Response rate,durability of response,and survival after thalidomide therapy for relapsed multiple myeloma

OBJECTIVE: To assess response rate, duration of response, progression-free survival, and toxicity of thalidomide in patients with relapsed multiple myeloma. PATIENTS AND METHODS: Thirty-two patients with relapsed multiple myeloma were entered into the study between April 29, 1999, and June 20, 2000. They were given oral thalidomide at a dosage of 200 mg/d for 2 weeks, which was then increased as tolerated to a maximum of 800 mg/d. The primary end point of the study was response rate. RESULTS: The median age of the patients was 67 years (range, 36-78 years). Prior chemotherapy had failed in all patients, and stem cell transplantation had failed in 5 patients (16%). There were 10 confirmed responses, yielding a response rate of 31%. In addition, there was 1 unconfirmed partial response and 7 minimal responses with no complete responses. The median duration of response was 11.9 months (range, 3.7-203 months). Overall, 20 patients have died, and 26 patients have experienced disease progression. The median follow-up of surviving patients was 28.5 months (range, 193-34.0 months), with a median progression-free survival of 8.6 months (95% confidence interval [CI], 4.7-16 months). The median progression-free survival among the responding patients was 15.7 months (95% CI, 8.6-25.6 months). The median overall survival for the entire group was 22 months (95% CI, 10.6-35.9 months). The most common treatment-related nonhematologic toxic effects (grade >3) were neuropathy (16%), sedation (13%), febrile neutropenia (6%), and constipation (6%). CONCLUSIONS: Thalidomide is useful in the treatment of patients with relapsed multiple myeloma and produced durable response in approximately one third of patients, with median response duration of nearly 1 year.     

Percutaneous direct endoscopic pancreatic necrosectomy

Approximately 10%-20% of the cases of acute pancreatitis have acute necrotizing pancreatitis. The infection of pancreatic necrosis is typically associated with a prolonged course and poor prognosis. The multidisciplinary, minimally invasive “step-up” approach is the cornerstone of the management of infected pancreatic necrosis (IPN). Endosonography-guided transmural drainage and debridement is the preferred and minimally invasive technique for those with IPN. However, it is technically not feasible in patients with early pancreatic/peripancreatic fluid collections (PFC) (< 2-4 wk) where the wall has not formed; in PFC in paracolic gutters/pelvis; or in walled off pancreatic necrosis (WOPN) distant from the stomach/duodenum. Percutaneous drainage of these infected PFC or WOPN provides rapid infection control and patient stabilization. In a subset of patients where sepsis persists and necrosectomy is needed, the sinus drain tract between WOPN and skin-established after percutaneous drainage or surgical necrosectomy drain, can be used for percutaneous direct endoscopic necrosectomy (PDEN). There have been technical advances in PDEN over the last two decades. An esophageal fully covered self-expandable metal stent, like the lumen-apposing metal stent used in transmural direct endoscopic necrosectomy, keeps the drainage tract patent and allows easy and multiple passes of the flexible endoscope while performing PDEN. There are several advantages to the PDEN procedure. In expert hands, PDEN appears to be an effective, safe, and minimally invasive adjunct to the management of IPN and may particularly be considered when a conventional drain is in situ by virtue of previous percutaneous or surgical intervention. In this current review, we summarize the indications, techniques, advantages, and disadvantages of PDEN. In addition, we describe two cases of PDEN in distinct clinical situations, followed by a review of the most recent literature.     

B cells are important as antigen presenting cells for induction of MHC-restricted arthritis in transgenic mice

Rheumatoid arthritis and its animal model, collagen-induced arthritis, are known as a T and B cell dependent disease. To analyze the role of B cells in arthritis, we generated B cell deficient (microMT) mice carrying HLA-DQ8 as transgene, Abetao.DQ8.micromt mice. HLA-DQ8 transgenic mice (Abetao.DQ8) are susceptible to collagen induced arthritis, an animal model for inflammatory arthritis. Deletion of IgM gene led to the absence of B cells while T cells were comparable to Abetao.DQ8 mice. Arthritis and autoantibodies was completely abrogated in B cell deficient DQ8 mice. T cell response and proinflammatory cytokine production in response to type II collagen and its derived peptides in vitro was significantly decreased despite an increased number of Mac-1 positive cells in DQ8.micromt mice compared to DQ8 mice suggesting B cells could be important for antigen presentation as well. In vitro substitution of B cells from wild type mice restored the response in DQ8.micromt mice. B cells could also present CII-derived peptides to antigen-specific DQ8-restricted hybridomas reinforcing the role of B cells in presentation of antigens to T cells. The data suggest that B cells can be involved in pathogenesis of arthritis by producing autoantibodies and antigen presentation.     

Neuroticism and brain responses to anticipatory fear

Personality is known to influence cognitive and affective functioning as well as the risk of psychiatric disorders. Exploration of the neurobiological correlates of personality traits has the potential to enhance understanding of their significance in development of related psychopathological states. The authors examined the association between individual differences in neuroticism and brain activity in response to threat of electric shocks. Fourteen right-handed healthy men underwent functional MRI during a 5-min experiment that involved repeated presentations of two 30-s alternating conditions. In 1 of these conditions, subjects were told to expect mild but painful electric shocks; there was no possibility of receiving shocks in the other condition. The results revealed that neuroticism correlated positively with the ratings of fear of shock and negatively (indicating suppression) with brain activity from safe to shock conditions in the anterior and posterior cingulate, superior/middle temporal gyrus extending to the hippocampus, precuneus, putamen, thalamus, and middle occipital gyrus. The observations support recent psychophysiological research that has demonstrated reduced processing of pain in subjects with higher levels of neuroticism, especially the anxiety component of this trait.     

Insulin replacement restores the behavioral effects of quinpirole and raclopride in streptozotocin-treated rats

Streptozotocin (STZ)-induced diabetes can modulate dopamine (DA) neurotransmission and thereby modify the behavioral effects of drugs acting on DA systems. Insulin replacement, and in some conditions repeated treatment with amphetamine, can partially restore sensitivity of STZ-treated rats to dopaminergic drugs. The present study sought to characterize the role of insulin and amphetamine in modulating the behavioral effects of drugs that selectively act on D2/D3 receptors. In control rats, quinpirole and quinelorane produced yawning, whereas raclopride and gamma-hydroxybutyric acid (GHB) produced catalepsy. Raclopride antagonized quinpirole- and quinelorane-induced yawning with similar potency. STZ treatment increased blood glucose concentration, decreased body weight, and markedly reduced sensitivity to quinpirole-induced yawning, quinelorane-induced yawning as well as to raclopride-induced catalepsy, while enhancing sensitivity to GHB-induced catalepsy. Repeated treatment with amphetamine partially restored sensitivity of STZ-treated rats to amphetamine-stimulated locomotion and also produced conditioned place preference, without affecting blood glucose and body weight changes. However, amphetamine treatment did not restore sensitivity to the behavioral effects of quinpirole, raclopride, or GHB, suggesting differential regulation of dopamine transporter activity and sensitivity of D2 receptors in hypoinsulinemic rats. Insulin replacement in STZ-treated rats normalized blood glucose and body weight changes and fully restored sensitivity to quinpirole-induced yawning, as well as to raclopride-induced catalepsy, while reducing sensitivity to GHB-induced catalepsy. Overall, these data indicate that changes in insulin status markedly affect sensitivity to the behavioral effects of dopaminergic drugs. The results underscore the importance of insulin in modulating DA neurotransmission; these effects might be especially relevant to understanding the co-morbidity of eating disorders and substance abuse.     

Integrating functional and anatomical information to facilitate cardiac resynchronization therapy

Multiple imaging modalities are required in patients receiving cardiac resynchronization therapy. We have developed a strategy to integrate echocardiographic and angiographic information to facilitate left ventricle (LV) lead position. Full three-dimensional LV-volumes (3DLVV) and dyssynchrony maps were acquired before and after resynchronization. At the time of device implantation, 3D-rotational coronary venous angiography was performed. 3D-models of the veins were then integrated with the pre- and post-3DLVV. In the case displayed, prior to implantation, the lateral wall was delayed compared to the septum. The LV lead was positioned into the vein over the most delayed region, resulting in improved LV synchrony.     

Non‐Robertsonian translocation t (2;11) is associated with infertility in an oligospermic man

Infertility is a major health problem which affects approximately 22% of married couples in reproductive age. Chromosomal defects are the most common genetic abnormalities in infertile men, with an incidence of cytogenetic abnormalities ranging from 2.1% to 15.5%. We describe here the clinical and cytogenetic studies carried out in a couple with repeated abortions. Cytogenetic analysis of the couple showed a de novo chromosomal translocation t (2;11)(p14;q21) in the male partner and a normal 46, XX karyotype in the female counterpart. Such an autosomal translocation may lead to the disruption of genes responsible for spermatogenesis or impaired synaptic complex pairing during meiosis resulting in reproductive failure.     

Efficacy of granulocyte-macrophage colony-stimulating factor or lamivudine combination with recombinant interferon in non-responders to interferon in hepatitis B virus-related chronic liver disease patients

BACKGROUND AND AIMS: Non-response to interferon (IFN) monotherapy is a major therapeutic problem in the management of chronic hepatitis B infection. The efficacy of combination therapy to enhance the immunomodulatory effect of IFN by combining granulocyte-macrophage colony-stimulating factor (GMCSF) or decreasing viral load by adding an antiviral agent such as lamivudine was evaluated prospectively. METHODS: Twenty-four patients with chronic hepatitis B who were non-responders to previous IFN therapy were randomized to receive an IFN and GMCSF (group A, n = 10) or IFN and lamivudine (group B, n = 14) combination for 6 months. The end-of-treatment response was assessed by hepatitis B virus (HBV)-DNA and hepatitis B e antigen (HBeAg) determination. RESULTS: All patients successfully completed both the treatment schedules. The mean age, alanine aminotransferase (ALT) levels, liver histology, HBV-DNA levels and distribution of HBV genotypes were comparable between the two groups. At the end of treatment there was a significant decrease in mean ALT levels. The HBV-DNA and HBeAg loss was seen in six of 10 (60%) patients in group A and in seven of 14 (50%) patients in group B. During a mean follow-up of 15 +/- 3 months, two of six (33%) patients in group A and three of seven (43%) patients in group B relapsed with HBV-DNA and HBeAg positivity, which meant an overall sustained response of 40% and 28%, respectively. None of the factors such as HBV viral load, ALT levels or liver histology could predict the non-response to combination therapy or occurrence of relapse. There was a trend in patients with genotype A compared with genotype D towards non-response to therapy, although the difference was not significant. CONCLUSIONS: The combination of IFN plus GMCSF or lamivudine was effective in non-responders to IFN monotherapy. Larger studies using such combination therapies would be helpful in improving treatment strategies for chronic hepatitis B.