Hemisynthesis of antineoplastic conjugates with nitrogen-mustard proteins

The synthesis of new conjugates with inhibitory action on tumour growth is investigated by linking amino functions of proteins compounds (lysozyme and alpha s-casein) through an amide linkage at the carboxylic function of nitrogen mustards (chlorambucil and melphalan). The polychlorambucil amides of lysozyme and alpha s-casein derivatives prepared showed experimental antitumour activity when these conjugates were screened against the experimental P388 leukemia. In the case of the conjugates lysozyme-melphalan, an antitumour activity is observed when the amino function of the drug is combined with the carboxylic functions of the protein contrary to the situation of the free amino function of the drug described into the literature.     

Perforated colorectal neoplasms: correlation of clinical, contrast enema, and CT examinations

Results of clinical, contrast enema (CE), and computed tomographic (CT) examinations in 39 patients with perforated colorectal neoplasms were retrospectively reviewed. Twenty patients were toxemic at initial presentation, but in only four patients was the diagnosis of perforated colorectal neoplasm initially suspected clinically. CE study was performed in 22 patients and enabled the diagnosis of perforated neoplasm in 11 cases, neoplasm alone in eight, and neither neoplasm nor perforation in three. CT was performed in 38 patients and enabled the diagnosis of perforated neoplasm in 36; pericolic phlegmon but no mass lesion was evident in two. In 16 patients, CT also demonstrated metastatic disease. Because of its reliability in establishing the diagnosis and staging the extent of the inflammatory and neoplastic disease, CT is indicated in cases of suspected or proved perforated colorectal neoplasm and in cases in which CE study findings are indeterminate or suggestive of perforated neoplasm.     

Frequent ongoing T-cell receptor rearrangements in childhood B- precursor acute lymphoblastic leukemia: implications for monitoring minimal residual disease

Crosslineage T-cell receptor delta (TCR delta) rearrangements are widely used as tumor markers for the follow up of minimal residual disease in childhood B-precursor acute lymphoblastic leukemia (ALL) by polymerase chain reaction (PCR). The major drawback of this approach is the risk of false-negative results due to clonal evolution. We investigated the stability of V delta 2D delta 3 rearrangements in a group of 56 childhood B-precursor ALL patients by PCR and Southern blot analysis. At the PCR level, V delta 2D delta 3-to-J alpha rearranged subclones (one pathway for secondary TCR delta recombination) were demonstrated in 85.2% of V delta 2D delta 3-positive patients tested, which showed that small subclones are present in the large majority of patients despite apparently monoclonal TCR delta Southern blot patterns. Sequence analysis of V delta 2D delta 3J alpha rearrangements showed a biased J alpha gene usage, with HAPO5 and J alpha F in 26 of 32 and 6 of 32 clones, respectively. Comparison of V delta 2D delta 3 rearrangement status between diagnosis and first relapse showed differences in seven of eight patients studied. In contrast, from first relapse onward, no clonal changes were observed in six patients studied. To investigate the occurrence of crosslineage TCR delta rearrangements in normal B and T cells, fluorescence-activated cell sorter-sorted peripheral blood CD19+/CD3- and CD19-/CD3+ cell populations from three healthy donors were analyzed. V delta 2D delta 3 rearrangements were detected at low frequencies in both B and T cells, which suggests that V delta 2-to-D delta 3 joining also occurs during normal B-cell differentiation. A model for crosslineage TCR delta rearrangements in B-precursor ALL is deduced that explains the observed clonal changes between diagnosis and relapse and is compatible with multistep leukemogenesis of B-precursor ALL.     

Plasma concentrations of epidural bupivacaine in mother and newborn: 0.125% versus 0.375%

Central venous plasma concentrations of bupivacaine were determined in two groups of 15 parturients each who were given epidural analgesia for labor and vaginal delivery. One group received 10 ml of 0.125% bupivacaine plus epinephrine 1:800,000, the other group received 7 ml of 0.375% bupivacaine plus epinephrine 1:800,000. Plasma concentrations of bupivacaine in the umbilical venous (UV) and the umbilical arterial (UA) blood of their babies were also determined. The mean UA, UV, and maternal central venous (MV) plasma concentrations of bupivacaine differed significantly between the two groups: in patients given 0.375% bupivacaine UA values were 63% higher (P less than 0.01), UV values were 57% higher (P less than 0.01), and the MV values were 34% higher (P less than 0.05) than in patients given 0.125% bupivacaine. The measured plasma concentrations speak in favor of the less concentrated solution of bupivacaine in epidural analgesia for obstetrics. Seven milliliters of bupivacaine 0.375% is suitable for epidural analgesia in obstetrics but a low concentration-low dose technique, using 10 ml of bupivacaine 0.125% plus epinephrine 1:800,000 is safer. It provides good analgesia with minimal or no motor block and is associated with low maternal and neonatal plasma concentrations of bupivacaine, well below toxic levels and, to our knowledge, lower than in any other study.     

A 2-year, randomized, comparative, placebo-controlled study on the effects of raloxifene on lipoprotein(a) and homocysteine

OBJECTIVES: Lipoprotein(a) (Lp(a)) and homocysteine (Hcy) are independent cardiovascular risk factors, which have been shown to be lowered by hormone replacement therapy (HRT). In this 2-year study, the long-term effects of raloxifene (Rlx) in two doses, on Lp(a) and Hcy, were studied and compared with the effects of continuously combined hormone replacement therapy (ccHRT). METHODS: In a prospective, randomized, double-blind, placebo-controlled 2-year study, 95 healthy, non-hysterectomized, early postmenopausal women, received daily either oral Rlx 60 mg (N=24) or 150 mg (N=23), ccHRT (conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg; N=24) or placebo (N=24). Fasting serum Lp(a) and plasma Hcy concentrations were measured at baseline and at 6, 12 and 24 months. RESULTS: The mean individual changes compared to baseline after 24 months were for Lp(a): Rlx 60: - 5%, Rlx 150: -7%, ccHRT: -34%, placebo: +1% and for Hcy: Rlx 60: -3%, Rlx 150: -4%, ccHRT: -4%, placebo: +6%. ANCOVA was significant for Lp(a) under ccHRT versus placebo (P=0.001) and for Lp(a) under ccHRT versus each of the two Rlx groups (P<0.05). CONCLUSIONS: Long-term treatment with Rlx was not as effective as ccHRT in lowering Lp(a). Although not significant and without an obvious dose-related response, the Hcy values showed the same trend for each treatment arm, which is in line with data reported earlier.