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Supplementary Figure 2

Supplementary Figure Legends

Table of microinjected drugs

Microinjection of olaratumab does not inhibit PDGFRα, ERK, or S6 phosphorylation.

All adverse events reported on the study

Supplementary Legend

Distinct drug induced phenotypes and apoptotic responses specific to drug mechanism of action are seen at sites of CIVO microinjection.

Purpose:A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS).Patients and Methods:We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue.Results:The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity.Conclusions:These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials.See related commentary by Sleijfer and Lolkema, p. 3897

Representative images of tumors from patients who received radiation treatment.

Device performance

Clinical Trial Design

Increased phosphorylation of PDGFR� and downstream effectors in an undifferentiated pleomorphic sarcoma displaying a lack of apoptotic response to microdosed doxorubicin.

To examine the impact of standardized patient encounters (SPEs) on gender-affirming communication skills and self-efficacy of pediatrics learners.Fourth-year medical students, pediatrics interns, psychiatry interns, and nurse practitioner trainees on 1-month adolescent medicine blocks completed a curriculum with e-learning activities that was expanded to include SPEs. Following e-learning, learners completed 2 SPEs featuring transgender adolescent cases. Faculty observers and standardized patients completed checklists focused on history-taking, counseling, and interpersonal communication, and provided learner feedback after each case. The curriculum was evaluated by comparing skills checklists scores from case 1 to case 2 via Wilcoxon signed-rank tests. Self-efficacy was assessed precurriculum (Assessment 1), post-e-learning (Assessment 2), and post-SPE (Assessment 3) using a previously developed instrument. Changes in self-efficacy scores were assessed via linear regression models with generalized estimating equations.Forty-three eligible learners participated in the study. The majority were pediatrics interns, and 5 learners had worked in a transgender clinic prior to the curriculum participation. Learners increased median total checklist scores between cases from 22 to 28 (P.001) (maximum score of 34). Learners' overall self-efficacy scores improved by 3.4 (confidence interval [CI]: 2.9-3.9; P.001) between Assessments 1 and 2 and by 1.5 (CI: 1.2-1.7; P.001) from Assessment 2 to 3. Similar improvements in checklist scores and self-efficacy occurred within stratified learner types.The combination of SPEs with e-learning is effective at improving self-efficacy and gender-affirming communication skills for a multidisciplinary pediatrics learners. The comprehensive curriculum allowed learners inexperienced with transgender youth to apply knowledge and practice skills.

Telescopic and conical dental solutions for tooth-borne, implant-borne, and combination tooth/implant-borne removable dental prosthetics have a long and rich history. Traditionally, these restorations have been based on analog techniques. The integration of digital technologies, however, has had a profound impact on these solutions in numerous ways, helping to facilitate efficient fabrication of many technical and clinical facets of these dental prosthetics. This article examines how digital technologies impact telescopic and conical clinical case workflows and technical protocols. It discusses such aspects as intraoral scanning, photogrammetry, primary and secondary telescopes and cones, tertiary structures, and temporary restorations.

Ampullary neuroendocrine tumors (NETs) make up

To evaluate if patient-derived organoids (PDOs) may predict response to neoadjuvant (NAT) chemotherapy in patients with pancreatic adenocarcinoma.PDOs have been explored as a biomarker of therapy response and for personalized therapeutics in patients with pancreatic cancer.During 2017-2021, patients were enrolled into an IRB-approved protocol and PDO cultures were established. PDOs of interest were analyzed through a translational pipeline incorporating molecular profiling and drug sensitivity testing.One hundred thirty-six samples, including both surgical resections and fine needle aspiration/biopsy from 117 patients with pancreatic cancer were collected. This biobank included diversity in stage, sex, age, and race, with minority populations representing 1/3 of collected cases (16% Black, 9% Asian, 7% Hispanic/Latino). Among surgical specimens, PDO generation was successful in 71% (15 of 21) of patients who had received NAT prior to sample collection and in 76% (39 of 51) of patients who were untreated with chemotherapy or radiation at the time of collection. Pathological response to NAT correlated with PDO chemotherapy response, particularly oxaliplatin. We demonstrated the feasibility of a rapid PDO drug screen and generated data within 7 days of tissue resection.Herein we report a large single-institution organoid biobank, including ethnic minority samples. The ability to establish PDOs from chemotherapy-naive and post-NAT tissue enables longitudinal PDO generation to assess dynamic chemotherapy sensitivity profiling. PDOs can be rapidly screened and further development of rapid screening may aid in the initial stratification of patients to the most active NAT regimen.

Objective To describe clinical characteristics and associated endometrial findings of transgender and gender nonbinary people using gender-affirming testosterone. Design Retrospective case series. Setting Academic medical center and public safety net hospital. Patient(s) Eighty-one patients using gender-affirming testosterone therapy undergoing hysterectomy for the indication of gender affirmation from 2000 to 2018. Intervention(s) None. Main Outcome Measure(s) Preoperative clinical characteristics and endometrium surgical pathology diagnoses. Result(s) Median age was 31 years (interquartile range [IQR] 27–40), and median body mass index 27 kg/m2 (IQR 24–30). Six patients (7%) were parous and 60 (74%) had amenorrhea. Thirty-three patients (40%) had proliferative and 40 (50%) atrophic endometrium. Endometrial polyps were found in nine patients (11%) of the sample. Endometrial findings were similar in the subgroup of 60 patients with preoperative amenorrhea. There were no cases of endometrial hyperplasia or malignancy. In bivariate analysis, those with proliferative endometrium were found to be, on average, 5.6 years younger than those with atrophic endometrium. There were no clinical factors associated with having proliferative versus atrophic endometrium in multivariable models. Conclusion(s) People using gender-affirming testosterone may have either proliferative or atrophic endometrium, including people who present with amenorrhea. Further study is needed to develop evidence-based guidelines for appropriate screening for endometrial hyperplasia or cancer in this population.

SUMMARY This review discusses the current evidence regarding perioperative hormone therapy for transgender individuals, with an emphasis on strategies to reduce the risk of perioperative venous thromboembolism. Historically, surgeons routinely discontinued estrogen therapy in the perioperative period with the goal of reducing the risk of venous thromboembolism. However, abrupt estrogen cessation may also lead to adverse emotional and physiologic effects, including an exacerbation of one's gender dysphoria. The data on the relationship of feminizing hormones and venous thromboembolism in the perioperative setting are largely based on extrapolation of hormone regimens that are no longer in use and may not accurately reflect the actual risk of venous thromboembolism. Future studies will allow surgeons to engage in evidence-based, patient-centered, informed consent while also minimizing the risk of complications, such as venous thromboembolism.

BACKGROUND The sexual health of transmasculine (TM) people—those who identify as male, men, or nonbinary and were assigned a female sex at birth—is understudied. One barrier to conducting HIV- and sexually transmitted infection (STI)–related research with this population is how to best capture sexual risk data in an acceptable, gender-affirming, and accurate manner. OBJECTIVE This study aimed to report on the community-based process of developing, piloting, and refining a digitally deployed measure to assess self-reported sexual behaviors associated with HIV and STI transmission for research with TM adults. METHODS A multicomponent process was used to develop a digital-assisted self-interview to assess HIV and STI risk in TM people: gathering input from a Community Task Force; working with an interdisciplinary team of content experts in transgender medicine, epidemiology, and infectious diseases; conducting web-based focus groups; and iteratively refining the measure. We field-tested the measure with 141 TM people in the greater Boston, Massachusetts area to assess HIV and STI risk. Descriptive statistics characterized the distribution of sexual behaviors and HIV and STI transmission risk by the gender identity of sexual partners. RESULTS The Transmasculine Sexual Health Assessment (TM-SHA) measures the broad range of potential sexual behaviors TM people may engage in, including those which may confer risk for STIs and not just for HIV infection (ie, oral-genital contact); incorporates gender-affirming language (ie, genital or frontal vs vaginal); and asks sexual partnership characteristics (ie, partner gender). Among 141 individual participants (mean age 27, SD 5 years; range 21-29 years; n=21, 14.9% multiracial), 259 sexual partnerships and 15 sexual risk behaviors were reported. Participants engaged in a wide range of sexual behaviors, including fingering or fisting (receiving: n=170, 65.6%; performing: n=173, 66.8%), oral-genital sex (receiving: n=182, 70.3%; performing: n=216, 83.4%), anal-genital sex (receptive: n=31, 11.9%; insertive: n=9, 3.5%), frontal-genital sex (receptive: n=105, 40.5%; insertive: n=46, 17.8%), and sharing toys or prosthetics during insertive sex (n=62, 23.9%). Overall barrier use for each sexual behavior ranged from 10.9% (20/182) to 81% (25/31). Frontal receptive sex with genitals and no protective barrier was the highest (21/42, 50%) with cisgender male partners. In total, 14.9% (21/141) of participants reported a lifetime diagnosis of STI. The sexual history tool was highly acceptable to TM participants. CONCLUSIONS The TM-SHA is one of the first digital sexual health risk measures developed specifically with and exclusively for TM people. TM-SHA successfully integrates gender-affirming language and branching logic to capture a wide array of sexual behaviors. The measure elicits sexual behavior information needed to assess HIV and STI transmission risk behaviors. A strength of the tool is that detailed partner-by-partner data can be used to model partnership-level characteristics, not just individual-level participant data, to inform HIV and STI interventions.

Among patients with distant metastatic melanoma, the site of metastases is the most significant predictor of survival and visceral-nonpulmonary metastases hold the highest risk of poor outcomes. However, studies demonstrate that a significant percentage of patients may be considered candidates for resection with improved survival over nonsurgical therapeutic modalities. We aimed at analyzing the results of resection in patients with melanoma metastasis to the pancreas by assessing the available evidence.The PubMed/MEDLINE, WoS, and Embase electronic databases were systematically searched for articles reporting on the surgical treatment of pancreatic metastases from melanoma. Relevant data from included studies were assessed and analyzed. Overall survival was the primary endpoint of interest. Surgical details and oncological outcomes were also appraised.A total of 109 patients treated surgically for pancreatic metastases were included across 72 articles and considered for data extraction. Overall, patients had a mean age of 51.8 years at diagnosis of pancreatic disease. The cumulative survival was 71%, 38%, and 26% at 1, 3 and 5 years after pancreatectomy, with an estimated median survival of 24 months. Incomplete resection and concomitant extrapancreatic metastasis were the only factors which significantly affected survival. Patients in whom the pancreas was the only metastatic site who received curative resection exhibited significantly longer survival, with a 1-year, 3-year, and 5-year survival rates of 76%, 43%, and 41%, respectively.Within the limitations of a review of non-randomized reports, curative surgical resection confers a survival benefit in carefully selected patients with pancreatic dissemination of melanoma.

Purpose: A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS). Patients and Methods: We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue. Results: The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity. Conclusions: These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials. See related commentary by Sleijfer and Lolkema, p. 3897

Introduction Evaluation of sexual functioning in transmasculine (TM) adults—those who identify as men, male, transmen, or non-binary yet were assigned a female sex at birth—is limited by lack of availability of brief screening measures. Aim Study aims were to (i) conduct initial psychometric evaluation of a brief screening tool to assess sexual functioning in TM adults for easy use in outpatient visits, epidemiologic studies, and assessment of treatment and surgical outcomes and (ii) assess the correlates of sexual functioning. Methods The 6-item version of the Female Sexual Function Index was adapted and piloted for use with TM adults. The resulting scale, the Transmasculine Sexual Functioning Index (TM-SFI), was administered to 150 TM adults via computer-assisted self-interview. A multivariable model was fit to assess demographic, psychosocial, and gender affirmation correlates of sexual functioning. Main Outcome Measure The main outcomes of this study were the calculated reliability and validity of the TM-SFI and fit cumulative logit models to estimate associations of medical gender affirmation (chest surgery) and body image self-consciousness with level of sexual functioning. Results Internal consistency reliability was good (Cronbach’s alpha = 0.80). Item correlations ranged from 0.21 to 0.80 (P < .05). All scale items loaded onto a single factor (eigenvalue = 11.13; factor loadings > 0.50), evidence of good construct validity. After controlling for potential confounders, participants who had chest surgery exhibited significantly higher odds of being in the highest sexual functioning tertile relative to those without chest surgery (adjusted odds ratio = 2.46; 95% confidence interval = 1.08–5.64; P = .033). Moderate-to-high body image self-consciousness was associated with lower odds of sexual functioning (adjusted odds ratio = 0.42; 95% confidence interval = 0.18–0.94; P = .035). Conclusion Initial evaluation of the TM-SFI warrants formal psychometric validation against clinical diagnoses of sexual functioning concerns in TM patients. The brief screener can be used to assess sexual functioning in TM adults and may identify TM who could benefit from clinical interventions to improve sexual functioning.

Background Therapeutic drug monitoring measures antiretroviral adherence more accurately than self-report but has not been available at the point-of-care (POC) until now. We compare a novel POC test for urine tenofovir to laboratory-based enzyme-linked immunosorbent assay (ELISA) testing in diverse patient populations urine pre-exposure prophylaxis (PrEP). Setting Urine samples were analyzed using ELISA and the POC lateral flow immunoassay (LFA) test from 2 cohorts of PrEP users taking tenofovir disoproxil fumarate/emtricitabine: the Partners PrEP Study, which recruited Kenyan and Ugandan heterosexual men and women, and the IBrEATHe Study, which recruited US transgender women and men using gender-affirming hormone therapy. Methods We calculated the sensitivity, specificity, and accuracy of the POC test compared with ELISA at a cutoff of 1500 ng/mL. Results Overall, 684 urine samples were tested from 324 participants in the 2 cohorts. In Partners PrEP, 454 samples from 278 participants (41% women) were tested with a median age of 33 years. In IBrEATHe, 231 samples from 46 individuals (50% transwomen) were tested with a median age of 31 years. Comparison of the LFA read-out to ELISA yielded 100% sensitivity [97.5% one-sided confidence interval (CI) = 99.3%], 98.3% specificity (95% CI = 95.2% to 99.7%), and 99.6% accuracy (95% CI = 98.7% to 99.9%). Conclusion The sensitivity, specificity, and accuracy of a novel POC test for urine tenofovir all exceeded 98% when compared with a laboratory-based ELISA method when tested in diverse patient populations. Given the LFA's high accuracy and expected low cost, this POC test is a promising tool to support antiretroviral adherence that could be widely scalable to real-world clinical settings.

The sexual partnerships of transmasculine adults—who were assigned female at birth and identify on the masculine gender continuum—remain understudied. This includes characteristics of transmasculine adults' sexual partnerships associated with engaging in HIV/sexually transmitted infection (STI) sexual risk behavior. This study examined individual- and partnership-level factors of transmasculine adults' sexual partnerships associated with using a protective barrier during sexual activity. Data came from cross-sectional surveys administered to 141 transmasculine adults. Participants provided demographic and sexual health information for up to three sexual partners from the past 12 months (n = 259 partnerships). Generalized estimating equations (GEEs) were used to investigate individual- and partnership-level factors associated with any use of a protective barrier during five sexual behaviors. Transmasculine participants engaged in an array of sexual behaviors with diverse sexual partners. Individual- and partnership-level factors of transmasculine adults' sexual partnerships were associated with their protective barrier use; however, these associations varied in statistical significance across the five sexual behaviors. At the individual level, younger participants had lower odds of protective barrier use during fingering or fisting. At the partnership level, protective barrier use was associated with a sexual partnership's configuration and the gender identity of a sexual partner. Relative to participants with cisgender female partners, those with cisgender male partners generally had lower odds of using a protective barrier. Study findings highlight the importance of studying factors associated with HIV/STI risk behavior located beyond the individual. These findings may have implications for improving measurements of HIV/STI-related risk for transmasculine adults.

BACKGROUND: This article is by a group of trans and nonbinary researchers and experts in the field of trans health who have conducted an analysis of trans health research needs. AIMS: To highlight topics that need further research and to outline key considerations for those conducting research in our field. METHODS: The first author conducted semi-structured interviews with all coauthors, and these were used to create a first draft of this manuscript. This draft was circulated to all authors, with edits made until consensus was reached among the authors. RESULTS: More comprehensive long-term research that centers trans people’s experiences is needed on the risks and benefits of gender affirming hormones and surgeries. The trans health research field also needs to have a broader focus beyond medical transition or gender affirmation, including general health and routine healthcare; trans people’s lives without, before, and after medical gender affirmation; and sexuality, fertility, and reproductive healthcare needs. More research is also needed on social determinants of health, including ways to make healthcare settings and other environments safer and more supportive; social and legal gender recognition; the needs of trans people who are most marginalized; and the ways in which healing happens within trans communities. The second part of this article highlights key considerations for researchers, the foremost being acknowledging trans community expertise and centering trans community members’ input into research design and interpretation of findings, in advisory and/or researcher roles. Ethical considerations include maximizing benefits and minimizing harms (beneficence) and transparency and accountability to trans communities. Finally, we note the importance of conferences, grant funding, working with students, and multidisciplinary teams. DISCUSSION: This article outlines topics and issues needing further consideration to make the field of trans health research more responsive to the needs of trans people. This work is limited by our authorship group being mostly White, all being Anglophone, and residing in the Global North.

The sexual partnerships of transmasculine (TM) adults-those assigned female at birth who identify as transgender men or a masculine spectrum gender identity-and characteristics associated with STI/HIV risk behavior remains understudied. Participants in the current study were TM adults (n = 141) receiving care at a community health center in Boston, Massachusetts between March 2015 and September 2016. Using generalized estimating equations, we examined individual- and partnership-level factors associated with TM adults' odds of engaging in sexual behavior with a sexual partner of unknown STI/HIV status in the past 12 months. TM adults with casual sexual partnerships (vs. monogamous partnerships) and those in partnerships with cisgender men, other TM individuals, or transfeminine partners (vs. cisgender women) had statistically significantly higher odds of engaging in sexual behavior with a partner of unknown STI/HIV status in the past 12 months. Findings may inform future efforts to improve sexual health communication and STI/HIV disclosure between TM adults and their sexual partners.

Background: TRIUMPH (Trans Research–Informed communities United in Mobilization for the Prevention of HIV) was a community-led, transgender-specific pre-exposure prophylaxis (PrEP) demonstration project at 2 community-based clinical sites in California. TRIUMPH used peer health education, community mobilization, and clinical integration of PrEP with hormone therapy to promote PrEP knowledge and acceptability. The goal of this study was to evaluate PrEP uptake, retention, and adherence among TRIUMPH participants and examine site-based differences. Methods: Eligible participants were adult transgender and gender diverse people interested in PrEP. Participants were seen at baseline and at 1, 3, 6, 9, and 12 months for PrEP provision, clinical visits, and HIV testing. PrEP uptake was defined as dispensation of PrEP, PrEP retention was defined as proportion of expected visits completed among those who initiated PrEP, and PrEP adherence was assessed by measuring tenofovir diphosphate concentrations in dried blood spots. Logistic regression models quantified the association of variables with PrEP outcomes. Results: TRIUMPH enrolled 185 participants; the median age was 28 years (interquartile range: 23–35), 7% was Black, and 58% was Latinx. PrEP uptake was as follows: 78% in Oakland and 98% in Sacramento; 91% among trans women, 96% among trans men, and 70% among nonbinary participants. Almost half (47%) rarely/never believed about HIV, and 42% reported condomless sex act in the past 3 months. Participants who reported higher numbers of sex partners were more likely to be retained and adherent; other predictors of adherence included not having a primary partner and not experiencing violence in the past 3 months. Conclusions: This community-led, trans-specific PrEP demonstration project documents high levels of PrEP initiation in a young transgender and gender diverse cohort at risk of HIV acquisition.

Background Sex hormone and preexposure prophylaxis (PrEP) drug interactions among transgender women (TGW), transgender men (TGM), and cisgender men (CGM) are not fully understood. Methods TGM and TGW on at least 6 months of stable sex hormone therapy containing testosterone or estradiol (respectively) were enrolled in a 4-week study of directly observed dosing of daily oral coformulated emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). TFV-DP in dried blood spots and sex hormones in serum were measured at weekly intervals. TFV-DP was compared with 2- and 4-week samples from Directly Observed Therapy Dried Blood Spots (DOT-DBS) Study (NCT02022657). Results From May 2017 to June 2018, 24 TGM and 24 TGW were enrolled. Testosterone (total and free) and estradiol concentrations were comparable before and after 4 weeks of PrEP use in TGM and TGW, respectively. Historical controls included 17 cisgender women (CGW) and 15 CGM. TFV-DP concentrations at week 4 were comparable between TGW and TGM (mean difference, −6%; 95% confidence interval [CI], −21% to 12%; P = .47), comparable between TGW and CGM (mean difference, −12%; 95% CI, −27% to 7%; P = .21) and were lower among TGM compared with CGW (mean difference, −23%; 95% CI, −36% to −7%; P = .007). All persons in all groups were projected to reach the TFV-DP threshold that has been associated with high protection from human immunodeficiency virus. Conclusions CGM, TGM, and TGW had comparable TFV-DP concentrations in dried blood spots after 4 weeks of directly observed daily FTC/TDF PrEP use. Serum hormone concentrations were not affected by FTC/TDF PrEP use. Clinical Trials Registration NCT04050371.