Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders

Although nonmyeloablative conditioning regimen transplantations (NMTs) induce engraftment of allogeneic stem cells with a low spectrum of toxicity, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion, using alemtuzumab, has been shown to reduce the incidence of GVHD. However, this type of maneuver, although reducing GVHD, may have an adverse impact on disease response, because NMTs exhibit their antitumor activity by relying on a graft-versus-malignancy effect. To explore the efficacy of alemtuzumab compared with methotrexate (MTX) for GVHD prophylaxis, we have compared the results in 129 recipients of a sibling NMT enrolled in 2 prospective studies for chronic lymphoproliferative disorders. Both NMTs were based on the same combination of fludarabine and melphalan, but the United Kingdom regimen (group A) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (group B) used cyclosporin A plus MTX for GVHD prophylaxis. Patients receiving alemtuzumab had a higher incidence of cytomegalovirus (CMV) reactivation (85% versus 24%, P <.001) and a significantly lower incidence of acute GVHD (21.7% versus 45.1%, P =.006) and chronic GVHD (5% versus 66.7%, P <.001). Twenty-one percent of patients in group A and 67.5% in group B had complete or partial responses 3 months after transplantation (P <.001). Eighteen patients in group A received donor lymphocyte infusions (DLIs) to achieve disease control. At last follow-up there was no difference in disease status between the groups with 71% versus 67.5% (P =.43) of patients showing complete or partial responses in groups A and B, respectively. No significant differences were observed in event-free or overall survival between the 2 groups. In conclusion, alemtuzumab significantly reduced GVHD but its use was associated with a higher incidence of CMV reactivation. Patients receiving alemtuzumab often required DLIs to achieve similar tumor control but the incidence of GVHD was not significantly increased after DLI.     

Primary hepatocellular carcinoma in idiopathic hemochromatosis after reversal of cirrhosis

Previous reports have emphasized the association of primary hepatocellular carcinoma in patients with idiopathic hemochromatosis with cirrhosis. In contrast, patients with idiopathic hemochromatosis without cirrhosis have no increased risk of hepatocellular carcinoma. Phlebotomy therapy, by preventing the accumulation of parenchymal iron and subsequent cirrhosis, is believed to prevent hepatocellular carcinoma in the precirrhotic stage of the disease. We report the case of a 67-yr-old man with a 32-yr history of idiopathic hemochromatosis complicated by cirrhosis, who had reversal of cirrhosis with phlebotomy therapy, yet developed hepatocellular carcinoma. There was no serologic or tissue evidence of hepatitis B infection.     

Phosphorylation of the insulin receptor by AMP-activated protein kinase (AMPK) promotes ligand-independent activation of the insulin signalling pathway in rodent muscle

Aims/hypothesis  

Muscle may experience hypoglycaemia during ischaemia or insulin infusion. During severe hypoglycaemia energy production is blocked, and an increase of AMP:ATP activates the energy sensor and putative insulin-sensitiser AMP-activated protein kinase (AMPK). AMPK promotes energy conservation and survival by shutting down anabolism and activating catabolic pathways. We investigated the molecular mechanism of a unique glucose stress defence pathway involving AMPK-dependent, insulin-independent activation of the insulin signalling pathway.     

Malignancy may adversely influence the quality and behaviour of oocytes

A case series of eight cycles of in-vitro fertilization (IVF) in five women diagnosed with malignant disorders is presented. These patients chose to defer definitive treatment for a chance for preservation of potential fertility. The response of these patients to ovarian stimulation, and the outcome, was compared with 17 IVF cycles in 12 age- matched patients with isolated tubal infertility. An apparent adverse influence of malignant disease on the quality and behaviour of oocytes was observed. Despite a comparable total number of oocytes per cycle in the two groups, a significantly reduced percentage of mature oocytes was retrieved per cycle from patients with malignant diseases. The oocytes from patients with malignant disorders were of a poorer quality and exhibited a significantly impaired fertilization rate compared to the controls. We propose that neoplastic processes, irrespective of the site or cell of origin, may have a detrimental impact on the biology of oocytes, an effect akin to that seen on spermatozoa in men with certain malignancies.      

Possible involvement of oxido-nitrosative stress induced neuro-inflammatory cascade and monoaminergic pathway: Underpinning the correlation between nociceptive and depressive behaviour in a rodent model

Background

Pain and depression are frequent co-morbid disorders. The prevalence rate of depression is several times higher in patients with chronic pain than in the general population but the mechanism underlying this association is unknown. A combination of interactions between neurotransmitters, neuropeptides, oxidative and nitrosative stress and cytokines are thought to take part in pathogenesis of pain as well as depression. Thus, the aim of the present study was two-fold, first to investigate the interplay between nociception and associated depression and second to investigate the protective potential of berberine against the reserpine-induced nociceptive and depressive behaviour and further to explore the role of oxidative–nitrosative stress mediated inflammatory cascade and apoptotic signalling pathway in this dyad.

Methods and results

Nociception and associated depression were induced by administration of reserpine (1 mg/kg subcutaneous daily) for three consecutive days. This behavioural deficit was integrated with decrease in the biogenic amine (dopamine, norepinephrine and serotonin) levels along with increased substance P concentration, oxidative–nitrosative stress, inflammatory cytokines, NF-κβ and caspase-3 levels in different brain regions (cortex and hippocampus) of the reserpinised rats.

Limitation

More studies are still warranted in similar rodent models of pain and depression, so, that the present findings can be further substantiated to establish the clinical effectiveness of berberine in a subset of patients suffering from pain as well as depression.

Conclusion

The findings from the current study suggested that reserpine-induced neurochemical alterations and dysregulation of oxidative–nitrosative stress induced inflammatory cascade underlies the co-morbidity of nociceptive behaviour and associated depression in rats.     

PICC-associated Bloodstream Infections: Prevalence,Patterns, and Predictors

Background

Growing use of peripherally inserted central catheters (PICCs) has led to recognition of the risk of PICC-associated bloodstream infection. We sought to identify rates, patterns, and patient, provider, and device characteristics associated with this adverse outcome.

Methods

A retrospective cohort of consecutive adults who underwent PICC placement from June 2009 to July 2012 was assembled. Using multivariable logistic and Cox-proportional hazards regression models, covariates specified a priori were analyzed for their association with PICC-associated bloodstream infection. Odds ratios (OR) and hazard ratios (HR) with corresponding 95% confidence intervals (CI) were used to express the association between each predictor and the outcome of interest.

Results

During the study period, 966 PICCs were inserted in 747 unique patients for a total of 26,887 catheter days. Indications for PICC insertion included: long-term antibiotic administration (52%, n = 503), venous access (21%, n = 201), total parenteral nutrition (16%, n = 155), and chemotherapy (11%, n = 107). On bivariate analysis, intensive care unit (ICU) status (OR 3.23; 95% CI, 1.84-5.65), mechanical ventilation (OR 4.39; 95% CI, 2.46-7.82), length of stay (hospital, OR 1.04; 95% CI, 1.02-1.06 and ICU, OR 1.03; 95% CI, 1.02-1.04), PowerPICCs (C. R. Bard, Inc., Murray Hill, NJ; OR 2.58; 95% CI, 1.41-4.73), and devices placed by interventional radiology (OR 2.57; 95% CI, 1.41-4.68) were associated with PICC-bloodstream infection. Catheter lumens were strongly associated with this event (double lumen, OR 5.21; 95% CI, 2.46-11.04, and triple lumen, OR 10.84; 95% CI, 4.38-26.82). On multivariable analysis, only hospital length of stay, ICU status, and number of PICC lumens remained significantly associated with PICC bloodstream infection. Notably, the HR for PICC lumens increased substantially, suggesting earlier time to infection among patients with multi-lumen PICCs (HR 4.08; 95% CI, 1.51-11.02 and HR 8.52; 95% CI, 2.55-28.49 for double- and triple-lumen devices, respectively).

Conclusions

PICC-associated bloodstream infection is most associated with hospital length of stay, ICU status, and number of device lumens. Policy and procedural oversights targeting these factors may be necessary to reduce the risk of this adverse outcome.     

Two-catheter approach for ablation of accessory pathways in different locations

Radiofrequency ablation is the treatment of choice for patients with Wolff-Parkinson-White syndrome and symptomatic tachyarrhythmias. The technique involves localising the pathway with multiple catheters at various sites followed by radiofrequency energy application at that site. Single catheter approach has been described for ablation of manifest left-sided accessory pathways. In this article, we report the ablation of accessory pathways in different locations in patients with Wolff-Parkinson-White syndrome by using a two-catheter approach. Twenty-three consecutive patients with symptomatic Wolff-Parkinson-White syndrome were taken up for radiofrequency ablation with this approach. Pathways could be successfully ablated in 11 out of 13 patients with left free wall, 5 out of 7 with right posteroseptal, one patient of left posteroseptal and each of the 2 patients of right mid septal locations giving an overall success in 19/23 (82.6%) patients. Hence, two-catheter approach can be used safely to ablate accessory pathways in different locations with high success rate, thus minimising the procedure time associated with conventional approach.     

Primary gallbladder cancer: recognition of risk factors and the role of prophylactic cholecystectomy

The objective of this article is to review the available literature on the epidemiology, predisposing factors, and conditions associated with primary gallbladder cancer, and to discuss the role of prophylactic cholecystectomy in high-risk patient populations. Gallbladder cancer is a highly malignant tumor with a poor 5-yr-survival rate. It is a tumor of the elderly and has striking genetic, racial, and geographic characteristics, with an extremely high prevalence in Native Americans and Chileans. Cholelithiasis is a well-established risk factor for gallbladder cancer and the risk seems to correlate with stone size. Polyps that are >1 cm, single, sessile, and echopenic are associated with a higher risk of malignancy. Anomalous junction of pancreaticobiliary ducts (AJPBD), especially without choledochal cyst, and porcelain gallbladder are additional factors that predispose to gallbladder cancer. Lesser associations include chronic bacterial infections of the gallbladder, typhoid carrier state, certain occupational and environmental carcinogens, hormonal changes in women, and certain social, dietary, and familial factors. It is important to identify high-risk groups for gallbladder cancer because of the dismal nature of this tumor. In patients with porcelain gallbladder and anomalous junction of the pancreatic and biliary ducts, cholecystectomy is recommended provided that the patient is a good operative candidate. Patients with large solitary polyps or gallstones require close ultrasonic follow-up. With the advent of endoscopic ultrasound it is expected that early changes of malignancy in polyps will be reliably detected, and more patients will potentially be cured with a simple cholecystectomy. Through a MEDLINE/PAPERCHASE search we identified and reviewed articles regarding gallbladder cancer published in English-language journals between 1966 and 1999, using the key words biliary tract and gallbladder diseases, cancer, neoplasms, surgery, cholelithiasis, gallstones, cholecystitis, gallbladder polyps, risk factors, chemical industry, occupational diseases, typhoid, porcelain gallbladder, bacteremia, and precancerous conditions. We also used the bibliography of relevant articles to increase our search. A total of 122 publications were selected using the mentioned data source.     

Fludarabine: a new agent with major activity against chronic lymphocytic leukemia

Fludarabine was used to treat 68 patients with previously treated chronic lymphocytic leukemia (CLL). Nine (13%) patients achieved a complete remission and 30 (44%) a partial remission. The response rates for Rai stages 0 to 2, 3, and 4 were 64%, 58%, and 50% respectively. Seventeen (43%) of the 40 Rai stage 1 to 3 patients and four (19%) of the Rai stage 4 patients returned to Rai stage 0. Survival was strongly correlated with the final Rai stage achieved. The survival of the 11 partial responders with residual disease consisting only of residual bone-marrow nodules was similar to the complete responders (36+ months) and superior to the other partial response patients (16 months). The response to fludarabine was rapid, with 36 (92%) of the 39 responders having achieved at least a partial response following the first three courses. Complete responses occurred in the blood, liver, spleen, and lymph nodes in 48% to 69% of the patients. Eradication of all disease in the bone marrow occurred in only 13% of the cases. Neutropenia and thrombocytopenia occurred in 56% and 25% of evaluable courses. Major infections occurred in 9% of evaluable courses and fevers of unknown origin or minor infections in 12% of courses respectively. Myelosuppression and infection were more common in patients with initial Rai stages 3 and 4 and in nonresponding patients. Other toxicity was mild. No CNS toxicity was noted.