A phase I/II trial of bortezomib combined concurrently with gemcitabine for relapsed or refractory DLBCL and peripheral T‐cell lymphomas

There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) and peripheral T‐cell lymphoma (PTCL). We conducted a phase I/II trial with bortezomib (dose‐escalated to 1·6 mg/m²) given concurrently with gemcitabine (800 mg/m²) days 1 + 8 q21 d. Of 32 patients, 16 each had relapsed/refractory PTCL and DLBCL. Median prior therapies were 3 and 35% had failed transplant. Among the first 18 patients, 67% experienced grade 3/4 neutropenia and/or grade 3/4 thrombocytopenia resulting in repeated treatment delays (relative dose intensity: 46%). Thus, the study was amended to give bortezomib and gemcitabine days 1 + 15 q28 d, which resulted in markedly improved tolerability. Among all patients, the overall response rate (ORR) was 24% with 19% complete remission (CR; intent‐to‐treat (ITT) ORR 16%, CR 13%), which met criteria for futility. The ORR for DLBCL was 10% (CR 10%) vs. 36% for PTCL (CR 27%). Among 6 PTCL patients treated on the modified schedule, ORR by ITT was 50% (CR 30%). Altogether, concurrent bortezomib/gemcitabine given days 1 + 8 q21 d was not tolerable, while modification to a bi‐monthly schedule allowed consistent treatment delivery. Whereas efficacy of this combination was low in heavily pre‐treated DLBCL, there was a signal of activity in relapsed/refractory PTCL utilizing the modified schedule.     

Final results of a long-term,clinical follow-up in fatty liver patients

Objective. There is increasing focus on non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to conduct a long-term clinical follow-up of patients with biopsy-confirmed fatty liver without inflammation or significant fibrosis (pure fatty liver), to analyse for potential risk factors at the time of index liver biopsy important for survival and the development of cirrhosis and to describe the causes of death. Material and methods. Patients were linked through their personal identification number to the Danish National Registry of Patients and the Register of Causes of Death. All admissions, discharge diagnoses and causes of death during follow-up were collected. All surviving patients were invited to a clinical follow-up. Results. The follow-up period was 20.4 and 21.0 years, respectively, for the NAFLD and alcoholic fatty liver disease (AFLD) groups. Two NAFLD patients (1.2%) developed cirrhosis during the follow-up period versus 54 (22%) AFLD patients. Sixty-four percent of 178 surviving patients out of an original cohort of 417 patients attended the clinical follow-up. In NAFLD patients, none of the risk factors studied was significant in relation to the risk of death. Patients with AFLD died primarily from cirrhosis and other alcohol-related disorders, whereas in patients with NAFLD the main causes of death were cardiovascular disease and cancer. Conclusions. For patients with pure non-alcoholic fatty liver, survival was good and independent of the histological, clinical and biochemical characteristics at the time of biopsy; the main causes of death were cardiovascular disease and cancer.     

Cerebrospinal fluid transthyretin in multiple sclerosis

Transthyretin is an important choroid plexus-specific transport protein that has been reported to be both elevated and decreased in the CSF of multiple sclerosis patients. We report that CSF transthyretin levels are not altered in MS, indicating that choroid plexus function with respect to this protein is unaffected in this disease.     

Long-term results of extracapsular cataract extraction with posterior chamber lens implantation: sodium hyaluronate 1% vs hydroxypropyl methylcellulose 2%.

We investigated the frequency of surgical complications and the long-term outcome in terms of visual acuity, intraocular pressure and post-operative complications in 206 extracapsular cataract extraction procedures with posterior chamber lens implantation using either sodium hyaluronate 1% (Healon) or hydroxypropyl-methylcellulose 2% over a follow-up period of 12 months. We found no significant difference in the results of using either of the two viscoelastic agents.     

Expression of the homeobox genes PAX6, OTX2, and OTX1 in the early human fetal retina

We studied the spatial and temporal expression of the homeobox genes PAX6, OTX2, and OTX1 using a developmental series of human fetal eyes aged from 6 to 10 weeks post-conception. Previous animal studies have shown that PAX6 may regulate progenitor cell proliferation, timing of differentiation and neural retina cell fate determination. OTX2 may play a role in development of the retinal pigment epithelium and photoreceptor differentiation, whereas OTX1 may be important in ciliary body development.     

鼠粒细胞-巨噬细胞集落刺激因子基因转染小鼠黑色素瘤B16F1细胞

目的：探讨基因转移载体脂质体介导转染的鼠粒细胞－巨噬细胞集落刺激因子（mGM-CSF)基因在B16F1细胞的表达动态及表达产物的生物活性。方法：脂质体和质粒DNA复合，转染10^6 B16F1细胞，连续5d换细胞培养液，并检测其中的mGM-CSF含量。采用[^3HTdR]渗入法，测定DA1G细胞和转染后第一天收获的以1：10对倍稀释到1：640的上清液及[^3HTdR]混合培养后，渗入到DA1G细胞的[^3HTdR]量（cpm)，以分析表达产物的生物活性。结果：转染B16F1细胞的mGM-CSF基因得到有效表达。但随着时间的推移，表达由第1天的135ng/ml下降到第5天的42.2ng/ml。渗入到DA1G细胞的[^3HTdR]量（cpm)随上清液的稀释而逐步下降，由1：10稀释度的9371下降到1：640时的3251。和DMEM混合培养的DA1G细胞的[^3HTdR]渗入量（cpm)仅为472。结论：脂质体作为基因转移载体可有效地介导mGM-CSF基因转染B16F1细胞，并获得有生物活性的表达。     

Selective degeneration of dorsal root ganglia and dorsal nerve roots in methyl mercury-intoxicated rats: a stereological study

The components of the nervous system of rats that are most critically affected by methyl mercury are still a matter of debate. A recent stereological study of rats with typical symptoms resulting from methyl mercury intoxication demonstrated that the morphology of cerebellar granule cells and Purkinje cells were unchanged at the light microscopic level, even though there was pronounced degeneration of myelinated axons in dorsal nerve root nerves. In the present study, unbiased stereological methods were used to quantify morphological changes in the dorsal root ganglion, and dorsal and ventral nerve roots of the rats used in the previous study. The rats were treated with methyl mercury (2 mg daily/kg, per os) for a 19-day period that was followed by a 32-day period without treatment. The means of the total numbers of A-cell and B-cell perikarya in the dorsal root ganglion of the intoxicated rats were reduced by 60% and 24%, respectively. The mean volume of A-cell perikarya in rats of the experimental group was reduced by 22%, whereas the mean volume of B-cell perikarya was the same in the two groups. In the experimental group, the total number of myelinated axons in the dorsal nerve roots was reduced by 60%, whereas no difference was found in the ventral nerve roots. The areas of axon and myelin sheath, dorsal and ventral nerve roots were not affected. This study demonstrates that extensive loss of dorsal root ganglion cells and myelinated axons in dorsal nerve roots precedes light microscopical changes in the ventral nerve roots and the cerebellum of rats intoxicated with methyl mercury. Received: 16 January 1998 / Revised, accepted: 23 February 1998     

The Role of TNF Receptor and TNF Superfamily Molecules in Organ Transplantation

The rapid increase in the number of molecules demonstrated to regulate immune responses has provided new opportunities for manipulation of the recipient immune response to transplanted organs. Molecules belonging to the TNF receptors and TNF superfamily are increasingly recognized as playing a major role in the regulation of immune responses to tumor, viral, and autoantigens. The mechanisms by which these molecules regulate immune responses are diverse. TNF receptor-related molecules have been shown to control the development of secondary lymphoid organs, affect the activation and survival of T cells and antigen presenting cells, and alter cytokine and chemokine production. An increasing amount of data suggest that some TNFR superfamily members are particularly important for the function of CD8+ T cells. Based on our current understanding of these molecules it seems highly likely that strategies that target selected TNFR/TNF superfamily molecules will be useful for controlling or preventing the rejection of transplanted organs and tissues.