"My UC Story": A Qualitative Descriptive Study Describing the Patient Journey for Ulcerative Colitis.

Background: Personal perspectives of patients are seldomly reported in the literature, most notably their journey to diagnosis. Literature is heavily focused on the patient journey from a healthcare professional's point of view during the treatment process. The objective of this study is to conduct a qualitative study on a video-sharing site, YouTube, to determine if the patient journey from a subjective perspective is truly linear for those who suffer from ulcerative colitis. Methods: Phrases searched on YouTube included "ulcerative colitis story" and "ulcerative colitis diagnosis story". Video monologues chronicling the patient journey before diagnoses were transcribed using the YouTube transcription function to identify patterns amongst users' experiences. Thematic analysis was used to identify whether certain themes were present in the monologues. Analysis was performed using NVivo 12 QRS International and used line-by-line coding to create an initial codebook that represented the concepts covered in the monologues. Results: We viewed a total of 48 videos and included 29 videos from 2010 to 2020 for qualitative analysis. Overall, three major themes were identified in the patient journey prior to ulcerative colitis diagnosis:1) initial symptoms, 2) initial encounter with the healthcare system, and 3) gastroenterologist referral. Conclusions: The literature depicts the patient journey as a linear path. This qualitative study discovers that the reality of the patient journey is, in fact, non-linear. Many creators did not identify pharmacists in their patient journey; however, we know from the literature that pharmacists are the most accessible healthcare professional. With the appropriate tools, pharmacists can help guide patients in prioritizing signs and symptoms to streamline the non-linear path that patients experience.

Dual Roles for Regulatory T-cell Depletion and Costimulatory Signaling in Agonistic GITR Targeting for Tumor Immunotherapy.

Agonistic monoclonal antibodies (mAb) targeting the T-cell receptor coregulatory molecule GITR exert potent therapeutic activities in preclinical tumor models. Although anti-GITR mAb are thought to act by depleting and destabilizing the intratumoral T regulatory cell (Treg) population, the precise mechanism of action is obscure. Here, we addressed this issue using a Treg fate-mapping approach, which revealed that Treg loss was primarily due to cell depletion, with minimal evidence of Treg conversion to a non-Foxp3-expressing population. Further characterization of persisting Tregs following anti-GITR mAb treatment showed that a highly activated subpopulation of CD44hiICOShi intratumoral Tregs were preferentially targeted for elimination, with the remaining Tregs exhibiting a less suppressive phenotype. With these changes in the Treg population, intratumoral CD8+ T cells acquired a more functional phenotype characterized by downregulation of the exhaustion markers PD-1 and LAG-3. This reversal of CD8+ T-cell exhaustion was dependent on both agonistic GITR signaling and Treg depletion, as neither mechanism by itself could fully rescue the exhaustion phenotype. Tests of anti-human GITR antibody MK-4166 in a humanized mouse model of cancer mimicked many of the effects of anti-mouse GITR mAb in syngeneic tumor models, decreasing both Treg numbers and immune suppressor phenotype while enhancing effector responsiveness. Overall, our results show how anti-GITR mAb shifts Treg populations to enable immune attack on tumors, with clinical implications for molecular markers to modify emerging treatments. Cancer Res; 77(5); 1108-18. ©2016 AACR.

Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients.

PURPOSE: Vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) play a significant role in glioblastoma angiogenesis and proliferation, making tyrosine kinase (TK) receptors logical targets for treatment. We evaluated AEE788, a reversible TK inhibitor that inhibits EGFR and VEGFR, in recurrent glioblastoma patients. METHODS: In this dose-escalation, phase I study, patients with recurrent glioblastoma received AEE788 once daily in 28-day cycles in stratified subgroups: those receiving (1) non-enzyme-inducing anticonvulsants drugs or no anticonvulsants (Group A) and (2) enzyme-inducing anticonvulsant drugs (Group B). A dose-expansion phase stratified patients by surgical eligibility. Primary objectives were to determine dose-limiting toxicity (DLT) and maximum tolerated dose; secondary objectives included evaluating (1) safety/tolerability, (2) pharmacokinetics, and (3) preliminary antitumor activity. RESULTS: Sixty-four glioblastoma patients were enrolled. Two Group A patients experienced DLTs (proteinuria and stomatitis) at 550 mg; 550 mg was, therefore, the highest dose evaluated and dose limiting. One Group B patient receiving 800 mg experienced a DLT (diarrhea). The initially recommended dose for dose-expansion phase for Group A was 400 mg; additional patients received 250 mg to assess the hepatotoxicity. Most frequently reported adverse events (AEs) included diarrhea and rash. Serious AEs, most commonly grade 3/4 liver function test elevations, were responsible for treatment discontinuation in 17% of patients. AEE788 concentrations were reduced by EIACD. The best overall response was stable disease (17%). CONCLUSIONS: Continuous, once-daily AEE788 was associated with unacceptable toxicity and minimal activity for the treatment of recurrent glioblastoma. The study was, therefore, discontinued prematurely.