Malignant melanoma incidence has been increasing for over 30 years, and despite promising new therapies, metastatic disease remains difficult to treat. We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4 and CD8 T cells transduced with a lentivirus carrying a tyrosinase-specific TCR and a marker protein, truncated CD34 (CD34t). This unusual MHC Class I-restricted TCR produces functional responses in both CD4 and CD8 T cells. Parameters monitored on transduced T cells included activation (CD25, CD69), inhibitory (PD-1, TIM-3, CTLA-4), costimulatory (OX40), and memory (CCR7) markers. For the clinical trial, T cells were activated, transduced, selected for CD34t cells, then re-activated, and expanded in IL-2 and IL-15. After lymphodepleting chemotherapy, patients were given transduced T cells and IL-2, and were followed for clinical and biological responses. Transduced T cells were detected in the circulation of three treated patients for the duration of observation (42, 523, and 255 days). Patient 1 tolerated the infusion well but died from progressive disease after 6 weeks. Patient 2 had a partial response by RECIST criteria then progressed. After progressing, Patient 2 was given high-dose IL-2 and subsequently achieved complete remission, coinciding with the development of vitiligo. Patient 3 had a mixed response that did not meet RECIST criteria for a clinical response and developed vitiligo. In two of these three patients, adoptive transfer of tyrosinase-reactive TCR-transduced T cells into metastatic melanoma patients had clinical and/or biological activity without serious adverse events.
Context: The prescription of opioids after elective surgical procedures has been a contributing factor to the current opioid epidemic in North America. Objective: To examine the opioid prescribing practices and rates of opioid consumption among patients undergoing common sports medicine procedures. Data Sources: A systematic review of the electronic databases EMBASE, MEDLINE, and PubMed was performed from database inception to December 2018. Study Selection: Two investigators independently identified all studies reporting on postoperative opioid prescribing practices and consumption after arthroscopic shoulder, knee, or hip surgery. A total of 119 studies were reviewed, with 8 meeting eligibility criteria. Study Design: Systematic review. Level of Evidence: Level 4. Data Extraction: The quantity of opioids prescribed and used were converted to milligram morphine equivalents (MMEs) for standardized reporting. The quality of each eligible study was evaluated using the Methodological Index for Non-Randomized Studies. Results: A total of 8 studies including 816 patients with a mean age of 43.8 years were eligible for inclusion. A mean of 610, 197, and 613 MMEs were prescribed to patients after arthroscopic procedures of the shoulder, knee, and hip, respectively. At final follow-up, 31%, 34%, and 64% of the prescribed opioids provided after shoulder, knee, and hip arthroscopy, respectively, still remained. The majority of patients (64%) were unaware of the appropriate disposal methods for surplus medication. Patients undergoing arthroscopic rotator cuff repair had the highest opioid consumption (471 MMEs), with 1 in 4 patients receiving a refill. Conclusion: Opioids are being overprescribed for arthroscopic procedures of the shoulder, knee, and hip, with more than one-third of prescribed opioids remaining postoperatively. The majority of patients are unaware of the appropriate disposal techniques for surplus opioids. Appropriate risk stratification tools and evidence-based recommendations regarding pain management strategies after arthroscopic procedures are needed to help curb the growing opioid crisis.
Patellar tendon ruptures are rare, but debilitating injuries are typically seen in young active males in the third and fourth decades of life. They can occur as a single acute injury or from repetitive microtrauma weakening the tendon. Patients typically present complaining of knee pain, swelling, and an inability to perform a straight leg raise. Most conventionally, these injuries are classified as acute (less than two weeks) or chronic (greater than two weeks) based upon the timing of presentation. In patients with patellar tendon ruptures and inability to perform a straight leg raise, patellar tendon repair is most often recommended. A subset of patients with chronic patellar tendon ruptures, however, presents several months after their initial injuries. These neglected patella tendon ruptures present a particularly challenging clinical scenario in which primary repair is often difficult or not possible. This case report describes a modification to an existing surgical technique for reconstructing the patellar tendon using an ipsilateral semitendinosus tendon autograft with suture tape augmentation.
Objective: To determine whether an educational intervention affects surgeon implant decision making measured by total implant costs for temporizing a knee-spanning external fixation construct.Design: A total of 24 cases were prospectively collected after an educational intervention and matched to 24 cases before intervention using Schatzker classification and by surgeon.
Using adoptive cell transfer to reintroduce engineered T cells into patients is an exciting new form of cancer immunotherapy. T cells play a central role in adaptive immunity by eliminating virus‐infected and tumor cells. T cell receptors (TCRs) facilitate this by recognizing antigenic peptides presented by major histocompatibility complexes (MHCs), triggering an immune response. While TCRs in gene‐modified T cells can be used for anti‐tumor clinical responses, clinical trials have shown adverse effects attributable to off‐target toxicity, which stems from the inherent cross‐reactivity of a TCR repertoire developed to engage the larger universe of potential peptide antigens. To understand and begin to address this challenge in immunotherapy, elucidation of TCR structural properties and biochemical characteristics is required.TIL 1383I is a T cell receptor (TCR) that targets the human tyrosinase peptide (hTyr) overexpressed in primary and metastatic melanoma. A recent phase I clinical trial of TIL 1383I using TCR‐gene modified T cells to treat melanoma resulted in one case of durable cancer remission but other cases with partial to no responses. To help understand and possibly engineer improved variants of TIL 1383I, we recombinantly expressed TIL 1383I and crystallized it in complex with its binding partner hTyr presented by HLA‐A2. We then used X‐ray crystallography to solve the structure. The structure provides insight into the binding geometry and amino acid residues in the interface between TIL 1383I and hTyr/HLA‐A2. We have also used surface plasmon resonance to determine the TIL 1383I binding affinity. From this work, we aim to design TCR variants with the goal of improving affinity and specificity toward the hTyr antigen.Support or Funding InformationHarper Cancer Research Institute, National Institutes of Health, National Science Foundation, American Cancer SocietyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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