal muscles represent approximately 50% of total body mass and receive a large proportion of total cardiac output, haematogenous metastases to skeletal muscle are extremely uncommon. Most skeletal muscle metastases are of pulmonary origin. Distant skeletal muscle metastasis from HNSCC is an extremely rare occurrence. Treatment options, depending upon the clinical setting, include observation, radiotherapy, chemotherapy and excision; these approaches rarely alter the patient outcome. The prognosis associated with skeletal muscle metastasis is thought to be poor, consistent with the fact that it generally occurs as a feature of systemic spread.