Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial.

OBJECTIVE: B cells and the humoral immune system have been implicated in the pathogenesis of multiple sclerosis (MS). This study sought to evaluate the efficacy, safety, and tolerability of add-on therapy with rituximab, a monoclonal antibody that depletes circulating B cells, in subjects with relapsing MS with breakthrough disease defined by clinical and MRI activity (Class III evidence). METHODS: Thirty subjects with a relapse within the past 18 months despite use of an injectable disease-modifying agent, and with at least 1 gadolinium-enhancing (GdE) lesion on any of 3 pretreatment MRIs, received rituximab administered at 375 mg/m(2) weekly x 4 doses. Three monthly posttreatment brain MRI scans were obtained beginning 12 weeks after the first infusion. Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) were obtained at baseline and throughout the posttreatment follow-up. RESULTS: GdE lesions were reduced after treatment with rituximab, with 74% of posttreatment MRI scans being free of GdE activity compared with 26% free of GdE activity at baseline (p < 0.0001). Median GdE lesions were reduced from 1.0 to 0, and mean number was reduced from 2.81 per month to 0.33 after treatment (88% reduction). MSFC improved as well (p = 0.02). EDSS remained stable. CONCLUSION: Rituximab add-on therapy was effective based upon blinded radiologic endpoints in this phase II study. In combination with standard injectable therapies, rituximab was well-tolerated with no serious adverse events. B-cell-modulating therapy remains a potential option for treatment of patients with relapsing MS with an inadequate response to standard injectable therapies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that add-on rituximab reduces gadolinium-enhancing brain lesions in multiple sclerosis.

Inhibition of angiogenesis by a Semliki Forest virus vector expressing VEGFR-2 reduces tumour growth and metastasis in mice.

Inhibition of tumour angiogenesis has been shown to restrict primary tumour growth and metastatic spread. This study examines the active induction of immune responses against tumour endothelial cells following immunization with recombinant Semliki Forest virus (rSFV) particles encoding murine vascular endothelial growth factor receptor-2 (VEGFR-2). This approach was tested in two murine tumour models, CT26 colon carcinoma and 4T1 metastasizing mammary carcinoma. Tumour growth and metastatic spread were shown to be significantly inhibited in mice that were prophylactically vaccinated or therapeutically treated with rSFV particles coding for VEGFR-2. Microvessel density analysis showed that immunization with rSFV led to significant inhibition of tumour angiogenesis. Therapeutic efficacy was found to be associated with the induction of an antibody response against VEGFR-2. Co-immunization of mice with rSFV particles encoding VEGFR-2 and interleukin (IL)-12 completely abrogated both the antibody response and the antitumour effect. However, co-immunization of mice with VEGFR-2 and IL-4 encoding particles was shown both to induce higher titres of anti-VEGFR-2 antibodies and lead to enhanced survival following tumour challenge when compared to mice vaccinated with VEGFR-2 particles alone. These findings indicate that active immunization with rSFV particles coding for VEGFR-2 can break immunological tolerance and could potentially be used as part of a novel treatment for cancer.

The heat shock response reduces myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in mice.

The stress response (SR) can block inflammatory gene expression by preventing activation of transcription factor nuclear factor-kappa B (NF-kappaB). As inflammatory gene expression contributes to the pathogenesis of demyelinating diseases, we tested the effects of the SR on the progression of the demyelinating disease experimental autoimmune encephalomyelitis (EAE). EAE was actively induced in C57BL/6 mice using an encephalitogenic myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide. Whole body hyperthermia was used to induce a heat shock response (HSR) in immunized mice 2 days after the booster MOG(35-55) peptide injection. The HSR reduced the incidence of EAE by 70%, delayed disease onset by 6 days, and attenuated disease severity. The HSR attenuated leukocyte infiltration into CNS assessed by quantitation of perivascular infiltrates, and by reduced staining for CD4 and CD25 immunopositive T-cells. T-cell activation, assessed by the production of interferon gamma (IFNgamma) in response to MOG(35-55), was also decreased by the HSR. The HSR reduced inflammatory gene expression in the brain that normally occurs during EAE, including the early increase in RANTES (regulated on activation of normal T-cell expressed and secreted) expression, and the later expression of the inducible form of nitric oxide synthase. The early activation of transcription factor NF-kappaB was also blocked by the HSR. The finding that the SR reduces inflammation in the brain and the clinical severity of EAE opens a novel therapeutic approach for prevention of autoimmune diseases.

Treatment of prognosis of primary breast lymphoma: a review of 13 cases.

Primary non-Hodgkin's lymphoma (NHL) of the breast is a rare entity that does not have a well-defined treatment strategy. At presentation, most patients are clinically thought to have a primary breast carcinoma, and the diagnosis of lymphoma is made at biopsy. Once the diagnosis of lymphoma is made, patients are treated with some combination of chemotherapy, radiation therapy, and surgery. We review The Cleveland Clinic Foundation experience with primary breast lymphoma. Between 1980 and 1996, 17 patients with primary breast lymphoma were seen at The Cleveland Clinic Foundation, and 13 had follow-up information available. All patients underwent a staging workup including computed tomography (CT) scan of the chest, abdomen, and pelvis, as well as bilateral bone marrow biopsies; all patients staged IE (breast involvement only) or IIE (limited to the breast and ipsilateral axilla) were included. We did not include patients with more extensive supradiaphragmatic nodal involvement who were stage IIE. Patients received some combination of surgery, radiation, and chemotherapy. The median follow-up was 34 months, with a range of 7 to 138 months. There was an equal incidence of right- versus left-sided lesions. Five patients survived at least 5 years from the time of diagnosis. Long-term survival in patients with primary NHL of the breast is possible. We recommend treating patients with aggressive NHL of the breast with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, followed by involved field radiation and treating those patients with indolent lymphoma with involved field radiation alone.

The acute effects of postoperative radiation therapy on the transverse rectus abdominis myocutaneous flap used in immediate breast reconstruction.

PURPOSE: To analyze the acute effects of postoperative radiation therapy on the transverse rectus abdominis myocutaneous (TRAM) flap reconstruction following modified radical mastectomy for breast cancer. METHODS AND MATERIALS: Twenty-five consecutive patients were treated with postoperative radiation therapy after TRAM flap reconstruction between 1985 and 1999. The radiation records for these patients were retrospectively reviewed. Information regarding treatment techniques, timing, and dose was obtained and correlated with the extent of erythema, desquamation, and the need for treatment break. RESULTS: The median age was 48 years. The median dose of chest wall radiation was 5040 cGy. Additional boost doses were delivered in 13 patients. Twelve patients (48%) developed mild erythema in the treatment field during the course of treatment and 13 patients (52%) developed moderate (40%) or brisk (12%) erythema. Only 10 patients (40%) developed any kind of desquamation; 5 patients (20%) developed dry desquamation and another 5 patients (20%) developed moist desquamation. No patients required a break in the course of treatment because of acute side effects. None of the parameters evaluated (the use of chemotherapy prior to radiation, the interval between surgery and radiation, smoking, prior incidence of fat necrosis, the use of bolus during radiation, and the use of a boost) were predictive of an increased incidence of either the extent of erythema or the development of desquamation in the treatment field. CONCLUSION: Postmastectomy radiation for TRAM flap reconstruction is well tolerated and is not associated with an increased incidence of acute side effects. Radiation technique and the use of preradiation chemotherapy do not appear to be correlated with an increased incidence of acute side effects.

Importance of high radiation doses (72 Gy or greater) in the treatment of stage T1-T3 adenocarcinoma of the prostate.

OBJECTIVES: To analyze the effect of total radiation dose on the outcome of patients treated with external beam radiotherapy for early-stage prostate cancer. METHODS: The records of a total of 738 patients with localized prostate cancer treated with external beam radiotherapy (RT) and no androgen deprivation at our institution between July 1986 and February 1999 were reviewed. Two risk groups were defined: favorable (Stage T1-T2, pretreatment prostate-specific antigen [PSA] level 10.0 ng/mL or less, and biopsy Gleason score 6 or less) and unfavorable (Stage T3 lesion or pretreatment PSA level greater than 10.0 ng/mL or biopsy Gleason score 7 or greater). The median RT dose was 70.0 Gy (range 57.6 to 78.0), with 192 patients (26%) receiving at least 72.0 Gy. The mean follow-up was 45 months. RESULTS: The 5-year biochemical relapse-free survival (bRFS) rate was 58%. The 5-year bRFS rate for patients who received radiation doses of 72 Gy or greater versus less than 72 Gy was 85% and 54%, respectively (P <0.001). On multivariate analysis of factors affecting bRFS rates, the number of follow-up PSA levels (P <0.001), tumor stage (P <0.001), pretreatment PSA (P <0.001), biopsy Gleason score (P <0.00 1), and RT dose (P = 0.001) were the only independent predictors of outcome. For favorable tumors, the 5-year bRFS rate for patients who received radiation doses of 72 Gy or greater versus less than 72 Gy was 98% and 81 %, respectively (P = 0.023). For unfavorable tumors, the 5-year bRFS rate for patients who received radiation doses of 72 Gy or greater versus less than 72 Gy was 75% and 41 %, respectively (P = 0.001). CONCLUSIONS: Patients receiving radiation doses of 72 Gy or higher had a significantly better outcome. The improvement was seen in all subgroups of patients. If these results are confirmed, radiation doses exceeding 72 Gy should be considered the standard of care. Inc.

B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide.

While the pathology of multiple sclerosis implicates a role for B cells and antibodies in the disease process, results from animal models have yielded conflicting results. To further characterize the role of B cells in experimental allergic encephalomyelitis (EAE), wild-type and B cell-deficient C57BL/6 mice were immunized with either a recombinant form of myelin oligodendrocyte glycoprotein (MOG) or with the encephalitogenic MOG(35-55) peptide. B cell-deficient mice did not develop EAE when immunized with MOG, although they were susceptible to MOG(35-55)-induced disease. In contrast, wild-type mice were fully susceptible to both MOG and MOG(35-55)-induced EAE. B cell-deficient mice immunized with MOG were primed to the encephalitogenic MOG(35- 55) epitope, as their spleen cells responded with Th1 cytokine production in a fashion similar to WT cells when challenged in vitro with MOG protein or MOG(35-55) peptide. These results demonstrate that the form of inducing antigen (protein vs. peptide) plays a role in the pathogenesis of EAE and may be relevant when applying results from the EAE model to multiple sclerosis.

T cells are the main cell type expressing B7-1 and B7-2 in the central nervous system during acute, relapsing and chronic experimental autoimmune encephalomyelitis.

T cell co-stimulation through the CD28 receptor on T cells is critical to the induction of experimental autoimmune encephalomyelitis (EAE). In this study, expression of the co-stimulatory ligands B7-1 (CD80) and B7-2 (CD86), as well as the receptors CD28 and CTLA-4, were quantitated in central nervous system (CNS) tissues from mice at various stages of EAE. Immunohistochemistry and flow cytometry of CNS-infiltrating cells revealed a high percentage of infiltrating T cells expressing B7-1 and B7-2 during acute, chronic and relapsing EAE. Of the infiltrating cells 10-20% were CTLA-4(+), most of which were CD4(+) T cells. B7-1 and B7-2 expression within the CNS during active EAE might increase the potential for local activation of autoimmune T cells; however, the high level of expression of B7 molecules may also provide a mechanism for the autoregulation of activated CTLA-4(+) T cells.

Pathogenesis of acute passive murine encephalomyelitis II. Th1 phenotype of the inducing population is not sufficient to cause disease.

The present study was designed to assess the pattern of cytokine expression over the course of disease in the central nervous system (CNS) of recipients of an encephalitogenic T-cell clone specific for proteolipid protein (PLP) peptide 139-151. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of CNS mRNA from samples taken during the onset of acute disease demonstrated upregulation of message for cytokines involved in the recruitment and activation of macrophages (GM-CSF, interleukin (IL)-3, IL-9) and the inflammatory cytokines tumor necrosis factor (TNF)-alpha and iNOS as well as message for IL-10 and transforming growth factor (TGF)beta. During the recovery stage message for most cytokines was absent, but during relapse inflammatory cytokine messages were again detectable. Message for the accessory molecules B7-2 and CTLA-4 was observed only on the day of onset of acute experimental allergic encephalomyelitis (EAE) and at relapse. The messages for these molecules were downregulated at the onset of recovery. These results illustrate the dynamic nature of the immune response during the course of EAE, and support a model of disease in which T-cells are involved in the regulation of disease while a nonspecific inflammatory reaction is responsible for the CNS damage observed during EAE.

Predictors of local recurrence following excision alone for ductal carcinoma in situ.

BACKGROUND: The treatment of ductal carcinoma in situ (DCIS) remains controversial, particularly in regard to the selection of patients who may be appropriately treated with wide excision alone. To help identify such patients, the authors assessed prognostic factors for local recurrence in patients with DCIS treated with excision alone. METHODS: The study population consisted of 59 patients diagnosed with DCIS between 1985 and 1990. All had been treated with excision alone, had their histologic slides available for re-review by a study pathologist, and had negative margins of excision on review. The median age at diagnosis was 54 years, and the median follow-up time was 95.5 months. Ninety-six percent presented with mammographic findings only; all patients had a reexcision. The size of the DCIS was assessed by the total number of low-power fields (LPF) in which DCIS was present (median LPF = 5). RESULTS: Ten patients experienced a local recurrence (LR) at 5-132 months (median, 37 months) after excision. The actuarial 5-year LR rate was 10%. Four of the recurrences were invasive carcinomas, and 6 were DCIS. No patients have developed metastatic disease or have died of disease. Lesion size >5 LPF was the only significant prognostic factor for local recurrence on univariate analysis (3% vs. 17% for < or = 5 vs. > or = 5 LPF, P = 0.02) and in proportional hazards models. Although patients with nuclear Grade 3 lesions had a higher LR rate than those with nuclear Grade 1 and 2 lesions (18% vs. 6% and 5%, respectively) and patients with close margins (< or = 1 mm) had a higher LR rate than patients with negative margins (>1 mm) (25% vs. 8%), these differences did not reach statistical significance. Among the 19 cases with margins negative by more than 1 mm, lesion size < or = 5 LPF, and nuclear Grade 1 or 2, there were no LRs; by contrast, the remaining 40 patients had a 5-year actuarial LR rate of 15% (P = 0.08). CONCLUSIONS: Lesion size was the only statistically significant prognostic factor for local recurrence in this series of patients with DCIS treated with excision alone. Other factors, such as margin status and nuclear grade, may also be useful in the identification of patients with DCIS who can be managed with excision alone. However, the most reliable and reproducible method of assessing these factors and the best way to combine them have not been determined.

MMPI, MMPI-2 and PTSD: overview of scores, scales, and profiles.

A number of issues should be considered when applying profile interpretations and subscales derived from the original MMPI. These issues and the overall utility of the MMPI-2 for posttraumatic stress disorder (PTSD) evaluations are summarized. The Keane PTSD scale is found to be an effective tool for differential diagnosis when a cut-off score of 28 is used. The Schlenger PTSD scale warrants additional study. Various MMPI-2 validity scales are useful in detecting malingering, but concurrence regarding cut-off scores is lacking. The 2-8/8-2 MMPI PTSD profile does not emerge as consistently on the MMPI-2 as it did on the MMPI, due to the frequent elevation of scale 7 on the MMPI-2.

Hypercalcemia caused by metastatic adamantinoma: response to radiotherapy.

Purpose. To describe successful palliation of a patient with metastatic adamantinoma presenting with lung metastases and hypercalcemia resulting from a parathormone-like substance released from the tumor.Methods and materials. The records of a patient with a history of a tibial adamantinoma who presented with symptoms of hypercalcemia 20 years after the original surgery, as well as the literature concerning hypercalcemia and adamantinoma were reviewed and summarized.Results. After thorough review of the literature we found no prior reports of radiation being used for palliation of hypercalcemia associated with metastatic adamantinoma.We report rapid improvement in symptoms and normalization of serum calcium levels following a course of radiation therapy. The patient remains asymptomatic 15 months following radiotherapy despite a gradual return of elevated serum calcium levels.Discussion. Radiation therapy should be considered as a palliative option for patients who are not surgical candidates presenting with medically refractory hypercalcemia.

Pathogenesis of acute passive murine encephalomyelitis I. Importance of host-derived cells as determined by kinetic analysis.

Kinetics of entry into the CNS of donor- and host-derived T-cells during the onset of acute murine EAE induced by the passive transfer of an encephalitogenic PLP(139-151)-specific T-cell clone was investigated. RT-PCR and spectratypic analysis of total RNA recovered from recipient mice demonstrated the presence in the CNS of donor- and host-derived T-cells 24 h post adoptive transfer. Donor-derived T-cells detected in the CNS decreased days 2-6 post transfer while host-derived T-cells persisted during this time. Beginning 3 days before clinical onset, an increase in the CNS of both T-cell populations was observed which persisted through disease onset. Similar analysis performed on recipients of an nonencephalitogenic PLP(139-151)-specific T-clone demonstrated a transient infiltration of donor- and host-derived T-cells beginning 4 days post transfer (dpt) and returning to background levels by day 7 post transfer. Results presented here suggest the importance of host-derived T-cells in the onset of acute passive murine EAE.

The Keane PTSD Scale extracted from the MMPI: sensitivity and specificity with Vietnam veterans.

A study was conducted to further investigate whether the Keane Posttraumatic Stress Disorder (PTSD) Scale of the Minnesota Multiphasic Personality Inventory (MMPI) can be employed as a separate instrument administered outside the context of the full MMPI. A group of Vietnam combat veterans with diagnosed PTSD and two comparison groups of veterans without PTSD (Vietnam combat and era veterans) were diagnosed by clinical interviews. Over 84% of the 64 veterans in the study were accurately classified by the Keane PTSD Scale into their original diagnostic groups. Excellent test sensitivity was demonstrated, with 90% of combat veterans with PTSD being properly classified by the Keane PTSD Scale when the recommended cutoff score of 30 was utilized. The clinical and research implications are discussed.

The potential for faking on the Mississippi Scale for Combat-Related PTSD.

The Mississippi Scale for Combat-Related PTSD is widely used in the assessment of post-traumatic stress disorder (PTSD). The high face-validity of the scale may make it vulnerable to faking, however. The present study found that the scores of individuals instructed to respond "as if" they had PTSD did not differ from the scores of veterans with PTSD. Furthermore, although veterans who were diagnosed as having PTSD were found to have significantly higher Mississippi Scale scores than those who did not meet diagnostic criteria for PTSD, the mean score for all groups (veteran and non-veteran) exceeded the originally recommended diagnostic cut-off score of 107. A cutoff score of 121 was found to best differentiate veterans with PTSD from veterans who did not meet diagnostic criteria for the diagnosis, with high sensitivity but relatively low specificity.

Formation of a gated channel by a ligand-specific transport protein in the bacterial outer membrane.

The ferric enterobactin receptor (FepA) is a high-affinity ligand-specific transport protein in the outer membrane of Gram-negative bacteria. Deletion of the cell-surface ligand-binding peptides of FepA generated mutant proteins that were incapable of high-affinity uptake but that instead formed nonspecific, passive channels in the outer membrane. Unlike native FepA, these pores acted independently of the accessory protein TonB, which suggests that FepA is a gated porin and that TonB acts as its gatekeeper by facilitating the entry of ligands into the FepA channel. The sequence homology among TonB-dependent proteins suggests that all ligand-specific outer membrane receptors may function by this gated-porin mechanism.

The interrelationship of substance abuse and posttraumatic stress disorder. Epidemiological and clinical considerations.

This chapter reviews the data available on the relationship of substance abuse and posttraumatic stress disorder (PTSD). Delimiting the review to those studies of Vietnam veterans, we found that levels of combat exposure seemed to be positively related to subsequent alcohol use, although not all studies confirmed this relationship. When studies of patients seeking treatment for PTSD were examined, we learned that 60-80% of these patients had concurrent diagnoses of substance abuse, alcohol abuse, or dependence. Methodological limitations of all the studies are discussed and conclusions regarding the status of the PTSD-substance abuse relationship are drawn cautiously. Alternative suggestions for treatment are presented and discussed.