Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis.

Importance: Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab. Objective: To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS. Design, Setting, and Participants: This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country. Exposure: Treatment with ocrelizumab or rituximab after 2015. Main outcomes and Measures: Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups. Results: Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses. Conclusion: In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials.

The First US Clinical Experience With Computer-Assisted Propofol Sedation: A Retrospective Observational Comparative Study on Efficacy, Safety, Efficiency, and Endoscopist and Patient Satisfaction.

BACKGROUND: Computer-assisted propofol sedation (CAPS) is now approved for moderate sedation of American Society of Anesthesiologists (ASA) class I and II patients undergoing routine endoscopy. As the first US medical center to adopt CAPS for routine clinical use, we compared patient and endoscopist satisfaction with CAPS versus midazolam and fentanyl (MF) sedation. METHODS: Patients who underwent elective outpatient upper endoscopy and colonoscopy with CAPS were compared with concurrent patients sedated with MF. The primary end points were patient satisfaction (measured by the validated Patient Sedation Satisfaction Index [PSSI]), and endoscopist satisfaction (Clinician Sedation Satisfaction Index [CSSI]). Secondary end points included procedural success rates, polyp detection rates, adverse events, and procedure/recovery times. Multivariable regression was used for comparative analysis. RESULTS: CAPS was utilized to sedate 244 patients, of whom 55 underwent upper endoscopy, 173 colonoscopy, and 16 double procedures. During the same period, 75 upper endoscopies, 223 colonoscopies, and 30 doubles were performed with MF on similar patients. For upper endoscopy, the procedural success rate was 98.2% for CAPS versus 98.7% for MF (P = .96), whereas for colonoscopy, the success rate was 98.9% vs 98.8% (P = .59). Colonoscopic polyp detection rate was 54.5% for CAPS and 59.3% for MF (P = .67). Procedure times were similar between CAPS and MF. For CAPS, the mean recovery time was 26.4 vs 39.1 minutes for MF (P < .001). One CAPS patient required mask ventilation, 4 experienced asymptomatic hypotension or desaturation, and 5 experienced marked agitation resulting from undersedation. For MF, 5 patients had hypotension or desaturation, and 8 experienced undersedation. For colonoscopy, the CAPS group had higher PSSI scores for sedation adequacy, the recovery process and global satisfaction, and higher CSSI scores for ease of sedation administration, the recovery process and global satisfaction. For upper endoscopy and doubles, the CAPS CSSI score was higher for the recovery process only. All P values were adjusted for confounding by using regression analysis. CONCLUSIONS: In low-risk patients, CAPS appears to be effective and efficient. CAPS is associated with higher satisfaction than MF for colonoscopies and, to a lesser extent, upper endoscopies.

Fyn is downstream of the HGF/MET signaling axis and affects cellular shape and tropism in PC3 cells.

PURPOSE: Fyn is a member of the Src family of kinases that we have previously shown to be overexpressed in prostate cancer. This study defines the biological impact of Fyn inhibition in cancer using a PC3 prostate cancer model. EXPERIMENTAL DESIGN: Fyn expression was suppressed in PC3 cells using an shRNA against Fyn (PC3/FYN-). Knockdown cells were characterized using standard growth curves and time-lapse video microscopy of wound assays and Dunn Chamber assays. Tissue microarray analysis was used to verify the physiologic relevance of the HGF/MET axis in human samples. Flank injections of nude mice were performed to assess in vivo growth characteristics. RESULTS: HGF was found to be sufficient to drive Fyn-mediated events. Compared to control transductants (PC3/Ctrl), PC3/FYN- showed a 21% decrease in growth at 4 days (P = 0.05). PC3/FYN- cells were 34% longer than control cells (P = 0.018) with 50% increase in overall surface area (P < 0.001). Furthermore, when placed in a gradient of HGF, PC3/FYN- cells showed impaired directed chemotaxis down an HGF gradient in comparison to PC3/Ctrl (P = 0.001) despite a 41% increase in cellular movement speed. In vivo studies showed 66% difference of PC3/FYN- cell growth at 8 weeks using bidimensional measurements (P = 0.002). CONCLUSIONS: Fyn plays an important role in prostate cancer biology by facilitating cellular growth and by regulating directed chemotaxis-a key component of metastasis. This finding bears particular translational importance when studying the effect of Fyn inhibition in human subjects.

Renal medullary-like carcinoma in an adult without sickle cell hemoglobinopathy.

BACKGROUND: A 42-year-old white man with no significant prior medical history presented with macroscopic hematuria of 2 months' duration. His family history was notable for a maternal grandfather with kidney cancer. INVESTIGATIONS: Urinalysis, CT, microscopic examination of tumor, immunohistochemical analysis of tumor, hemoglobin electrophoresis, molecular cytogenetic analysis, gene sequencing. DIAGNOSIS: Renal medullary-like carcinoma in an adult without sickle cell trait, sickle cell disease or other hemoglobinopathies. MANAGEMENT: The patient underwent laparoscopic nephrectomy to remove the tumor and received adjuvant sorafenib (400 mg per day) as part of the E2805 ASSURE (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) trial. Metastatic recurrence of the tumor occurred 9 months after nephrectomy, for which the patient underwent tumor debulking and retroperitoneal lymph node dissection, followed by chemotherapy consisting of gemcitabine (2,000 mg/m(2)) and doxorubicin (50 mg/m(2)), both given on day 1 of a 14-day cycle. After six cycles of drug treatment, the patient had achieved a partial response. The patient was managed by active surveillance for 4 months, when he developed further symptoms and disease progression was detected. Third-line systemic therapy in the form of 21-day cycles of cisplatin (80 mg/m(2) on day 1) and etoposide (100 mg/m(2) on days 1-3) has recently been initiated.

Fyn: a novel molecular target in cancer.

Fyn is 59-kDa member of the Src family of kinases that is historically associated with T-cell and neuronal signaling in development and normal cellular physiology. Whereas Src has been heavily studied in cancer, less attention has been traditionally awarded to the other Src kinases such as Fyn. Our group has shown that Fyn is particularly upregulated in prostate cancer in contrast to the alternative members of the Src family. This suggests that it may mediate several important processes attributed to Src kinases in prostate cancer and other malignancies. These functions include not only cellular growth and proliferation but also morphogenesis and cellular motility. Together, these suggest a role for Fyn in both progression and metastasis. As several agents in clinical development affect Fyn activation, understanding the role that Fyn plays in cancer is of great importance in oncology. Cancer 2010. (c) 2010 American Cancer Society.