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Supplementary Figures S1-S6. Supplementary Figure S1. Liquid chromatography electrospray ionization tandem mass spectrometry analysis; Supplementary Figure S2. TM4SF1 expression in human breast and colon cancers; Supplementary Figure S3A. Clearance of anti-TM4SF1 antibody from HUVEC surface; Supplementary Figure S3B. Uptake of anti-TM4SF1 antibody in HUVEC; Supplementary Figure S4A. NSCLC killing by anti-TM4SF1 ADC; Supplementary Figure S4B. Tumor cell killing by anti-TM4SF1 ADC; Supplementary Figure S5. Expression level of TM4SF1 and other endothelial cell markers in tumor xenografts; Supplementary Figure S6. Clearance of anti-TM4SF1 ADCs; tolerance in mice.

Supplementary Data from First-in-Class Anti-immunoglobulin–like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors

Purpose:In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.Patients and Methods:Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated.Results:Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti–PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation.Conclusions:This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti–PD-1/PD-L1 agent.

Purpose:In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.Patients and Methods:Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated.Results:Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti–PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation.Conclusions:This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti–PD-1/PD-L1 agent.

Joint arthroplasty of the first metatarsophalangeal (MTP) joint is an accepted surgical option for patients with hallux rigidus. However, this procedure has been reported to have a high complication rate and unpredictable survivorship. Implant arthroplasty failure is a devastating complication that results in significant osseous defect with altered biomechanics of the foot. Commonly, salvage options are limited to arthrodesis with bone grafting. However, outcomes are rarely reported. The purpose of this study is to investigate the fusion rates of first metatarsophalangeal joint arthrodesis after conversion from failed implant arthroplasty. A systematic review of electronic databases to find reports of conversion arthrodesis after failed implant arthroplasty was performed. Six studies involving a total of 76 patients with a weighted mean age of 54.9 met the inclusion criteria. Out of the 6 included articles, the nonunion rate was 16.5% at a weighted mean follow-up of 48.1 months. The nonunion rate in the current report is higher than reported nonunion rates of primary arthrodesis. More prospective studies with consistent and standard outcome measures are needed to further determine the success rate of this salvage procedure. Levels of Evidence: 4, Systematic Review of Level 4 Studies

Objectives Dolutegravir/lamivudine (DTG/3TC) is indicated for treatment-naive and experienced people with HIV; however, questions remain about its utility in a test-and-treat setting because of potential transmitted resistance and baseline hepatitis B virus (HBV) co-infection. We present feasibility and efficacy of DTG/3TC in newly diagnosed individuals in a test-and-treat setting. Design The single-arm STAT study evaluated DTG/3TC in a US test-and-treat setting. Methods Eligible adults initiated DTG/3TC 14 days or less after HIV-1 diagnosis without availability of baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance less than 30 ml/min per 1.73 m2, participants remained on study with treatment modification. Efficacy endpoints included proportions of participants with HIV-1 RNA less than 50 copies/ml at Week 24, regardless of antiretroviral regimen, among all participants (intention-to-treat exposed) and those with available HIV-1 RNA data (observed). Results Of 131 participants enrolled, 8% were female and 50% were non-white. Through Week 24, treatment was modified in eight participants [five with HBV co-infection, one with baseline M184V, one for adverse event (rash), one participant decision]. At Week 24, 78% (102/131) of all participants and 92% (102/111) of those with available data achieved HIV-1 RNA less than 50 copies/ml. Incidence of drug-related adverse events was low (7%); no drug-related serious adverse events occurred. Conclusion These data demonstrate the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting, with therapy adjustments for baseline resistance or HBV co-infection occurring safely via routine clinical care as needed [ClinicalTrials.gov, NCT03945981; see Supplemental Digital Content 1, video abstract (Video abstract summarizing the STAT study design and results), http://links.lww.com/QAD/C189].

Supplemental Digital Content is Available in the Text., Background: With the highest rates of HIV/AIDS in the United States, Black Americans are still underrepresented in HIV medical research. Setting: BRAAVE (NCT03631732) is a randomized, phase 3b, multicenter, open-label US study. Methods: Adults identifying as Black or African American and virologically suppressed on 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus third agent were randomized (2:1) to switch to open-label bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) once daily or stay on baseline regimen (SBR) for 24 weeks, after which SBR had delayed switch to B/F/TAF. Resistance to non-NRTIs, protease inhibitors, and/or NRTIs was permitted; integrase strand transfer inhibitor resistance was exclusionary. Primary endpoint was proportion of participants with HIV-1 RNA ≥50 copies/mL at week 24 (snapshot algorithm; noninferiority margin of 6%). Results: Of 558 screened, 495 were randomized/treated (B/F/TAF n = 330; SBR n = 165). Overall, 32% were ciswomen, 2% transwomen, and 10% had an M184V/I mutation. At week 24, 0.6% on B/F/TAF vs 1.8% on SBR had HIV-1 RNA ≥50 copies/mL (difference −1.2%; 95% confidence interval −4.8% to 0.9%), demonstrating noninferiority of B/F/TAF vs SBR. Proportions with HIV-1 RNA

Despite numerous publications emphasizing the value of dose finding, drug development in oncology is dominated by the mindset that higher dose provides higher efficacy. Examples of dose finding implemented by biopharmaceutical firms can change this mindset. The purpose of this article is to outline a pragmatic dose selection strategy for immuno-oncology (IO) and other targeted monoclonal antibodies (mAbs). The approach was implemented for pembrolizumab. Selecting a recommended phase II dose (RP2D) with a novel mechanism of action is often challenging due to uncertain relationships between pharmacodynamics measurements and clinical end points. Additionally, phase I efficacy and safety data are generally inadequate for RP2D selection for IO mAbs. Here, the RP2D was estimated based on phase I (clinical study KN001 A and A2) pharmacokinetics data as the dose required for target saturation, which represents a surrogate for maximal pharmacological effect for antagonist mAbs. Due to limitations associated with collecting and analyzing tumor biopsies, characterizing intratumoral target engagement (TE) is challenging. To overcome this gap, a physiologically-based pharmacokinetic model was implemented to predict intratumoral TE. As tumors are spatially heterogeneous, TE was predicted in well-vascularized and poorly vascularized tumor regions. Additionally, impact of differences in target expression, for example, due to interindividual variability and cancer type, was simulated. Simulations showed that 200 mg every 3 weeks can achieve ≥ 90% TE in clinically relevant scenarios, resulting in the recommendation of 200 mg every 3 weeks as the RP2D. Randomized dose comparison studies (KN001 B2 and D) showing similar efficacy over a fivefold dose/exposure range confirmed the RP2D as the pivotal dose.

Background Telemedicine use has expanded rapidly since the COVID-19 pandemic in order to adhere to social distancing protocols and has been met with much enthusiasm. However, less is known about the use of telemedicine in sports and exercise medicine (teleSEM) and its utility to treat emergent craniofacial injuries. Given how common facial trauma is among athletes and its possible complications, incorporation of telemedicine in sports-related injuries may prove to be quintessential for athletes and coaches. Methods A comprehensive literature search of the MEDLINE, PubMed, Google Scholar, EMBASE, and Cochrane Central Register of Controlled Trials was conducted for studies published through December 2020 with multiple search terms related to telemedicine in sports and trauma care. Results Overall, teleSEM is appreciated by both patients and physicians alike. Studies show that the satisfaction rate among patients and physicians are high. Sports-related telemedicine visits can help improve resource utilization and total costs. Facial trauma studies also reveal that the level of concurrency of treatment options between telemedicine visits and in-person consultations is almost perfect. Further, there are many additional ways that teleSEM can be implemented in treating injured athletes, including possible collaboration between athletic coaches and physicians as well as mobile device applications. Telemedicine may be particularly useful in treating acute injuries in low-resourced areas with limited equipment and training. Conclusion Telemedicine has been widely employed for sports-related injuries and in traumatic care. Patients and providers alike have noted its utility over other methods of communication with physicians. Our findings suggest that telemedicine has a significant potential in treating sports-related injuries and improving the efficiency of diagnoses and treatments. It may enhance outcomes for participants in athletic events. This may become a key aspect of determining whether a player can return to immediate competition.

Ankle arthrodesis (AA) provides reliable pain relief, good patient satisfaction scores, and improved overall function. However, this procedure has been associated with numerous complications and sequelae, such as pseudoarthrosis, malunion, gait abnormalities, increased demand on surrounding joints, and a long period of convalescence. Conversion to total ankle arthroplasty (TAA) is a potential option in the management of these complex and challenging situations. The purpose of this study is to investigate the outcomes of AA conversion to TAA. A systematic review of electronic databases was performed. Six studies involving 172 ankles met inclusion criteria. The weighted mean preoperative Visual Analogue Scale (VAS) score at the time of TAA conversion was 7.8 and the weighted mean postoperative VAS score at the time of final follow-up was 2.5. The weighted mean preoperative AOFAS score at the time of TAA conversion was 32 and the weighted mean postoperative AOFAS score at the time of final follow-up was 72.4. The rate of salvage tibiotalocalcaneal arthrodesis was 2.3% and rate of transtibial amputation was also 2.3% after attempted conversion from initial AA to TAA. Conversion of AA to TAA appears to be a viable option to improve patient outcomes and prevent extensive hindfoot arthrodesis and transtibial amputation. More prospective studies with consistent reporting of outcomes, complications, and revision rates with long-term follow-up are needed.

Total ankle replacement has become a viable alternative to ankle arthrodesis in the surgical management of advanced ankle arthritis. Total ankle replacement has generally been reserved for patients who are older and for those who will have a lower demand on the replacement. The purpose of the current study is to review patient outcomes, complications, and implant survival in patients younger than 55 years who underwent total ankle replacement at a single institution. A single-center chart and radiographic review was performed of consecutive patients who underwent total ankle replacement for treatment of end-stage ankle arthritis. All surgeries were performed by 1 of 5 fellowship-trained foot and ankle surgeons at a single institution. A total of 51 patients met inclusion criteria with a mean follow-up of 31.2 months (SD = 16.2). Implant survival was 94%, There were 7 major complications (13%) requiring an unplanned return to the operating room and 8 minor complications (15%) that resolved with conservative care. The results of this study show that total ankle replacement is a viable treatment option for patients younger than 55 years. Levels of Evidence: A retrospective case series

Objectives Burden of illnesses has been described in the literature using the health-related quality of life (HRQoL) in people with chronic conditions. However, the studies reporting trends of burden are sparse. The aim of this study was to explore the trends of burden of chronic illness from the perspective of HRQoL. Study design This was a secondary analysis of administrative database. Methods Seven data sets of the Canadian Community Health Survey from 2001 to 2014 were obtained for the analysis. Multiple linear and logistic regression models were used on each data set to assess the burden of illness on the Health Utilities Index Mark III (HUI3), life satisfaction (LS), and perceived health (PH). Results People with the effect of stroke constantly had low scores on the HUI3, LS, and PH. Regression analyses revealed that arthritis, back problem, and mood disorder have greater impact on the HUI3 score. Effect of stroke, mood disorder, and anxiety disorder stably had the largest negative impact on LS, while chronic obstructive pulmonary disease (COPD), effect of stroke, and cancer had the largest effect on PH. Conclusion This study identified that arthritis, back pain, mood disorder, effect of stroke, and COPD constantly have high burden on health outcomes compared with other chronic condition over the past decade.