Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival

Transplant outcome was analyzed in 690 recipients of bone marrow transplants (BMTs) for acute lymphoblastic leukemia (ALL) in first (n = 299) or second remission (n = 391). Actuarial 5-year leukemia-free survival was 42% +/- 9% (95% confidence interval) and 26% +/- 6%, respectively; relapse rates were 29% +/- 9% and 52% +/- 8%, respectively. Five-year leukemia-free survival was 56% +/- 18% in children and 39% +/- 10% in adults (P less than .02) transplanted in first remission. In first-remission adults, non-T-cell phenotype, male to female donor-recipient sex-match and graft-v-host disease (GVHD) were associated with decreased leukemia-free survival; inclusion of corticosteroids in the regimen to prevent GVHD was associated with increased leukemia-free survival. Variables associated with decreased leukemia-free survival after second-remission transplants were age greater than or equal to 16 years and relapse occurring while on therapy. Variables associated with increased probability of relapse were similar for first- and second-remission transplants and included GVHD prophylaxis without methotrexate and absence of GVHD. In first- remission transplants, leukocyte count greater than or equal to 50 x 10(9)/L at diagnosis was also associated with increased relapse; in second remission, relapse while receiving chemotherapy was also associated with increased posttransplant relapse. These data emphasize the importance of both disease- and transplant-related variables in predicting outcome after BMT. They may be used to explain differences between studies, design future trials, and identify persons most likely to benefit from BMT.     

Factor VIII gene inversions in severe hemophilia A: results of an international consortium study

Twenty-two molecular diagnostic laboratories from 14 countries participated in a consortium study to estimate the impact of Factor VIII gene inversions in severe hemophilia A. A total of 2,093 patients with severe hemophilia A were studied; of those, 740 (35%) had a type 1 (distal) factor VIII inversion, and 140 (7%) showed a type 2 (proximal) inversion. In 25 cases, the molecular analysis showed additional abnormal or polymorphic patterns. Ninety-eight percent of 532 mothers of patients with inversions were carriers of the abnormal factor VIII gene; when only mothers of nonfamilial cases were studied, 9 de novo inversions in maternal germ cells were observed among 225 cases (approximately 1 de novo maternal origin of the inversion in 25 mothers of sporadic cases). When the maternal grandparental origin was examined, the inversions occurred de novo in male germ cells in 69 cases and female germ cells in 1 case. The presence of factor VIII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors (130 of 642 [20%]) than patients with severe hemophilia A without inversions (131 of 821 [16%]).     

Use of the MIRUS™ system for general anaesthesia during surgery: a comparison of isoflurane,sevoflurane and desflurane

The MIRUS? system enables automated end-expired control of volatile anaesthetics. The device is positioned between the Y-piece of the breathing system and the patient’s airway. The system has been tested in vitro and to provide sedation in the ICU with end-expired concentrations up to 0.5 MAC. We describe its performance in a clinical setting with concentrations up to 1.0 MAC. In 63 ASA II–III patients undergoing elective hip or knee replacement surgery, the MIRUS? was set to keep the end-expired desflurane, sevoflurane, or isoflurane concentration at 1 MAC while ventilating the patient with the PB-840 ICU ventilator. After 1 h, the ventilation mode was switched from controlled to support mode. Time to 0.5 and 1 MAC, agent usage, and emergence times, work of breathing, and feasibility were assessed. In 60 out of 63 patients 1.0 MAC could be reached and remained constant during surgery. Gas consumption was as follows: desflurane (41.7?±?7.9 ml h^?1), sevoflurane (24.3?±?4.8 ml h^?1) and isoflurane (11.2?±?3.3 ml h^?1). Extubation was faster after desflurane use (min:sec): desflurane 5:27?±?1:59; sevoflurane 6:19?±?2:56; and isoflurane 9:31?±?6:04. The support mode was well tolerated. The MIRUS? system reliable delivers 1.0 MAC of the modern inhaled agents, both during mechanical ventilation and spontaneous (assisted) breathing. Agent usage is highest with desflurane (highest MAC) but results in the fastest emergence. Trial registry number: Clinical Trials Registry, ref.: NCT0234509.     

National survey on endoscopy training in the UK

IntroductionGastrointestinal (GI) endoscopy is an important skill for both gastroenterologists and general surgeons but concerns have been raised about the provision and delivery of training. This survey aimed to evaluate and compare the delivery of endoscopy training to gastroenterology and surgical trainees in the UK.MethodsA nationwide electronic survey was carried out of UK gastroenterology and general surgery trainees.ResultsThere were 216 responses (33% gastroenterologists, 67% surgeons). Gastroenterology trainees attended more non-training endoscopy lists (mean: 3.0 vs 1.2) and training lists than surgical trainees (mean: 0.9 vs 0.5). A significantly higher proportion of gastroenterologists had already achieved accreditation in gastroscopy (60.8% vs 28.9%), colonoscopy (66.7% vs 1.4%) and flexible sigmoidoscopy (33.3% vs 3.0%). More gastroenterology trainees aspired to achieve accreditation in gastroscopy (97.2% vs 79.2%), flexible sigmoidoscopy (91.7% vs 70.1%) and colonoscopy (88.8% vs 55.5%) by completion of training. By completion of training, surgeons were less likely than gastroenterologists to have completed the required number of procedures to gain accreditation in gastroscopy (60.3% vs 91.3%), flexible sigmoidoscopy (64.6% vs 68.6%) and colonoscopy (60.3% vs 70.3%).ConclusionsThis survey highlights marked disparities between surgical and gastroenterology trainees in both aiming for and achieving accreditation in endoscopy. Without changes to the delivery and provision of training as well as clarification of the role of endoscopy training in a surgical training programme, future surgeons will not be able to perform essential endoscopic assessment of patients as part of their management algorithm.     

Inhibition of placental P-glycoprotein: impact on indinavir transfer to the foetus

AIMS

To investigate the effect of P-gp inhibition on the maternal to foetal transfer of indinavir.

METHODS

Term human placentae (n = 12) were from non-HIV infected women. Maternal to foetal transfer of indinavir was examined in the absence and presence of P-gp inhibitors PSC833 (n = 7) or ritonavir (n = 5), in the perfused human placenta. Antipyrine and [³H]-vinblastine were included as markers of passive diffusion and P-gp transport, respectively. These markers and indinavir were added to maternal perfusate at 0 min; PSC833 or ritonavir was added at 25 min. Steady-state maternal to foetal transfer clearance was calculated during control and inhibitor phases. Indinavir and vinblastine clearances were normalized to antipyrine clearance (clearance index).

RESULTS

Indinavir clearance index increased between the control (0.25 ± 0.03) and PSC833 phases (0.37 ± 0.14) (95% CI of the difference −0.23, −0.002). Vinblastine clearance index increased from (0.25 ± 0.08) to (0.34 ± 0.06) in the control and PSC833 phases, respectively (95% CI of difference −0.14, −0.05). Indinavir clearance index was unchanged between control (0.34 ± 0.14) and ritonavir phases (0.39 ± 0.13) (95% CI of the difference −0.19, 0.08). Vinblastine clearance index increased from (0.24 ± 0.12) to (0.32 ± 0.12) in the control and ritonavir phases, respectively (95% CI of the difference −0.15, −0.009).

CONCLUSIONS

Maternal to foetal transfer clearance of indinavir and vinblastine increased following P-gp inhibition. The potential role for co-administration of P-gp inhibitors with PIs to reduce perinatal HIV transmission warrants further investigation.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• We have shown previously using the dually perfused isolated human placenta model that the maternal to foetal transfer of the antiviral protease inhibitor drug indinavir is substantially lower than the transfer in the opposite direction.
• This finding is not consistent with passive diffusion and indicates that a carrier-mediated mechanism is involved in retarding the movement in the maternal to foetal direction.
• The efflux transporter P-gp located in the apical membrane domain of the placental trophoblast cells has been implicated as the likely cause of the differential bi-directional transport.

WHAT THIS STUDY ADDS

• The present study also utilizes the human perfused human isolated placenta to investigate the possible inhibitory effects of the P-gp inhibitor PSC833 and the P-gp substrate/inhibitor ritonavir on the maternal to foetal transfer clearance of indinavir.
• The studies, which were conducted such that each placenta served as its own control, demonstrated a statistically significant increase in the maternal to foetal transfer of indinavir in the presence of PSC833 but not in the presence of ritonavir, a protease inhibitor that is often used in combination with other protease inhibitors in dual therapy.
• The lack of effect of ritonavir is most likely related to the relatively low inhibitory activity at the clinically relevant concentration used in this study.

     

Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for end-stage alcoholic liver disease

BACKGROUND/AIMS: Alcoholic cirrhosis is a common indication for liver transplantation. The present study was aimed to assess the influence of superimposed alcoholic hepatitis on the outcome of liver transplantation in patients with alcoholic cirrhosis.METHODS: Survival rates of 68 patients transplanted for alcoholic cirrhosis were compared with those of 101 patients transplanted for miscellaneous causes. Within the alcoholic group, explanted livers were searched for data of acute alcoholic hepatitis. The survival rate of patients with alcoholic hepatitis superimposed on liver cirrhosis was compared to that of patients with liver cirrhosis alone. Clinical severity of alcoholic hepatitis was assessed with Maddrey's score.RESULTS: Survival was similar in alcoholics and patients with other causes of liver disease. Among patients transplanted for alcoholic cirrhosis, survival was similar in patients with superimposed alcoholic hepatitis (n=36) and in cases with liver cirrhosis alone (n=32). There was no difference in survival between patients with mild (n=26) and severe (n=10) alcoholic hepatitis. Seven alcoholics (10%) returned to ethanol consumption. Recidivism was not associated with either alcoholic hepatitis in the explanted liver or graft loss.CONCLUSIONS: Survival after liver transplantation in patients with alcoholic cirrhosis plus alcoholic hepatitis detected in the explanted liver is similar to that of patients transplanted for other reasons. Even the presence of severe alcoholic hepatitis does not worsen the outcome of liver transplantation for end-stage alcoholic liver disease.     

Deformation of swollen erythrocytes provides a model of sickling- induced leak pathways, including a novel bromide-sensitive component

Deoxygenation-induced red blood cell (RBC) sickling probably activates multiple cation leak pathways. In an attempt to model this, we examined the net passive K efflux ("K leak") from normal and sickle RBCs undergoing elliptical deformation in hypotonic media (200 mOsmol/L). This hypotonic deformation activates two deformation-dependent K leak pathways that are not detectable during the balanced leak (Kefflux = Nainflux) resulting from deformation of RBCs in isotonic medium. These are (1) a calcium-dependent leak component and (2) a novel leak pathway that is inhibited by substitution of bromide (but not sulfamate) for chloride, which converts the unbalanced K leak (Kefflux > Nainflux) of hypotonic deformation to a residual balanced leak. This dramatic effect of hypotonic deformation is reversible, is detected in both normal and sickle RBCs, and is inhibited significantly by 4,4'-diisothiocyano-2,2'- stilbene disulfonate. Remarkably, bromide also inhibits by 55% the K leak resulting from authentic deoxygenation-induced RBC sickling and, thereby, blunts the imbalance of accompanying monovalent cation leaks. The unique effect of bromide is not readily explainable on the basis of known behaviors of known ion leak/transport pathways. The mechanical threshold for triggering K leak during hypotonic deformation is at applied shear stress of 164 dyne/cm2, a value similar to the abnormal susceptibility we previously found for oxygenated sickle RBCs during isotonic deformation. These data suggest that membrane stretch accompanying hypotonic deformation activates the same multiple leak pathways that contribute to net K leak during authentic RBC sickling, including a previously unknown bromide-sensitive leak.     

Murine thymocytes proliferate in direct response to interleukin-7

The ability of interleukin-7 (IL-7) to stimulate murine thymocyte proliferation was investigated. IL-7, either alone or in concert with lectin, induced proliferation of adult thymocytes as well as day 13 fetal and adult CD4-/CD8-thymocytes. The IL-7-induced proliferative response of unfractionated thymocytes could not be inhibited by antibodies to IL-2, or IL-4, IL-6, or the IL-2 receptor. In addition, IL-2, IL-4, and IL-6 were not produced by thymocytes activated with IL- 7, as judged by the absence of biologically active cytokine in IL-7- stimulated culture supernatants. IL-7 could act in concert with IL-2 and IL-4 or with IL-4 to enhance the proliferative response of thymocyte cultures. Thus, IL-7 may cause proliferation of thymocytes directly, not indirectly, through production of IL-2, IL-4, or IL-6. IL- 7 may then play a significant role in differentiation of T lymphocytes.     

Immunohistochemical localization of membrane and alpha-granule proteins in plastic-embedded mouse bone marrow megakaryocytes and murine megakaryocyte colonies

Using an immunoperoxidase technique that permits optimal antigen localization at the light microscope level, we have detected two platelet alpha-granule constituents and three platelet membrane glycoproteins in mouse bone marrow megakaryocytes and in murine megakaryocyte colonies grown in soft agar culture for three to seven days. Using polyclonal antibodies prepared against human platelet proteins, we have demonstrated labeling for von Willebrand factor, fibrinogen, and the membrane glycoproteins IIIa and GMP-140 in both bone marrow megakaryocytes and megakaryocyte colonies after seven days of culture. Using monoclonal antibodies to membrane glycoproteins IIb and GMP-140, we have demonstrated label in mouse bone marrow megakaryocytes. Granulocyte and macrophage colonies were negative for each of these markers. Murine bone marrow megakaryocytes and megakaryocyte colonies demonstrated a similar enzyme histochemical pattern: weakly positive for alpha-naphthyl acetate esterase and negative for chloroacetate esterase. These data indicate that megakaryocytes grown in soft agar culture express many of the same glycoproteins as bone marrow megakaryocytes. Furthermore, the ability of antibodies directed against human platelet membrane glycoproteins to identify murine megakaryocyte glycoproteins indicates that these constituents have been highly conserved during evolution.