Osteoarthritis (OA) is a chronic condition characterized by pain during joint movement. Additionally, patients with advanced disease experience pain at rest (i.e., ongoing pain)that is generally resistant to non-steroidal anti-inflammatory drugs (NSAIDs). Injection of monosodium iodoacetate (MIA) into the intra-articular space of the rodent knee is a well-established model of OA that elicits weight-bearing asymmetry and referred tactile and thermal hypersensitivity. Whether ongoing pain is present in this model is unknown. Additionally, the possible relationship of ongoing pain to MIA dose is not known. MIA produced weight asymmetry, joint osteolysis, and cartilage erosion across a range of doses (1, 3, and 4.8 mg). However, only rats treated with the highest dose of MIA showed conditioned place preference to a context paired with intra-articular lidocaine, indicating relief from ongoing pain. Diclofenac blocked the MIA-induced weight asymmetry but failed to block MIA-induced ongoing pain. Systemic AMG9810, a TRPV1 antagonist, effectively blocked thermal hypersensitivity, but failed to block high dose MIA-induced weight asymmetry or ongoing pain. Additionally, systemic or intra-articular HC030031, a TRPA1 antagonist, failed to block high dose MIA-induced weight asymmetry or ongoing pain. Our studies suggest that a high dose of intra-articular MIA induces ongoing pain originating from the site of injury that is dependent on afferent fiber activity but apparently independent of TRPV1 or TRPA1 activation. Identification of mechanisms driving ongoing pain may enable development of improved treatments for patients with severe OA pain and diminish the need for joint replacement surgery.
A predominant complaint in patients with neuropathic pain is spontaneous pain, often described as “burning”. Recent studies have demonstrated that negative reinforcement can be used to unmask spontaneous neuropathic pain allowing for mechanistic investigations. Here, ascending pathways that might contribute to evoked and spontaneous components of experimental neuropathic pain model were explored. Desensitization of TRPV1 positive fibers with systemic resiniferatoxin (RTX) abolished spinal nerve ligation (SNL) injury-induced thermal hypersensitivity and spontaneous pain, but had no effect on tactile hypersensitivity. Ablation of spinal NK-1 receptor expressing neurons blocked SNL-induced thermal and tactile hypersensitivity as well as spontaneous pain. Following nerve injury, upregulation of neuropeptide Y (NPY) is observed almost exclusively in large diameter fibers and inactivation of the brainstem target of these fibers in the n. gracilis prevents tactile, but not thermal, hypersensitivity. Blockade of NPY signaling within the n. gracilis failed to block SNL-induced spontaneous pain or thermal hyperalgesia while fully reversing tactile hypersensitivity. Moreover, microinjection of NPY into n. gracilis produced robust tactile hypersensitivity, but failed to induce conditioned place aversion. These data suggest that spontaneous neuropathic pain and thermal hyperalgesia are mediated by TRPV1 positive fibers and spinal NK-1 positive ascending projections. In contrast, the large diameter dorsal column projection can mediate nerve injury-induced tactile hypersensitivity, but does not contribute to spontaneous pain. As inhibition of tactile hypersensitivity can be achieved either by spinal manipulations or by inactivation of signaling within the n. gracilis, the enhanced paw withdrawal response evoked by tactile stimulation does not necessarily reflect “allodynia”.
Background: TILs and iGES are associated with pathologic complete response (pCR) and relapse-free survival (RFS) in HER2+ breast cancer, however they have typically not been compared. Here we examine the prognostic value of iGES vs. TILs, alone and together, in two different HER2+ neoadjuvant trials: the chemotherapy plus HER2targeting trial C40601, and the all-biologic trial PAMELA.Methods: Gene expression profiling by mRNA sequencing (RNAseq) and TILs (per 2014 TILs working group) as a continuous variable were assessed on 230 C40601 and 139 PAMELA pre-treatment samples. iGES scores were calculated by extracting the median expression of all genes within a signature. Association with pCR and RFS was studied by logistic regression and Cox analyses. To compare the goodness of fit of different models, we used the Akaike Information Criterion (AIC). To compare the prognostic ability of two nested models, we used the Likelihood-Ratio test (LRT).Results: Every 1% increase in TILs was associated with a significant 1% increase in the odds of pCR in C40601 (odds ratio [OR] 1.01, p < 0.01) and a 2% increase in PAMELA (OR 1.02, p ¼ 0.04). TILs were not associated with RFS at 7 years in C40601 (Hazard ratio [HR] 0.99, p ¼ 0.21). Of the 210 iGES tested, 130 (61.9%) were correlated with TILs across the 2 trials (p < 0.05), and 13 iGES were also significantly associated with higher pCR rates in both studies (ORs range 1.05-2.33, p < 0.05). 11 of 13 iGES outperformed TILs for pCR prediction, 7 of which were B-cell-related iGES. In a multivariate Cox model including clinical factors and PAM50 subtype, 8 of these iGES, but not TILS, were independently associated with RFS (iGES HRs range 0.56-0.72, p values < 0.05; TILs HR 0.99, p ¼ 0.38).Conclusions: In C40601 and PAMELA, multiple, mostly B-cell-related, iGES performed better than TILs for pCR prediction. In C40601, TILs did not provide additional RFS information to clinical parameters, subtype, and multiple GES. When both TILs and iGES are available, the prognostic value of RNA-based signatures is superior.
Background Due to wide-ranging impacts of Ulcerative Colitis (UC), regulatory authorities emphasize the importance of including validated patient-reported symptom severity measures in clinical trials. Aim To describe the development and validation of the Ulcerative Colitis-Symptom Questionnaire (UC-SQ). Methods The UC-SQ was developed in a qualitative study involving a targeted literature review, semi-structured concept elicitation interviews, and combined concept elicitation/cognitive interviews. Measurement properties, including item-level analyses, factor structure, reliability, validity, responsiveness, and clinically meaningful change were evaluated using data from a phase 2b, randomized trial in adults with UC ( N = 113). Results Fourteen symptom concepts were elicited across 22 interviews, with saturation at the fifth interview. Twenty-two items were unmodified as cognitive interview participants interpreted underlying concepts correctly. Instructions were clear and items were relevant, with appropriate response options and recall periods. Reduction to 17 items was completed prior to psychometric testing. Two items (joint pain/constipation) did not contribute to reliability in initial testing and were included as non-scored items. The 15-item UC-SQ showed evidence of internal consistency ( α = 0.86) and test–retest reliability (intraclass correlation coefficient = 0.88). The UC-SQ discriminated by disease severity as defined by Mayo and Inflammatory Bowel Disease Questionnaire scores ( p < 0.0001). Convergent validity was supported by strong correlations with criterion measures. The UC-SQ was responsive in patients indicating change in other measures. A 10-point decrease from baseline indicated within-patient meaningful improvement. Conclusions The UC-SQ is reliable, valid and responsive, with a 10-point improvement estimating within-patient clinically meaningful improvement. The tool is fit-for-purpose as a key endpoint in pivotal UC trials. Supplementary Information The online version contains supplementary material available at 10.1007/s10620-022-07807-y.
155 Background: Outcomes remain poor in triple-class exposed (to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody) patients (pts) with relapsed and refractory multiple myeloma (RRMM), and there is no standard of care. Ide-cel, a BCMA-directed CAR T cell therapy, showed deep, durable responses in heavily pretreated RRMM pts in the pivotal phase 2 KarMMa trial ( J Clin Oncol 38:2020. Suppl; abstr 8503). Limited data are available on pts’ experience with prior therapies and expectations on ide-cel. By embedding pt interviews in KarMMa, we assessed pts’ initial knowledge of and expectations on ide-cel beyond pt-reported outcome measures prior to ide-cel therapy. Methods: This qualitative study was conducted in triple-class exposed pts refractory to their last regimen who entered the KarMMa trial (NCT03361748). Pts were invited to participate in the optional interview component that included up to 11 interviews. We present results of the first interviews that occurred between initial consent and leukapheresis. The interview topics were pts’ initial knowledge of ide-cel, decision making, expectations, hopes, and concerns, and current well-being. All interviews were recorded, transcribed, and coded. Results: Forty-seven pts from 14 clinical sites participated in the interviews. Most pts were able to describe the overall process of CAR T cell therapy and one third first heard about the therapy from their local healthcare professionals. According to patients, key decision-making factors were potential outcomes with ide-cel, recommendation from a doctor, and lack of other options. The most frequently perceived differences between ide-cel and prior treatments are shown (Table). Pt hopes were mostly focused on remission and improved quality of life. Most pts reported some restrictions on their daily activities due to the disease. Conclusions: RRMM pts need new treatment options. Most pts reported the limitations of prior therapies, expectations on ide-cel, impact of the disease, and differentiated ide-cel from other treatments. The ongoing interviews will further assess pt experience during and after ide-cel therapy. Clinical trial information: NCT03361748 . [Table: see text]
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