How real are observed trends in small correlated datasets?

The eye may perceive a significant trend in plotted time-series data, but if the model errors of nearby data points are correlated, the trend may be an illusion. We examine generalized least-squares (GLS) estimation, finding that error correlation may be underestimated in highly correlated small datasets by conventional techniques. This risks indicating a significant trend when there is none. A new correlation estimate based on the Durbin-Watson statistic is developed, leading to an improved estimate of autoregression with highly correlated data, thus reducing this risk. These techniques are generalized to randomly located data points in space, through the new concept of the nearest new neighbour path. We describe tests on the validity of the GLS schemes, allowing verification of the models employed. Examples illustrating our method include a 40-year record of atmospheric carbon dioxide, and Antarctic ice core data. While more conservative than existing techniques, our new GLS estimate finds a statistically significant increase in background carbon dioxide concentration, with an accelerating trend. We conclude with an example of a worldwide empirical climate model for radio propagation studies, to illustrate dealing with spatial correlation in unevenly distributed data points over the surface of the Earth. The method is generally applicable, not only to climate-related data, but to many other kinds of problems (e.g. biological, medical and geological data), where there are unequally (or randomly) spaced observations in temporally or spatially distributed datasets.

Persistent postsurgical pain after video-assisted thoracic surgery--an observational study.

BACKGROUND: The risk of persistent postsurgical pain (PPP) and subsequent pain-related functional impairment may potentially be reduced by video-assisted thoracic surgery (VATS) compared to thoracotomy. The aim of the study was therefore to assess in detail the incidence and consequences on activities of daily living of PPP after VATS. METHODS: Using a prospective observational design, 47 patients undergoing VATS completed both preoperative, early postoperative and 3 months follow-up. Preoperative pain, pain characteristics, psychological factors, pain-related functional impairment and quantitative sensory testing (QST) including nociceptive thresholds were compared with postoperative data. RESULTS: Only five (11%) patients developed PPP with NRS > 3 originating from the surgical area. However, about 30% of patients still reported some pain-related functional impairment from the surgical area within four well-defined domains of everyday activities. Psychological and sensory thermal tests did not predict persistent postoperative pain, except preoperative pin-prick sensitivity was higher in patients with PPP. Postoperative pain 7 days after surgery was significantly higher in PPP patients. Preoperative pain originating from remote areas did not predict PPP. CONCLUSION: The incidence of PPP, nerve damage (based on QST) and pain-related functional impairment following VATS was lower than reported following thoracotomy. No psychological or other factors predicted PPP. These findings call for further large-scale studies to support VATS to decrease PPP.

Evolution of trends in the live kidney transplant donor-recipient relationship.

OBJECTIVE: This study examined the changing demographics and age profile between living donors and their recipients. A 46-year review of living donor renal transplants in a single transplant center was performed. PATIENTS: The study included 923 consecutive living donor renal transplants from January 1966 until December 2011. RESULTS: These 923 living donor kidneys transplants represent 41% of all transplants performed during this 46-year review. The majority involved sibling donation (39.5%) followed by parent to child (32.5%). Dividing the 46-year timeframe into quartiles, the mean age of donors has remained stable at 39.3 ± 10.9 years. In contrast, the mean age of recipients has trended upwards, from 28 ± 10.7 years in the first quartile (1966-1978) to 37 ± 17.5 years in the latest quartile (2001-2011). This represents an increase every year of approximately 4 months (P < .001). Over the same period, the difference between a given donor's age and their recipient's has decreased every year by approximately 4 months (P < .001). In a linear regression model of donor-recipient categories and their age difference over time, we found that both the child-to-parent and grandchild-to-grandparent groups had the largest effect on the donor-recipient age difference when compared to the classic parent-to-child relationship. CONCLUSION: This review of center-specific data shows that the difference in the age of the donor to their recipient has been narrowing over time. We have determined that this is primarily due to changes in donor-recipient demographics with an increasing number of younger donors to older recipients. Although the medical risks to donors living with a single kidney have yet to be shown different than that of the general population, the increasing volume of donors who are younger and those with no relation to the recipient should prompt closer follow-up within the transplantation medical community.

Quantitative sensory testing of persistent pain after video-assisted thoracic surgery lobectomy.

BACKGROUND: Video-assisted thoracic surgery (VATS) lobectomy may potentially reduce the risk of post-thoracotomy pain syndrome (PTPS). However, it may still carry a risk of intraoperative nerve damage and thereby development of PTPS. Thus, our aim was to present a detailed long-term neurophysiological characterization of PTPS after VATS. METHODS: Quantitative sensory testing, using thermal and mechanical stimuli, was performed in 13 PTPS patients and 35 pain-free patients recruited 33 months after VATS lobectomy. RESULTS: When comparing the operated side with the control side in PTPS patients, increased thresholds of tactile and warmth detection were observed, while in pain-free patients, increased thresholds of warmth detection, cool detection, and heat pain were demonstrated. At the anterior porthole, pain-free patients displayed increased threshold to thermal detection when compared with the control side. Only side-to-side difference for tactile detection threshold was increased in PTPS patients compared with pain-free patients. Assessment of central sensitization showed no significant differences within or between PTPS and pain-free patients nor did group comparison of area of hypo- and hyperaesthesia to cool. Anxiety and depression scores (HADS) were higher in PTPS patients, but the area of hyper- and hypoaesthesia did not differ significantly between HADS groups. CONCLUSIONS: Increased sensory thresholds suggest nerve injury to be present on the operated side in both PTPS and pain-free patients. However, no significant quantitative differences between PTPS and pain-free patients could be found, implicating the presence of factors other than intercostal nerve injury as important for development of PTPS after VATS lobectomy.

Does ultrasonic energy for surgical dissection reduce the incidence of renal transplant lymphocele?

OBJECTIVE: To determine the difference in post-renal transplant lymphocele rate based on the surgical dissection technique for control of lymphatics by examining the historical case group under the direction of a single, university-based surgeon in a retrospective, cohort study. PATIENTS: Five hundred thirty-two consecutive renal transplant patients from January 1994 to December 2009. FINDINGS: Of the 532 cases studied, 259 (48.7%) had suture ligation and 273 (51.3%) employed ultrasonic dissection (UD) for control of lymphatics during renal transplantation. There was no difference found in the rate of lymphocele formation, requiring either percutaneous or surgical drainage, when surgical ties (8.9%) were compared to UD (9.2%; P=.999). Logistic regression analysis showed that the odds ratio for developing a lymphocele was independent of surgical dissection technique. Within the logistic analysis, the prediction for lymphocele was increased 3.29 times for pediatric patients (P=.002) and increased 2.97 times for those who received a living donor graft (P=.001), and there was a trend for those with a history of more than one renal transplant of 2.01 times (P=.079). SUMMARY: Surgical dissection technique was not a factor in the development of post-renal transplant lymphocele. Younger age, living donor transplant, and repeat transplant status were found to be predictive variables for symptomatic lymphoceles requiring drainage, which may be considered when patients present for posttransplant evaluations for laboratory alterations.

Fatigue, mood and quality of life improve in MS patients after progressive resistance training.

Fatigue occurs in the majority of multiple sclerosis patients and therapeutic possibilities are few. Fatigue, mood and quality of life were studied in patients with multiple sclerosis following progressive resistance training leading to improvement of muscular strength and functional capacity. Fatigue (Fatigue Severity Scale, FSS), mood (Major Depression Inventory, MDI) and quality of life (physical and mental component scores, PCS and MCS, of SF36) were scored at start, end and follow-up of a randomized controlled clinical trial of 12 weeks of progressive resistance training in moderately disabled (Expanded Disability Status Scale, EDSS: 3-5.5) multiple sclerosis patients including a Control group (n = 15) and an Exercise group (n = 16). Fatigue (FSS > 4) was present in all patients. Scores of FSS, MDI, PCS-SF36 and MCS-SF36 were comparable at start of study in the two groups. Fatigue improved during exercise by -0.6 (95% confidence interval (CI) -1.4 to 0.4) a.u. vs. 0.1 (95% CI -0.4 to 0.6) a.u. in controls (p = 0.04), mood improved by -2.4 (95% CI -4.1 to 0.7) a.u. vs. 1.1 (-1.2 to 3.4) a.u. in controls (p = 0.01) and quality of life (PCS-SF36) improved by 3.5 (95% CI 1.4-5.7) a.u. vs. -1.0 (95% CI -3.4-1.4) a.u. in controls (p = 0.01). The beneficial effect of progressive resistance training on all scores was maintained at follow-up after further 12 weeks. Fatigue, mood and quality of life all improved following progressive resistance training, the beneficial effect being maintained for at least 12 weeks after end of intervention.

Resistance training improves muscle strength and functional capacity in multiple sclerosis.

OBJECTIVE: To test the hypothesis that lower extremity progressive resistance training (PRT) can improve muscle strength and functional capacity in patients with multiple sclerosis (MS) and to evaluate whether the improvements are maintained after the trial. METHODS: The present study was a 2-arm, 12-week, randomized controlled trial including a poststudy follow-up period of 12 weeks. Thirty-eight moderately impaired patients with MS were randomized to a PRT exercise group (n = 19) or a control group (n = 19). The exercise group completed a biweekly 12-week lower extremity PRT program and was afterward encouraged to continue training. After the trial, the control group completed the PRT intervention. Both groups were tested before and after 12 weeks of the trial and at 24 weeks (follow-up), where isometric muscle strength of the knee extensors (KE MVC) and functional capacity (FS; combined score of 4 tests) were evaluated. RESULTS: KE MVC and FS improved after 12 weeks of PRT in the exercise group (KE MVC: 15.7% [95% confidence interval 4.3-27.0], FS: 21.5% [95% confidence interval 17.0-26.1]; p < 0.05), and the improvements were better than in the control group (p < 0.05). The improvements of KE and FS in the exercise group persisted at follow-up after 24 weeks. Also, the exercise effects were reproduced in the control group during the 12-week posttrial PRT period. CONCLUSIONS: Twelve weeks of intense progressive resistance training of the lower extremities leads to improvements of muscle strength and functional capacity in patients with multiple sclerosis, the effects persisting after 12 weeks of self-guided physical activity. LEVEL OF EVIDENCE: The present study provides level III evidence supporting the hypothesis that lower extremity progressive resistance training can improve muscle strength and functional capacity in patients with multiple sclerosis.

Synergistic immune responses induced by endogenous retrovirus and herpesvirus antigens result in increased production of inflammatory cytokines in multiple sclerosis patients.

Human endogenous retroviruses (HERV) and herpesviruses are increasingly associated with the pathogenesis of the neurological inflammatory disease multiple sclerosis (MS). Herpesviruses are capable of HERV activation and simultaneous presence of HERV and herpesvirus antigens have a synergistic effect on cell-mediated immune responses, which tend to be higher in MS patients in comparison with healthy individuals. Here, we investigate whether these synergistic immune responses are reflected in changes in the production of proinflammatory cytokines. Using enzyme-linked immunosorbent assays (ELISAs), we have performed a comparative study between MS patients and healthy controls to investigate the production of interferon (IFN)-gamma, interleukin (IL) 2, or IL-10 as well as the balance between Th1 and Th2 responses in supernatants from peripheral blood mononuclear cells (PBMC) stimulated with HERV and herpes antigen combinations. We have found a significant disproportion in Th1/Th2 responses in PBMCs from MS patients caused by the joint presence of HERV and herpes antigens. The results also showed a significantly higher IFN-gamma production in cells from MS patients; additionally, this production correlated with the synergistic cell proliferations whereas we did not find such a correlation in healthy controls. Our findings suggest that the increased production of IFN-gamma and the induced imbalance in Th1/Th2 responses favouring the inflammatory reactions in MS patients may lead to progression of the disease.

Health-related quality of life in secondary progressive multiple sclerosis.

Common disability scales in multiple sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as depression, fatigue and pain substantially influence wellbeing in MS. Health-related quality of life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens. We analysed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 secondary progressive MS (SPMS) patients participating in a randomized trial of interferon-beta1a (IFN-beta1a), 22 mug subcutaneously weekly, or matching placebo. The results did not reveal any beneficial effect of IFN-beta1a in any outcome measure. NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables. SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores. Increased fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores. SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and fatigue strongly influenced this. MS.

Cellular association and cytotoxicity of doxorubicin-loaded immunoliposomes targeted via Fab' fragments of an anti-CD74 antibody.

The purpose of our research was to evaluate in vitro therapeutic efficacy of doxorubicin (DXR)-loaded immunoliposomes with Fab' fragments of the anti-CD74 antibody LL1 attached to the surface. LL1 is well suited for targeting purposes because it is internalized very fast by B-lymphoma cells. However, at in vivo application whole antibodies show fast clearance in circulation. Taking this fact into consideration, this study was initiated to elucidate the prospects of using Fab' fragments of LL1 in stead of the whole antibody for future targeting in vivo of DXR-loaded liposomes. The Fab' fragments were covalently attached to the surface of sterically stabilized liposomes by use of a PEG-based heterobifunctinal coupling agent. LL1 Fab' conjugated sterically stabilized DXR liposomes showed approximately six times faster accumulation of the drug in Raji human B-lymphoma cells than nontargeted liposomes. In vitro cytotoxicity, quantitated by a tetrazolium assay, against Raji cells gave IC(50) values of 0.13, 0.45, and 0.11 microM for DXR-loaded immunoliposomes, DXR-loaded liposomes and free drug, respectively. The results from this study suggest that DXR-loaded immunoliposomes targeted with Fab' fragments from the anti-CD74 antibody LL1 could be a useful system for future in vivo experiments.

Presence of Epstein-Barr virus and human herpesvirus 6B DNA in multiple sclerosis patients: associations with disease activity.

OBJECTIVE: To assess the presence of Epstein-Barr virus (EBV) and human herpesvirus 6B (HHV-6B) DNA in saliva and plasma from multiple sclerosis (MS) patients enrolled in a randomized, double-blind, placebo-controlled valacyclovir treatment study. METHODS: DNA was prepared following ultracentrifugation of saliva and plasma. EBV and HHV-6B DNAs were determined by real-time polymerase chain reaction. RESULTS: EBV and HHV-6B DNAs were detected in 41% and 65% of saliva samples, respectively. In patients treated with valacyclovir, the percentage of saliva samples with EBV was significantly reduced (9%; P = 0.000017), whereas the frequency of HHV-6B positive samples was unchanged (57%; P = 0.38). Longitudinal studies demonstrated a time-dependent reduction in the frequency of saliva samples containing EBV following valacyclovir treatment. In contrast, plasma contained EBV and HHV-6B DNAs in 17% and 25% of the samples, respectively, and these numbers were not significantly reduced following valacylovir treatment (13% and 16%, respectively), nor were they different from those of healthy controls (6% and 39%, respectively). Patients with high disease activity had a significantly higher frequency of EBV (P = 0.018) and HHV-6B (P = 0.023) positive samples than did patients with low disease activity. The presence of EBV and HHV-6B was strongly correlated in plasma (P < 0.00000001), but not in saliva (P = 0.41). CONCLUSION: MS patients express EBV and HHV-6B in both saliva and plasma, but only the expression of EBV in saliva is significantly reduced following valacyclovir treatment. Although EBV and HHV-6B DNAs can be detected in plasma from healthy individuals, the co-expression of both these viruses in MS patients is highly significant and further associated with clinical activity. The observations of viral DNA in plasma are consistent with an underlying immunologic defect in MS.

Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis.

OBJECTIVE: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose-response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif), 22 micro g subcutaneously once weekly, in patients with secondary progressive MS. METHODS: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 micro g once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate. RESULTS: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 micro g v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted. CONCLUSIONS: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose-response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.

Antibodies against a human endogenous retrovirus and the preponderance of env splice variants in multiple sclerosis patients.

The human endogenous retrovirus HERV-H is associated with multiple sclerosis (MS). Previously performed reverse transcriptase-polymerase chain reactions (RT-PCR) on virion-RNA demonstrated sequence variants of the HERV-H family located in the particulate fraction of MS patient plasma samples and not in controls. In this study a significantly elevated level of antibodies towards peptides derived from HERV-H/RGH-2 DNA sequences in serum and cerebrospinal fluid (CSF) from MS patients is demonstrated. Further, Wistar rats immunized with purified virions develop a specific serologic response, indicating that some virion proteins are encoded by HERV-H-related sequences. Also shown is that in RNA from blood cells, a HERV-H protease-env splice variant can be found together with an env splice variant in about 40% of MS patients but only in 10% of controls. The results substantiate the association between activated HERV-H and MS, but a causal relationship is yet to be demonstrated. HERV-H could represent a causal factor either by eliciting an autoimmune response or through the pathogenic potential of the retrovirus itself.

Altered CD8+ T cell responses to selected Epstein-Barr virus immunodominant epitopes in patients with multiple sclerosis.

An increased frequency of antiviral CD8+ T cells is seen in chronic viral infections. During herpes virus infections the expanded CD8+ T cells are thought to control the reactivation of the latent infection. Because multiple sclerosis (MS), a presumed autoimmune disease of the central nervous system, has been associated with a late Epstein-Barr virus (EBV) infection, we wished to examine whether the CD8+ T cell response to EBV epitopes differed between MS patients and healthy controls. Here we report an increased frequency of CD8+ T cells responding to EBV epitopes from nuclear antigen 3 A (HLA-A2/CLG) and latent membrane protein 2 (HLA-B7/RPP) in MS patients. Noticeably, the altered CD8+ T cell response occurred to some but not all EBV epitopes and did not reach the high level seen during acute infection. The responses towards two immunodominant epitopes from human cytomegalovirus (HCMV) were similar in MS patients and normal controls. Together, our data demonstrate the presence of an increased frequency of CD8+ T cells reacting with two epitopes from EBV in patients with MS. The altered response to only two of the tested EBV epitopes would be consistent with the presence of cross-reactive epitopes.

Pretargeting for cancer radioimmunotherapy with bispecific antibodies: role of the bispecific antibody's valency for the tumor target antigen.

The use of a divalent effector molecule improves bispecific antibody (bsMAb) pretargeting by enabling the cross-linking of monovalently bound bsMAb on the cell surface, thereby increasing the functional affinity of a bsMAb. In this work, it was determined if a bsMAb with divalency for the primary target antigen would improve bsMAb pretargeting of a divalent hapten. The pretargeting of a (99m)Tc-labeled divalent DTPA-peptide, IMP-192, using a bsMAb prepared by chemically coupling two Fab' fragments, one with monovalent specificity to the primary target antigen, carcinoembryonic antigen (CEA), and to indium-loaded DTPA [DTPA(In)], was compared to two other bsMAbs, both with divalency to CEA. One conjugate used the whole anti-CEA IgG, while the other used the anti-CEA F(ab')(2) fragment to make bsMAbs that had divalency to CEA, but with different molecular weights to affect their pharmacokinetic behavior. The rate of bsMAb blood clearance was a function of molecular weight (IgG x Fab' < F(ab')(2) x Fab' < Fab' x Fab' conjugate). The IgG x Fab' bsMAb conjugate had the highest uptake and longest retention in the tumor. However, when used for pretargeting, the F(ab')(2) x Fab' conjugate allowed for superior tumor accretion of the (99m)Tc-IMP-192 peptide, because its more rapid clearance from the blood enabled early intervention with the radiolabeled peptide when tumor uptake of the bsMAb was at its peak. Excellent peptide targeting was also seen with the Fab' x Fab' conjugate, albeit tumor uptake was lower than with the F(ab')(2) x Fab' conjugate. Because the IgG x Fab' bsMAb cleared from the blood so slowly, when the peptide was given at the time of its maximum tumor accretion, the peptide was captured predominantly by the bsMAb in the blood. Several strategies were explored to reduce the IgG x Fab' bsMAb remaining in the blood to take advantage of its 3-4-fold higher tumor accretion than the other bsMAb conjugates. A number of agents were tested, including those that could clear the bsMAb from the blood (e.g., galactosylated or nongalactosylated anti-id antibody) and those that could block the anti-DTPA(In) binding arm [e.g., DTPA(In), divalent-DTPA(In) peptide, and DTPA coupled to bovine serum albumin (BSA) or IgG]. When clearing agents were given 65 h after the IgG x Fab' conjugate (time of maximum tumor accretion for this bsMAb), (99m)Tc-IMP-192 levels in the blood were significantly reduced, but a majority of the peptide localized in the liver. Increasing the interval between the clearing agent and the time the peptide was given to allow for further processing of the bsMAb-clearing agent complex did not improve targeting. At the dose and level of substitution tested, galacosylated BSA-DTPA(In) was cleared too quickly to be an effective blocking agent, but BSA- and IgG-DTPA(In) conjugates were able to reduce the uptake of the (99m)Tc-IMP-192 in the blood and liver. Tumor/nontumor ratios compared favorably for the radiolabeled peptide using the IgG x Fab'/blocking agent combination and the F(ab')(2) x Fab' (no clearing/blocking agent), and peptide uptake 3 h after the blocking agent even exceeded that of the F(ab')(2) x Fab'. However, this higher level of peptide in the tumor was not sustained over 24 h, and actually decreased to levels lower than that seen with the F(ab')(2) x Fab' by this time. These results demonstrate that divalency of a bsMAb to its primary target antigen can lead to higher tumor accretion by a pretargeted divalent peptide, but that the pharmacokinetic behavior of the bsMAb also needs to be optimized to allow for its clearance from the blood. Otherwise, blocking agents will need to be developed to reduce unwanted peptide uptake in normal tissues.

A randomized, double-blind, placebo-controlled MRI study of anti-herpes virus therapy in MS.

OBJECTIVE: To evaluate the effect of treatment with the antiherpes drug valacyclovir on MRI-evident lesions in patients with relapsing-remitting MS in a phase 2, randomized, double-blind, placebo-controlled study. BACKGROUND: It has been postulated from virologic studies that herpesvirus infection could play a role in the progression of MS. METHODS: Patients were eligible for the study if they had had two or more MS relapses in the 2-year period before enrollment. Seventy patients with Expanded Disability Status Scale scores of 0 to 5.5 were randomly assigned to receive 1 gram of valacyclovir (n = 36) or placebo (n = 34) three times daily for 24 weeks. Patients underwent MRI every fourth week for 32 weeks: twice during pretreatment, six times during treatment, and once after treatment. Scoring of neurologic disability was performed at the start and end of the treatment period. The primary endpoint was the number of new active MRI-evident lesions over 24 weeks of treatment. Secondary endpoints included other MRI measures and clinical endpoints. RESULTS: The mean number of new active lesions +/- SD per patient during 24 weeks of treatment with valacyclovir was 11.9 +/- 17.6 and that during placebo treatment was 14.5 +/- 21.4. A protocol-planned exploratory analysis stratified patients according to baseline activity; this analysis showed that patients with high levels of disease activity in the valacyclovir treatment group (n = 17) developed fewer new active lesions per scan than did those in the placebo treatment group (n = 11). The median number (Q(1), Q(3) range) of active lesions was 2.0 (1.38, 3.96) in the valacyclovir treatment group and 6.5 (2.63, 9.0) in the placebo treatment group. CONCLUSIONS: Valacyclovir treatment did not reduce the formation of active lesions in patients with relapsing-remitting MS who had two or more relapses during the previous 2-year period. In a subgroup of patients with high levels of disease activity who had more than one active MRI-evident lesion during 4 weeks, valacyclovir treatment was associated with a reduced number of new active MRI-evident lesions and with an increase in the number of scans free of new active lesions. The results of the exploratory subgroup analysis provide support for further studies of antiherpes therapy for patients with MS and high levels of MRI-evident disease activity.

Convergent synthesis of fully functionalized ring C allocolchicinoids. Benzannulation approach.

[reaction: see text]. A novel convergent approach to fully functionalized ring C allocolchicinoids is developed which is based on the benzannulation reaction of Fischer carbene complexes with alkynes. The efficacy of this strategy was established with the conversion of bromide 1a (R1 = Me, R2 = H) to the biaryl phenol 3a (R = Me, R(L) = Pr, R(S) = H) via the carbene complex 2a. Bromide 1b (R1 = t-Bu, R2 = OMe) was then used for the analogous preparation of the diastereomeric allocolchicinoids 3b (R = Me, R(L) = Pr, R(S) = H).

Radioimmunotherapy of a human lung cancer xenograft with monoclonal antibody RS7: evaluation of (177)Lu and comparison of its efficacy with that of (90)Y and residualizing (131)I.

UNLABELLED: Tumor targeting and therapeutic efficacy of (177)Lu-labeled monoclonal antibody (mAb) RS7 (antiepithelial glycoprotein-1) was evaluated in a human nonsmall cell lung carcinoma xenograft model. The potential of (177)Lu-labeled RS7 was compared with that of RS7 labeled with (90)Y and a residualizing form of (131)I. METHODS: A 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) conjugate of RS7 was used for radiolabeling with (177)Lu-acetate or (88/90)Y-acetate. Biodistribution and therapy studies were conducted in nude mice with subcutaneous Calu-3 xenografts. Therapy studies were performed using the maximal tolerated doses (MTDs) of (90)Y-DOTA-RS7 (3.9 MBq [105 microCi]) and (177)Lu-DOTA-RS7 (10.2 MBq [275 microCi]) and compared with the data obtained using the MTD (13.0 MBq [350 microCi]) of a residualizing form of (131)I-RS7. RESULTS: Radiolabeling of RS7-DOTA conjugate with (177)Lu-acetate was facile. (177)Lu-DOTA-RS7 displayed biodistribution results that were nearly identical to that of the (88)Y analog in a paired-label study. The mean percentage injected doses per gram (%ID/g) for (177)Lu-RS7 and (88)Y-RS7 (in parentheses) in tumor were 38.3 %ID/g (39.1 %ID/g), 63.0 %ID/g (66.0 %ID/g), 63.0 %ID/g (65.8 %ID/g), and 34.0 %ID/g (34.9 %ID/g) on days 1, 3, 7, and 14, respectively. Elimination of established tumors, with an initial mean tumor volume of 0.24 cm(3), was shown using doses of (177)Lu-DOTA-RS7 ranging from 5.6 to 9.3 MBq (150--250 microCi) per nude mouse, with no significant difference in response rate noted between the doses in this range. Specificity of the therapeutic effect was shown in an isotype-matched control experiment, in which (177)Lu-DOTA-RS7 was markedly more effective than the (177)Lu-DOTA control antibody. A comparison of the therapeutic efficacies of (177)Lu-DOTA-RS7 and (90)Y-DOTA-RS7, using mice with established tumors with an initial mean tumor volume of 0.85 cm(3), indicated similar tumor growth inhibition and similar tumor regrowth profiles. The therapy data were similar to those obtained with residualizing (131)I-RS7 obtained at the same time. CONCLUSION: (177)Lu-RS7 is an effective radioimmunoconjugate for radioimmunotherapy. With its radiophysical properties similar to those of (131)I, coupled with its facile and stable attachment to mAb, (177)Lu promises to be an alternative to (131)I, and a complement to (90)Y, in radioimmunotherapy.