Search

PURPOSE: This prospective clinical trial examined the effect on teeth and implants when rigidly or non-rigidly connected in a cross-arch model. MATERIALS AND METHODS: Thirty patients received 2 implants, 1 on each side of the mandible, and were restored with 3-unit fixed partial dentures connected either rigidly or non-rigidly to an abutment tooth. Patients were followed for at least 5 years post-restoration. RESULTS: Repeated-measures analysis revealed no significant difference in crestal bone loss at implants (rigid versus non-rigid methods). An overall significant difference (P < .001) was found comparing methods for teeth. Paired t tests revealed no significant differences in crestal bone levels for implants or teeth at the 5-year recall. Kaplan-Meier methods and the Cox proportional hazards model showed no differences between attachment methods with regard to success based on survival and bone loss criteria. During the 5-year recall period, 1 implant (rigid side) was removed. Four implants developed bone loss greater than 2 mm during the course of this trial. One tooth on the rigid side and 2 teeth on the non-rigid side had greater than 2 mm of crestal bone loss and were removed secondary to fractures. In all, 5 abutment teeth were removed, all of which had been treated with root canal therapy and fractured at the interface of the post within the tooth. There was no clear relationship of tooth fracture to attachment. Repeated-measures analysis of mobility values revealed no significant changes over the time course of this study, and paired t tests revealed no statistically significant differences between implants for mobility. Repeated-measures analysis and paired t tests for probing depth revealed no significant changes over the time course of this study. There were no significant differences in soft tissue indices for either attachment method. The percentage of patients who had measurable intrusion was 66% for the non-rigid group, and 44% for the rigid group; 25% of the non-rigid teeth had greater than 0.5 mm intrusion, compared with 12.5% for the rigid group. For the 2 time periods evaluated, there was no significant increase in intrusion over time. The non-rigid-side implant required more nonscheduled visits to treat problems than the rigid implant and the teeth. Discussion: Most patients were treated successfully with rigid or non-rigid attachment of implants to teeth. CONCLUSION: The high incidence of intrusion and non-scheduled patient visits suggest that alternative treatments without connecting implants to teeth may be indicated. [ABSTRACT FROM AUTHOR]

Clinical success of an endosseous implant to replace a single tooth is not only defined by its survival. Esthetic parameters have become integral aspects in defining success and failure. All-ceramic abutments have started to play a major role in achieving an esthetically successful result. The material itself, however, is not the exclusive determinant for esthetic success. It is the appropriate design and proper handling of the material and the abutment that enables the clinician to achieve esthetic outcomes that were not possible with traditional metal alloys. This article explores the rationale for using zirconia for prosthetic implant components, explains specific material properties, and discusses strategies and guidelines for the design and successful clinical implementation of CAD/CAM-fabricated zirconia implant abutments. [ABSTRACT FROM AUTHOR]

Objective: Folate receptor alpha (FRα) is overexpressed on >90% of high-grade epithelial ovarian cancers (EOC). Targeting FRα with antibody-drug conjugates has proven utility in the platinum-resistant setting. It is also a potential therapeutic target for immuno-oncologic agents, such as peptide vaccines that work primarily via adaptive and humoral immunity. We tested the hypothesis that FRα peptide immunization could improve outcomes in patients with EOC following response to platinum-based therapy., Methods: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS)., Results: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event., Conclusion: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222., Competing Interests: Conflicts of interest KK is listed as a coinventor on a patent entitled ‘Immunity to folate receptors’, which is owned by the Mayo Clinic and was previously licensed to Marker Therapeutics. KK reports receiving commercial research support from Marker Therapeutics. REO reports institutional research grants from ArsenalBio, AstraZeneca/Merck, Atara Biotherapeutics/Bayer, Genentech, Genmab, GSK, Gynecologic Oncology Group Foundation, Juno Therapeutics, Kite/Gilead, Ludwig Institute for Cancer Research, Lyell Therapeutics, Marker Therapeutics, OnCusp Therapeutics, Regeneron, Sellas Life Sciences, Stemcentrx, Syndax, TapImmune, and TCR2 Therapeutics; participating in advisory boards with Bayer, Carina Biotech, Immunogen, Miltenyi, Loxo, Regeneron, R-Pharm, Seattle Genetics, and Tesaro/GSK; personal fees from GOG Foundation; travel fees from Hitech Health. RMW reports grants or funding from Anixa Biosciences, Merck, OnTarget; consulting, DSMB, or advisory fees from Eisai, Sonnet Biotherapeutics, Genentech, Abbvie, Shattuck Labs, Merck, GSK/Tesaro, Legend Biotech, Novocure, Clovis, AstraZeneca, Regeneron, Mersana, Seagen; travel support from Eisai, Tapimmune/Marker Therapeutics; speakers bureau fees from GSK, CurioScience, Onclive; stock from Ovation Diagnostics. MSB is listed as a coinventor on pending patents entitled, “Combinations of Dendritic Cell-Based Vaccines” and “Checkpoint Inhibitors and Dendritic Cell-Based Vaccines and Uses Thereof;” reports institutional research support from Alkermes, Bristol-Myers Squibb, Genentech, Marker Therapeutics, Merck, nFerence, Pharmacyclics, Regeneron, Sorrento, TILT Biotherapeutics, Transgene, and Viewpoint Molecular Therapeutics; and is has served as a consultant/SAB member for Marker Therapeutics, Sorrento Therapeutics, TILT Biotherapeutics, and Viewpoint Molecular Targeting., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This article provides clinicians with 3 main factors that relate to long-term success. Long term in this article represents the lifespan of the patient, often requiring more than 40 years of function on the implant restoration. Literature is reviewed and used to provide evidence for these recommendations. Cases are presented to demonstrate these critical factors., Competing Interests: Disclosure Dr M.S. Block has a financial association with X-Nav (stocks) and Jet Investments (stocks)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Integrating routine SARS-CoV-2 testing in dialysis facilities may benefit patients receiving dialysis by mitigating risks of serious illness and reducing transmission. Patient acceptance of nonmandatory testing is unknown., Objective: To evaluate the acceptance of 2 SARS-CoV-2 testing strategies among patients in hemodialysis facilities nationwide., Design, Setting, and Participants: This nationwide cluster (dialysis facility-level) randomized trial investigated the acceptance of SARS-CoV-2 testing among patients receiving maintenance hemodialysis at facilities located in 22 states., Intervention: Anterior nares real-time reverse transcriptase-polymerase chain reaction tests offered once every 2 weeks (static testing facilities) vs offered once a week, once every 2 weeks, or once a month depending on county COVID-19 infection prevalence (dynamic testing facilities). Facilities were randomized by county, and tests were offered for 3 months between February 4 and July 24, 2023., Main Outcomes and Measures: The primary outcome was test acceptance. Secondary outcomes included the proportion of patients who accepted at least 1 test., Results: In total, 62 hemodialysis facilities were randomized and 57 participated. Among 2389 participating patients, the median age was 64 (IQR, 54-74) years, 1341 (56%) were male, 138 (6%) were categorized as American Indian, 60 (3%) Asian, 885 (37%) Black, 75 (3%) Native Hawaiian or Pacific Islander, 338 (14%) Hispanic, and 876 (37%) White; and 1603 (67%) had diabetes. A median of 6 (IQR, 6-6) tests were offered per patient in the static arm and 4 (3-6) tests in the dynamic arm. Test acceptance was low: 8% of offered tests were accepted in each of the test arms. Among 503 patients who accepted at least 1 test, the median percentage of offered tests that were accepted was 16% (IQR, 17%-42%) using the static testing strategy and 50% (IQR, 33%-75%) using the dynamic testing strategy (P < .001). Older patients (odds ratio [OR], 1.08 [95% CI, 1.01-1.16] per 5-year age increment), patients with (vs without) diabetes (OR, 1.59 [95% CI, 1.18-2.16]), and women compared with men (OR, 1.30 [95% CI, 0.98-1.73]) were more likely to accept multiple tests. Patients designated in the electronic health record as Hispanic were more likely than patients designated as White (OR, 1.78 [95% CI, 1.15-2.76]) to accept at least 1 test, whereas patients living in zip codes electing Republican representatives to Congress were less likely than patients living in zip codes electing Democratic representatives (OR, 0.34 [95% CI, 0.17-0.69]) to accept multiple tests., Conclusions and Relevance: In this cluster randomized trial evaluating 2 SARS-CoV-2 testing strategies in dialysis facilities, test acceptance was low, and a dynamic testing strategy anchored to COVID-19 infection prevalence did not outperform a static testing strategy of every 2 weeks., Trial Registration: ClinicalTrials.gov Identifier: NCT05225298.

Background: Clinicians have to decide which implant system to use for their patients. Factors influencing a clinician's choice of a specific implant are not well-established., Purpose: The purpose of this study was to identify factors that may influence clinician's choice of implant., Study Design, Setting, Sample: This cross-sectional study used a survey instrument that was sent to dentists. Inclusion criteria included if the doctor's name was the addressee and if their website indicated they utilize implants. Exclusion criteria included if the email address was directed to individuals other than the clinician or if the respondent does not place implants as indicated by their website., Predictor Variable: The predictor variable was the provider type (oral and maxillofacial surgeon, general dentist, prosthodontist, or periodontist)., Main Outcome Variable: The outcome variables were factors that may influence clinician's choice of implants, measured by their ranked responses., Covariates: Age and sex were the covariates., Analyses: The survey data were evaluated as group in total and separated for each provider type. Factors affecting clinical choice were ranked. A mean score was determined. Responses were evaluated using analysis of variance with significance at P value < .05 to determine if there were differences among the groups., Results: After applying inclusion and exclusion criteria, the final study sample consisted of 353 clinicians, of whom 230 (65.1%) responded to the survey. Factors scored as extremely or somewhat important were ranked from high to low as follows: clinical trial evidence (92%), ease of use (88%), familiarity with system (73%), restorative dentist's preference (72%), cost (63%), sales representative (59%), key opinion leader (66%), a laboratory's preference (45%), implant company providing continuing education (66%), and implant company can grow practice (65%). There were differences among providers for the factors that influence choice of implant for cost (P value = .02), sales representative (P value = .015), the key opinion leader (P value = .01), laboratory preference (P value = .002), providing continuing education (P value = .02), and implant company can grow my practice (P value = .035)., Conclusion and Relevance: Four factors that highly influenced provider's choice of a specific implant were evidence for success, ease of use, cost, and familiarity with the implant., (Copyright © 2024 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Melanoma is the deadliest form of skin cancer. The median age at diagnosis is 66. While most patients are treated with immunotherapy, the use of targeted therapy is a valid alternative for patients whose tumors harbor a BRAF or c-KIT driver mutation. These agents, while effective, come with a variety of side effects which limit their use, especially in older patients. We sought to assess the efficacy and toxicity of these agents in older melanoma patients. Melanoma patients over 65 treated with BRAF/MEK or c-KIT inhibitors were retrospectively identified, and their data were analyzed for treatment efficacy and toxicity. All data were compared using the Chi-square test for categorical comparisons and the Kruskal-Wallis method for median comparisons. One hundred and sixteen patients were identified. One hundred and six patients were treated with BRAF/MEK inhibitors. The assessed response rate (RR) was 83% and was comparable across different subgroups, including advanced line patients and those with a more aggressive disease. The median progression free survival (PFS) was 7.9 months, and the median overall survival (OS) was 15.7 months. Twenty-seven percent experienced grade 3-4 toxicity leading to a 24% treatment discontinuation rate. Another 10 patients were treated with the c-KIT inhibitor imatinib, for whom the assessed RR was 55%. The median PFS was 4.3 months, and the median OS was 22.6 months. Forty percent needed dose reductions, yet none had to stop treatment due to adverse effects. The use of targeted therapy in older patients is effective yet challenging due to toxicity. Deploying mitigation strategies can help maximizing their usefulness., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Vulvar melanoma and vaginal melanoma are rare and difficult to treat. We describe the last three decades in a cohort predominantly treated surgically with adjuvant therapy., Methods: All new patients between 1993 and 2021 followed until 2024. Collection of demographic and oncologic data allowed comparisons and Kaplan-Meier method was used to evaluate overall survival (OS) and progression free survival (PFS) stratified by adjuvant therapy type, diagnosis before and after 2011, and between vulvar and vaginal melanomas., Results: Consultation for 63/72 patients (87.5 %) were for primary treatment. Most patients had vulvar melanoma (50/72, 69.4 %), received surgery (65/72, 90.3 %), and adjuvant treatment (40/72, 55.6 %) with immunotherapy, chemotherapy, and/or targeted therapy. Median survival for 63 patients presenting for primary treatment was 54.2 months, and 9/13 patients who were disease free after five years later received adjuvant immunotherapy. Survival did not vary by adjuvant therapy type or diagnosis after 2011 but was significantly less for vaginal melanoma. Following recurrence seven patients experienced complete response including three patients receiving combined nivolumab with ipilimumab and two nivolumab alone experienced., Conclusions: Survival was not significantly different by adjuvant therapy type or after 2011. Most patients who were disease-free five years after surgery had received adjuvant therapy. Seven patients experienced complete responses to therapy after recurrence of whom five received immune checkpoint inhibitors. Although survival is not improved as in cutaneous melanomas by immune checkpoint inhibitors, signal continues for the use of immune checkpoint inhibitors in gynecologic melanomas., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Introduction: Early reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO-1 inhibitor epacadostat in patients with recurrent OCCC., Methods: This single arm, two-stage, phase 2 trial included those with measurable disease and 1-3 prior regimens. Patients received intravenous pembrolizumab 200 mg every 3 weeks and oral epacadostat 100 mg twice a day. Primary endpoint was overall response rate (ORR), secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). The study was powered to detect an absolute 25% increase in response (15% to 40%)., Results: Between September 28, 2018 and April 10, 2019, 14 patients enrolled at first stage. Rate of accrual was 2.3 patients per month. Median age was 65 years (44-89), 10 (71.4%) had ≥2 prior regimens. ORR was 21% (95% CI 5-51%) within 7 months of study entry with 3 partial responses, and 4 had stable disease (disease control rate 50%). Median PFS was 4.8 months (95% CI: 1.9-9.6), OS 18.9 months (95% CI: 1.9-NR). Most common grade ≥ 3 adverse events were electrolyte abnormalities and gastrointestinal pain, nausea, vomiting, bowel obstruction. In July 2019, the study reached the pre-specified criteria to re-open to second stage; however, the study closed prematurely in February 2021 due to insufficient drug supply., Conclusions: Pembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with OCCC., Competing Interests: Declaration of competing interest Dr. Lilian Gien received consulting fees from Merck – Advisor Board – October 2021. She also received Speaker Honorarium – January 2021 – from Merck. Dr. Danielle Enserro received funding from NCI for Cooperative Group/NCTN Grant Funding for all aspects of this trial including travel to Group meetings, trial design, statistical design and analysis, study monitoring, writing/editing of abstracts/manuscripts, etc. Dr. Matthew S. Block received grants or contracts from Merck – drug only contract for investigator-sponsored trial; Regeneron, Sorrento, Transgene, TILT Biotherapeutics, Alkermes, Bristol-Myers Squibb, Genentech, nFerence, Pharmacyclics and Viewpoint Molecular Therapeutics – institutional payment for clinical trial. He also has a patent filed for Dendritic Cell Based Vaccines Combined with Penbrolizumab for the Treatment of Advanced Ovarian Cancer – patent filed; author has waived rights to personal financial gain. He has participated on a Data Safety Monitoring Board or Advisory Board from TILT Biotherapeutics, Sorrento, and Viewpoint Molecular Therapeutics – no payment received. Dr. Linda Duska has multiple grants from sponsors for clinical trials. These grants go to her institution and not to her. These include, but are not limited to: (research funding (to institution) for investigator initiated trials for Merck, clinical trial grants (to institution) from Genentech/Roche, AbbVie/(GOG 3005), Acrivon, Advaxis, Aduro BioTech, Alkermes, Blueprint, Constellation, Eisai, GlaxoSmithKlein/Novartis, Immunogen, Inovio, Iovance, Karyopharm, KSQ Therapeutics, Lycera, Merck, Morab, MorphoTek, Naveris, Nurix, OncoQuest, Pfizer, Syndax, Tesaro, and Zentalis. She has Royalties or licenses (all up to date) with Wiley and ASCO (Editor of ASCO Connection). She received consulting fees from Regeneron, Aadi Bioscience and Merck for serving on Scientific Advisory Boards. She received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Advance Medical, CEA Group and Clinical Care Options (CME). She has participated on a Data Safety Monitoring Board or Advisory Board for Innovio DSMB (to institution) and Aegenus DSMB (to institution). She served as Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid as Secretary Treasurer for SGO (unpaid) and Editorial Board, British Journal of OB/GYN. Dr. Andrea E. Wahner-Hendrickson received Grants or contracts from TORL Therapeutics (funding to institution for clinical trial, OXCIA (advisory board – unpaid), Prolynx (funding to institution for clinical trial and Mayo Ovarian SPORE (P50 CA1363939). She participated on a Data Safety Monitoring Board or Advisory Board for OXCIA (unpaid). She also served in a Leadership or fiduciary role in other board, society, committee or advocacy group – MOCA (unpaid). Dr. Premal H. Thaker received grants to his institution from Merck and GlaxoSmithKline. She received consulting fees from Immunon. She also participated on a Data Safety Monitoring Board or Advisory Board with AstraZeneca, Clovis Oncology, GlaxoSmithKline, Seagen, Agenus, Immunon, Immuogen, Mersana, Novocure, R-Pharm, Zentalis, Aadi Pharmaceuticals, Merck, Caris Iovance and Verastem. She also has stock or stock options with Immunon. Dr. Floor Backes received grants or contracts from Merck, Eisai, ImmunoGen, Clovis, Beigene, Natera, Tempus and AstraZeneca (research grants paid to the institution). Royalties or licenses from UptoDate (personal fees). She also received consulting fees from Agenus, Merck, Clovis, Immunogen, Eisai, AstraZeneca, GlaxoSmithKline, Myriad, BioNTech and Daiichi Sankyo (Advisory boards – personal fees). She received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Clinical Educational Concepts, Clinical Care Options, Medscape/WebMD, Med Learngin, 13Health, CMR Institute, Global Learning Initiative/Prova, OncLive, Targeted Oncology and Research To Practice (CME lectures – personal fees). She received support for attending meetings and/or travel from GlaxoSmithKline. She participated on a Data Safety Monitoring Board – see consulting fees. She served in a Leadership or fiduciary role on other board, society, committee or advocacy group, paid or unpaid from Society of Gynecologic Oncology (Board member – unpaid), NRG Oncology Developmental Therapeutics Committee – Co-Chair and IGCS Education360 – Co-Chair. Dr. Carolyn Y. Muller received a grant to her institution from New Mexico Minority Underserved NCORP to support enrollment to all NCI NCTN trials. She has a contract to her institution to enroll to GOG Partners trials from GOG Partners Foundation (Segan, GSK, Mersana, Alkemes, Merck, Verastem, Immunogen, etc). She received contracts to her institution for enrollment to specific clinical trials from Linneus Therapeutics. She serves as Chair, Board of Directors of the New Mexico Cancer Research Alliance (unpaid position that manages an affiliate consortium to provide access to clinical trials across the states many health systems). Dr. Paul DiSilvestro serves on the NRG Oncology Board of Directors in a leadership or fiduciary role. Dr. David M. Gershenson's institution received a grant from Novartis. He has royalties or licenses from Elsevier and UpToDate. He received consulting fees to himself from Verastem. He received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Yale University and University of Washington. He serves in a Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from International Consortium for Low Grade Serous Ovarian Cancer. He has stock in Bristol Myers Squibb, Johnson & Johnson and Proctor & Gamble. He has other financial or non-financial interests himself in Audi AB, Verastem AB, Springworks AB and Onconova AB. Dr. Kathleen N. Moore has grants/contracts from Clovis Oncology Pharmaceutical, Eli Lilly and Company, Genentech, GSK plc Pharmaceutical, Merck, PTC Therapeutics Pharmaceuticals, Verastem Oncology and Biotech. She received support for attending meetings and/or travel from Duality, GSK and Regeneron. She participates on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Aravive, Aadi Bioscience, Alkermes, Blueprint Medicines, Caris, Clovis Oncology Pharmaceutical, Duality, Eisai Pharmaceutical, EMD Serono Inc., Eli Lilly and Company, Genentech Biotechology, GSK plc Pharmaceutical, ImmunoGen Biotechnology, InxMed, I-MAB Biotech, Iovance, Jiangsu Hengrui Medicine Pharmaceutical, Merck, Mereo BioPharma Group, Mersana Therapeutics Inc., Myriad Genetics, Novartis Pharmaceuticals, Onconova Therapeutics Inc., OncXerna Therapeutics, Inc., Regeneron, VBL, and Verastem Oncology. She serves in a leadership or fiduciary role for GOG Partners and ASCO. Dr. Carol Aghajanian received Clinical Trial funding to her institution (MSK) from: Abbvie – MSKPI – GOG 3005; AstraZeneca – MSK PI, SOLO1/GOG 3004; National Coordinating Investigator and MSK PI, DO81RC00001; ENGOT-ov46; AGO-OVAR 23; GOG-3025; Clovis – MSK PI, ARIEL 2 &3; Genentech/Roche – MSK PI, GOG3015 (IMagyn050). She also participates on an Advisory Board for Blueprint Medicine – Advisory Board 6/30/21 (no consulting fee); Mrck – Global Cervical and Ovaian Cancer Virtual Advisory Board 7/10/23 (no consulting fee) and AstraZeneca – AZ Evolve dmc 4/26/23-ongoing, She also serves on the GOG Foundation, Board of Directors (unpaid, occasional travel cost reimbursement to attend meetings) and NRG Oncology Board of Directors (unpaid)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune demyelinating disease rarely associated with malignancy. We report the clinical, MRI, immunopathology, and treatment response in a person with MOGAD and melanoma., Methods: This is a case report of a person with a multidisciplinary evaluation at a tertiary referral center., Results: A 52-year-old man presented with progressive encephalomyelitis that led to identification of metastatic melanoma. Investigations revealed positive MOG-IgG at high titers in serum (1:1,000; normal, <1:20) and CSF (1:4,096; normal, <1:2). MRI demonstrated multifocal T2 lesions with enhancement in the brain and spine. Brain biopsy showed demyelination and inflammation. MOG immunostaining was not present in the tumor tissue. He initially improved with methylprednisolone, plasmapheresis, prolonged oral steroid taper, and cancer-directed treatment with BRAF and MEK 1/2 inhibitors, but then developed bilateral optic neuritis. IV immunoglobulin (IVIG) was initiated. Five months later, he developed metastases and immune checkpoint inhibitor (ICI) treatment was started, which precipitated optic neuritis and myelitis despite IVIG and prednisone. Tocilizumab, an interleukin-6 receptor blocker, was started with excellent and sustained clinical and radiologic response., Discussion: This case revealed a presentation of MOGAD concurrent with melanoma without tumor MOG immunostaining. We highlight tocilizumab as a dual-purpose treatment of MOGAD and the neurologic immune-related adverse effect of ICI.

Purpose: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers., Patients and Methods: A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75-175 mg/m2, BEV 30-70 mg/m2). Pharmacokinetic analyses were performed., Results: No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%-61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies., Conclusions: The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2)., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Patients may need removal of their teeth with placement of implants for rehabilitation. The clinical problem is the status of the remaining teeth and how this affects the timing for implant placement and the method for provisionalization. The importance of this review is to document the different strategies including sequential tooth removal and grafting and the use of teeth to provide a fixed provisional rather than a removable provisional, to provide surgeons with a reference to maintain patient function during their rehabilitation., Methods: Pubmed.gov was the information source. Years reviewed included 1990 to 2022. Inclusion criteria included only articles in peer-reviewed journals. Variables evaluated included the success for placing implants immediately into extraction sites, and the methods to transition between steps in their rehabilitation. Data collected were results of systematic reviews and independent clinical series, as well as case reports of prosthetic methods for transitioning., Results: The search used terms which included implants in extraction sites (n = 205) and transitioning teeth to implants (n = 153). Twenty-one articles were reviewed involving extraction sites and 19 articles reviewed concerning transitioning from teeth to implants. The placement of implants immediately into excretion sites did have a relative risk for failure compared to implant placement in healed sites. The use of non-restorable teeth to support a fixed provisional prosthesis was successful; however, variability in reporting prevented a statistical analysis., Conclusion: The surgeon needs to utilize teeth to provide support during treatment phases in order to provide the patient with a fixed provisional prosthesis to allow for implant integration and to provide time for graft healing. Specific methods used for transitioning do not have a significant evidence base to recommend one method but routine prosthetic techniques have been used and are reported in case reports., (Copyright © 2024 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet their use is associated with immune-related adverse events (irAEs). Estimating the prevalence and patient impact of these irAEs in the real-world data setting is critical for characterizing the benefit/risk profile of ICI therapies beyond the clinical trial population. Diagnosis codes, such as International Classification of Diseases codes, do not comprehensively illustrate a patient's care journey and offer no insight into drug-irAE causality. This study aims to capture the relationship between ICIs and irAEs more accurately by using augmented curation (AC), a natural language processing-based innovation, on unstructured data in electronic health records., Methods: In a cohort of 9,290 patients treated with ICIs at Mayo Clinic from 2005 to 2021, we compared the prevalence of irAEs using diagnosis codes and AC models, which classify drug-irAE pairs in clinical notes with implied textual causality. Four illustrative irAEs with high patient impact-myocarditis, encephalitis, pneumonitis, and severe cutaneous adverse reactions, abbreviated as MEPS-were analyzed using corticosteroid administration and ICI discontinuation as proxies of severity., Results: For MEPS, only 70% (n = 118) of patients found by AC were also identified by diagnosis codes. Using AC models, patients with MEPS received corticosteroids for their respective irAE 82% of the time and permanently discontinued the ICI because of the irAE 35.9% (n = 115) of the time., Conclusion: Overall, AC models enabled more accurate identification and assessment of patient impact of ICI-induced irAEs not found using diagnosis codes, demonstrating a novel and more efficient strategy to assess real-world clinical outcomes in patients treated with ICIs.

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations., Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data., Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers., Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD., (© 2024. The Author(s).)

Both targeted therapies and immunotherapies provide benefit in resected Stage III melanoma. We hypothesized that the combination of targeted and immunotherapy given prior to therapeutic lymph node dissection (TLND) would be tolerable and drive robust pathologic responses. In NeoACTIVATE (NCT03554083), a Phase II trial, patients with clinically evident resectable Stage III melanoma received either 12 weeks of neoadjuvant vemurafenib, cobimetinib, and atezolizumab (BRAF-mutated, Cohort A, n = 15), or cobimetinib and atezolizumab (BRAF-wild-type, Cohort B, n = 15) followed by TLND and 24 weeks of adjuvant atezolizumab. Here, we report outcomes from the neoadjuvant portion of the trial. Based on intent to treat analysis, pathologic response (≤50% viable tumor) and major pathologic response (complete or near-complete, ≤10% viable tumor) were observed in 86.7% and 66.7% of BRAF-mutated and 53.3% and 33.3% of BRAF-wild-type patients, respectively (primary outcome); these exceeded pre-specified benchmarks of 50% and 30% for major pathologic response. Grade 3 and higher toxicities, primarily dermatologic, occurred in 63% during neoadjuvant treatment (secondary outcome). No surgical delays nor progression to regional unresectability occurred (secondary outcome). Peripheral blood CD8 + T CM cell expansion associated with favorable pathologic responses (exploratory outcome)., (© 2024. The Author(s).)

Introduction: Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes., Methods: In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma., Results: The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF -targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF -targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF -wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis., Conclusion: Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI., Competing Interests: Conflicts of Interest: None.

Purpose: The purpose of this article is to provide clinicians with options to restore the adult patient with an impacted maxillary canine using dental implants. Literature was reviewed to provide evidence for the methods suggested., Methods: The search strategy utilized pubmed.gov to identify articles pertinent to identified treatment options. The search used terms which included dental implants and impacted tooth, tilted implants and fixed partial prostheses, 6 mm dental implants, and 4 mm dental implants. Articles were included if they reported dental implant procedures associated with impacted canines in adults, or if they reported on the use of tilted implants, immediate implant placement at time of canine removal, or the use of short implants. Articles with less than 12 months follow up were excluded., Results: The search identified articles which included dental implants and impacted tooth (n = 142), tilted implants and fixed partial (n = 36), 6 mm dental implants (n = 182), and 4 mm dental implants (n = 162). From this search, 28 articles were collated that satisfied the inclusion criteria. The use of tilted implants had success rates ranging from 93% to 99%. Short implants had success rates ranging from 87 to 90% in the posterior maxilla. Immediate implant placement after removal of the impacted canine lacked long term reports. Two cases are included to demonstrate treatment planning using navigation to guide implant placement in an adult patient with an impacted maxillary canine., Conclusions: The evidence-based literature concerning implant placement associated with adult maxillary canines is limited. There is evidence to support tilting implants to avoid the impacted canine, or the use of short implants splinted together to avoid the impacted tooth. Other options had insufficient data to offer support., (Copyright © 2023 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

The optimal detection strategies for effective convalescent immunity after SARS-CoV-2 infection and vaccination remain unclear. The objective of this study was to characterize convalescent immunity targeting the SARS-CoV-2 spike protein using a multiparametric approach. At the beginning of the pandemic, we recruited 30 unvaccinated convalescent donors who had previously been infected with COVID-19 and 7 unexposed asymptomatic controls. Peripheral blood mononuclear cells (PBMCs) were obtained from leukapheresis cones. The humoral immune response was assessed by measuring serum anti-SARS-CoV-2 spike S1 subunit IgG via semiquantitative ELISA, and T-cell immunity against S1 and S2 subunits were studied via IFN-γ enzyme-linked immunosorbent spot (ELISpot) and flow cytometric (FC) activation-induced marker (AIM) assays and the assessment of cytotoxic CD8 + T-cell function (in the subset of HLA-A2-positive patients). No single immunoassay was sufficient in identifying anti-spike convalescent immunity among all patients. There was no consistent correlation between adaptive humoral and cellular anti-spike responses. Our data indicate that the magnitude of anti-spike convalescent humoral and cellular immunity is highly heterogeneous and highlights the need for using multiple assays to comprehensively measure SARS-CoV-2 convalescent immunity. These observations might have implications for COVID-19 surveillance, and the determination of optimal vaccination strategies for emerging variants. Further studies are needed to determine the optimal assessment of adaptive humoral and cellular immunity following SARS-CoV-2 infection, especially in the context of emerging variants and unclear vaccination schedules.

Background: Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing., Methods: ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies., Results: Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells., Conclusions: These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy., Competing Interests: Competing interests: MC is an inventor on a patent filed by the University of Arkansas, entitled ‘Inhibition of dendritic cell-driven regulatory T cell activation and potentiation of tumor antigen-specific T cell responses by interleukin-15 and MAP kinase inhibitor.’ KLK and MB are inventors on a patent filed by the Mayo Clinic, entitled ‘Dendritic Cell Based Vaccines Combined with Pembrolizumab for the Treatment of Advanced Ovarian Cancer.’, (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Metastatic uveal melanoma (MUM) has a poor prognosis and treatment options are limited. These patients do not typically experience durable responses to immune checkpoint inhibitors (ICIs). Oncolytic viruses (OV) represent a novel approach to immunotherapy for patients with MUM., Methods: We developed an OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-β) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNβ-TYRP1), and conducted a Phase 1 clinical trial with a 3 + 3 design in patients with MUM. VSV-IFNβ-TYRP1 was injected into a liver metastasis, then administered on the same day as a single intravenous (IV) infusion. The primary objective was safety. Efficacy was a secondary objective., Results: 12 patients with previously treated MUM were enrolled. Median follow up was 19.1 months. 4 dose levels (DLs) were evaluated. One patient at DL4 experienced dose limiting toxicities (DLTs), including decreased platelet count (grade 3), increased aspartate aminotransferase (AST), and cytokine release syndrome (CRS). 4 patients had stable disease (SD) and 8 patients had progressive disease (PD). Interferon gamma (IFNγ) ELIspot data showed that more patients developed a T cell response to virus encoded TYRP1 at higher DLs, and a subset of patients also had a response to other melanoma antigens, including gp100, suggesting epitope spreading. 3 of the patients who responded to additional melanoma antigens were next treated with ICIs, and 2 of these patients experienced durable responses., Discussion: Our study found that VSV-IFNβ -TYRP1 can be safely administered via intratumoral (IT) and IV routes in a previously treated population of patients with MUM. Although there were no clear objective radiographic responses to VSV-IFNβ-TYRP1, dose-dependent immunogenicity to TYRP1 and other melanoma antigens was seen., Competing Interests: KP: Imanis Life Sciences stock; Vyriad stock. RM: Zentalis pharmaceuticals consulting. AD: Guardant health advisory board; TP therapeutics advisory board; Novartis clinical trial support; Sorrento therapeutics clinical trial support; Syntrix therapeutics clinical trial support; AnHeart Therapeutics clinical trial support; Merck clinical trial support; Intellisphere LLC honoraria. NP: Imanis life sciences LLCprincipal scientist. LK: Immunocore consulting; Novartis consulting. MS: Bristol-Myers Squibb grant/contract; Sorrento therapeutics grant/contract; other intellectual property. RV: Oncolytics Biotech, Canada scientific advisory board; Greenfire/MGFB scientific advisory board. RD: Bristol Myers Squibb funding; Elsai consulting; Elsevier advisory board; EMD Serono Inc consulting; Genzyme Corporation case series discussion; Immunovaccine Technologies consulting; Natera advisory board; Regeneron Pharmaceuticals consultant; Sanofi Genzyme advisory board. MB: Alkermes grant/contract; Bristol-Meyers Squibb grant/contract; Genentech grant/contract; Immune Design grant/contract; Marker Therapeutics grant/ contract; Merck grant/contract; nFerence grant/contract; Pharmacyclics grant/contract; TILT Biotherapeutics grant/contract; Transgene grant/contract; Viewpoint MolecularTargeting grant/contract. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission., (Copyright © 2023 Smith, Peng, Pulido, Weisbrod, Strand, Allred, Newsom, Zhang, Packiriswamy, Kottke, Tonne, Moore, Montane, Kottschade, McWilliams, Dudek, Yan, Dimou, Markovic, Federspiel, Vile, Dronca and Block.)

Purpose: Patients receiving full arch implant borne maxillary prostheses require functional, esthetic, and long term success. The importance of this review is to document the difficulty with implant maintenance, the prevalence of peri-implant disease, and the improvement in biologic health when using a prosthesis that can be maintained to minimize plaque. The objective is to provide surgeons with a reference to optimize surgical procedures that can result in improved hygiene and long term maintenance, as well as acceptable functional and esthetic goals., Methods: Pubmed.gov was the information source. Years reviewed included 1990-2022. Inclusion criteria included only articles in journals referenced in pubmed.gov. The reports excluded were case reports, reports that only included implant survival, and articles without a statistical analysis to generate meaningful conclusions. Biological complications included bone loss, hygiene difficulty, mucositis and recession, the incidence of peri-implantitis, and how complications related to patient co-morbidities. Data collected included outcomes of the study including statistical significance., Results: The search identified articles for review using terms which included full arch maxillary restorations (n = 736), long term success with full arch maxillary prostheses (n = 22), ceramic full arch restorations (n = 102), and complications with full arch restorations (n = 231). From this search, 53 articles were collated that satisfied the inclusion criteria. Factors found to be significant contributors to biological complications included bone loss and peri-implant disease, difficulty with daily hygiene access, plaque and biofilm coverage, and the need for continued maintenance for long term implant health., Conclusion: The surgeon needs to place implants to allow a full arch maxillary prosthesis to be fabricated with full access to the implants for maintenance, which should decrease the incidence of biological complications. With excellent maintenance full arch implant restorations can have limited peri-implant disease., (Copyright © 2023 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Our objectives were to determine the incidence, timing, and risk factors for venous thromboembolisms (VTEs) in patients with advanced stage epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT). We explored the utilization of direct-acting oral anticoagulants (DOACs) for VTE treatment., Methods: This retrospective cohort study included patients with advanced stage EOC receiving NACT followed by interval cytoreductive surgery (ICS) at a single institution. Risk factors were compared between patients with versus without VTE between EOC diagnosis and 180 days after ICS. Bleeding complications were compared between patient who received a DOAC versus non-DOAC., Results: VTE cases occurred amongst 33 of the 154 (21.4%) patients with 4 (2.6%) concurrent with EOC diagnosis, 9 (5.8%) between EOC diagnosis and NACT start, 13 (8.4%) between NACT start and ICS, and 7 (4.5%) within 180 days after ICS. There were no statistically significant differences in risk factors assessed (age, body mass index, functional status, histology, Khorana score, and smoking history) between patients with versus without VTE. Eleven patients (33.3%) received a DOAC for VTE treatment. There were no significant differences in number of intraoperative blood transfusions (p = 0.38), blood loss (p = 0.95), or bleeding complications (p = 0.53) between patients treated with a DOAC versus a non-DOAC., Conclusion: There is a high incidence of VTE events (21.4%) in patients with advanced stage EOC undergoing NACT. Two-thirds of the VTEs may have been prevented with thromboprophylaxis as they occurred between EOC diagnosis and ICS. These data support consideration of thromboprophylaxis in all patients with advanced stage EOC undergoing NACT., (Copyright © 2023 Elsevier Inc. All rights reserved.)

PG545 (Pixatimod) is a highly sulfated small molecule known for its ability to inhibit heparanase and disrupt signaling mediated by heparan-binding-growth factors (HB-GF). Previous studies indicated that PG545 inhibits growth factor-mediated signaling in ovarian cancer (OC) to enhance response to chemotherapy. Here we investigated the previously unidentified mechanisms by which PG545 induces DNA damage in OC cells and found that PG545 induces DNA single- and double-strand breaks, reduces RAD51 expression in an autophagy-dependent manner and inhibits homologous recombination repair (HRR). These changes accompanied the ability of PG545 to inhibit endocytosis of the heparan-sulfate proteoglycan interacting DNA repair protein, DEK, leading to DEK sequestration in the tumor microenvironment (TME) and loss of nuclear DEK needed for HRR. As a result, PG545 synergized with poly (ADP-ribose) polymerase inhibitors (PARPis) in OC cell lines in vitro and in 55% of primary cultures of patient-derived ascites samples ex vivo. Moreover, PG545/PARPi synergy was observed in OC cells exhibiting either de novo or acquired resistance to PARPi monotherapy. PG545 in combination with rucaparib also generated increased DNA damage, increased antitumor effects and increased survival of mice bearing HRR proficient OVCAR5 xenografts compared to monotherapy treatment in vivo. Synergistic antitumor activity of the PG545/rucaparib combination was likewise observed in an immunocompetent syngeneic ID8F3 OC model. Collectively, these results suggest that targeting DEK-HSPG interactions in the TME through the use of PG545 may be a novel method of inhibiting DNA repair and sensitizing cells to PARPis., (© 2023. The Author(s).)

Purpose: Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking., Patients and Methods: We performed a single-arm, multicenter clinical trial using "flip dose" ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network., Results: From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%-66%] and 37% (95% CI, 19%-55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%-95%) and 68% (95% CI, 46%-83%), respectively. Median RFS was 10.3 months (95% CI, 5.7-25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities., Conclusions: Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing., (©2023 American Association for Cancer Research.)

Background: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features., Methods: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1., Results: Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10-2.46; P = 0.015; N = 325 published set HR, 2.87; 95% CI, 2.17-3.81; P = 2.2 × 10-13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599; HR, 2.22; 95% CI, 1.66-2.95; P = 4.1 × 10-8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10-7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10-4) in covariate-adjusted analysis., Conclusions: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment., Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial., (©2023 American Association for Cancer Research.)

Purpose: Surgeons placing implants use navigation for implant placement accuracy. The importance of this review is to document the sources of error that are involved with navigation so surgeons can recognize factors to decrease error. The objective is to provide surgeons with a reference to optimize navigation., Methods: Pubmed.gov was the information source. Years reviewed included 2010 to 2022. The inclusion criteria included only articles in peer-reviewed journals. In vitro results were included only if they involved testing of variables microgap, cone beam computerized tomography (CBCT) accuracy evaluation, or accuracy of printed models. Variables were searched and evaluated. Data collected included the objectives and outcomes of the study including statistical significance. The conclusions made by the authors were confirmed by evaluating the data analysis, and then these conclusions were listed in each error-related topic., Results: The search used terms which included guided implant surgery complications (n = 4,029), accuracy of CBCT scanners (n = 319), accuracy of implant navigation (n = 983), and the error between drills and static guides (n = 3). From this search, 70 articles were collated that satisfied the inclusion criteria. There are multiple sources of error that are less than 1 mm, including but not limited to errors associated with the scanner and method for scanning, errors associated with merging scanned files with the CBCT scan, errors using different guide stent fabrication methods, errors associated with intraoperative techniques, the learning curve, and planning error. If small errors are not taken into consideration, implant placement errors can exceed 1-2 mm of platform location and angulation errors in excess of 8°., Conclusion: The surgeon needs to take into consideration controllable factors that will result in the avoidance of implant malposition and thus be able to effectively utilize navigation for accurate implant placement., (Copyright © 2022 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Clinical stage III melanoma, defined as resectable RECIST measurable nodal disease with or without in-transit metastases, represents approximately 15% of new melanoma diagnoses every year with additional cases presenting as recurrent nodal disease following previous treatment of a primary melanoma. The standard of care for patients with resectable clinical stage III melanoma is surgical resection, consisting of therapeutic lymph node dissection and/or resection of in-transit disease and consideration of adjuvant systemic therapy and occasionally adjuvant radiation. These patients have high rates of regional recurrence and progression to metastatic disease postsurgery, highlighting the need for better treatment options. With the success of immune checkpoint inhibitors in both the adjuvant and metastatic settings, the use of these agents in the neoadjuvant setting has been an emerging area of research interest. In this chapter, we will discuss the rationale for neoadjuvant immunotherapy; review impactful clinical trials; and define response monitoring, surgical considerations, emerging therapies, and unanswered questions for neoadjuvant therapy as a recent paradigm shift in the management of clinical stage III melanoma.

Purpose: Patients with failing implants or teeth may require multiple procedures to correct their problems. The purpose of this article was to describe an algorithmic approach for clinicians to use to simplify the restoration of the patient., Methods: The topics for this article were used to search for references using PubMed. Topics included the effect of thickening thin gingiva to promote stable soft tissue margins, the use of different bone graft materials for sockets and for ridge augmentation, and methods to use digital technology for efficient planning. Other sources were book chapters, which had an extensive reference section including multiple case series and clinical trial results. Based on the search results, references were chosen that would verify the techniques suggested to be used for these problems. For this narrative, diagnostic information is described using virtual digital methods rather than analog methods to develop the final prosthetic plan, which guides the surgical procedures. The surgical phases are described in detail., Results: The gingiva needs to be healthy and thick to support a hard tissue graft. The timing of procedures begins with assessment of the quality of the soft tissue and the loss of both soft and hard tissues. The operative procedures should be based on the final prosthetic plan, created digitally, to provide information that is required to properly position soft and hard tissue grafts and the implants., Conclusions: This organized, algorithmic approach can be used for many situations that clinicians are seeing in their daily practice due to complications that can occur., (Copyright © 2022 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy that usually occurs in the head/neck or extremities. However, there are reports of MCC developing in the lymph nodes or parotid gland without evidence of a primary cutaneous lesion., Methods: We reviewed 415 patients with biopsy-proven MCC. Patients with MCC of unknown primary (n = 37, 9%, MCCUP) made up the study cohort. The primary endpoints of the study were rate of recurrence, disease-free survival, and overall survival., Results: Patients with MCCUP presented with tumors in lymph nodes (n = 34) or parotid gland (n = 3). Nodal disease was most commonly detected in the inguinal/external iliac (n = 15) or axillary (n = 14) regions. The mean age at diagnosis was 70 years and 24% were female. Patients presented with distant metastases in 24.3% of cases. Patients with stage IIIA disease treated with regional lymph node dissection (RLND) had a lower risk of disease recurrence (hazard ratio 0.26, p = 0.046). Recurrence-free survival was 59.3% at 5 years. Disease-specific survival was 63.3% at 5 years., Conclusion: Patients with MCCUP have a high risk of recurrence and mortality. The optimal treatment for MCCUP has yet to be elucidated, although therapeutic RLND appears beneficial for these patients., (© 2022 Wiley Periodicals LLC.)

Importance: Long-term success with a dental implant restoration relies on a stable connection between the abutment and the implant. The purpose of this article is to review current knowledge of the abutment interface, identify problems that develop due to wear and mismatch of parts, and use a problem list to propose a solution. The objective was to provide a concise overview that clinicians can then use to choose a system that addresses the problems of the abutment implant interface., Observations: Manufacturing methods will result in surface variations across the surface of the abutment and implant. Microgaps change in dimension upon function due to wear. Bacterial leakage can lead secondary to functional wear, and the microgap will get larger. The increase in the microgap with function has been clinically verified. Micromotion will result in larger areas of surface gap in both flat and conical connections, with gaps larger than the size of bacteria., Conclusions and Relevance: For an ideal abutment, an implant system must have high tolerances for manufacturing with minimal gap formation along the abutment to implant surface; a connection that is resistant to micromotion; screws that have minimal deformation during loading; and a microgap less than 1 micron which is maintained during implant function., (Copyright © 2022 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Most gene-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are nonreplicating vectors. They deliver the gene or messenger RNA to the cell to express the spike protein but do not replicate to amplify antigen production. This study tested the utility of replication in a vaccine by comparing replication-defective adenovirus (RD-Ad) and replicating single-cycle adenovirus (SC-Ad) vaccines that express the SARS-CoV-2 spike protein. SC-Ad produced 100 times more spike protein than RD-Ad and generated significantly higher antibodies against the spike protein than RD-Ad after single immunization of Ad-permissive hamsters. SC-Ad-generated antibodies climbed over 14 weeks after single immunization and persisted for more than 10 months. When the hamsters were challenged 10.5 months after single immunization, a single intranasal or intramuscular immunization with SC-Ad-Spike reduced SARS-CoV-2 viral loads and damage in the lungs and preserved body weight better than vaccination with RD-Ad-Spike. This demonstrates the utility of harnessing replication in vaccines to amplify protection against infectious diseases.

Purpose: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics., Methods: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions., Results: A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively., Conclusion: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R Olofsson Bagge: Advisory boards for Amgen, Bristol-Myers Squibb, Merck Sharp & Dhome, Novartis, Roche, and Sanofi Genzyme. Speaker honorarium from Roche and Pfizer. Institutional research grant from Astra Zeneca and SkylineDx. L Ny: Consultant/advisory role for Bristol-Myers Squibb, Merck Sharp & Dhome, Novartis, Pierre Fabre, Sanofi Genzyme and Zealth. Speaker honorarium from Bristol-Myers Squibb, Leo Pharma, Merck Sharp & Dhome, Novartis, and Pfizer. Institutional research support from Merck Sharp & Dhome and Syndax Pharmaceuticals. T Hieken: Institutional research funding from Genentech and SkylineDx. M Block: Advisory Boards TILT Biotherapeutics, Viewpoint Molecular Targeting and Sorrento Therapeutics. Grant/Research support from: Genentech, Marker Therapeutics, Immune Design, Pharmacyclics, Merck, Bristol-Myers Squibb, Transgene, Viewpoint Molecular Targeting and Sorrento Therapeutics. F Dimitriou: Honoraria and travel support from Merck Sharp & Dohme and Sun Pharma. AM Menzies: Advisory boards for Bristol-Myers Squibb, Merck Sharp & Dhome, Novartis, Roche, Pierre-Fabre and Qbiotics. RPM Saw: Honoraria for advisory board participation from Merck Sharp & Dhome, Novartis and Qbiotics, and speaking honoraria from Bristol-Myers Squibb and Novartis. A Rogiers: Speaker fee from Merck Sharpe and Dohme. G Karakousis: Investigator intitated research trial institutional support from Merck. L Pallan: Speakers fees and travel support from Bristol-Myers Squibb. Conference attendance support from Eli-Lilly. JT Vetto: Speakers fee from CastleBiosciences. D Gyorki: Advisory board Amgen, Provectus and Bayer. Speaker fees Bristol-Myers Squibb and Merck Sharp & Dhome. PA Ascierto: Consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen and iTeos. Research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer and Sanofi. R Dummer: intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA and touchIME outside the submitted work. J Schachter: Advisory board Merck Sharp & Dhome. Speaker honoraria Bristol-Myers Squibb, Merck Sharp & Dhome, Novartis and Medison. N Asher: Advisory boards for Medison, Bristol-Myers Squibb, Merck Sharp & Dhome, Novartis, Roche, and Sanofi. Speaker honoraria from Medison, Bristol-Myers Squibb, Merck Sharp & Dhome, Novartis, and Sanofi. Institutional research grants from Medison and Novartis. H Helgadottir: Advisory boards for Merck Sharp & Dhome and Novartis. Speaker honorarium from Bristol-Myers Squibb. MS Carlino: Advisory board member for Amgen, Bristol-Myers Squibb, Eisai, Ideaya, Merck Sharp & Dhome, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck and Sanofi, and honoraria from Bristol-Myers Squibb, Merck Sharp & Dhome, and Novartis. J Weber: Consult for Merck, Genentech, Astra Zeneca, GlaxoSmithKline, Novartis, Nektar, Celldex, Incyte, Biond, ImCheck, Sellas, Evaxion and EMD Serono. Advisory board member Bristol-Myers Squibb. Equity in Biond, Evaxion, Instil Bio and Neximmune. Scientific advisory boards for CytoMx, Incyte, ImCheck, Biond, Sellas, Instil Bio OncoC4 and Neximmune. Institutional research support from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Moderna, Pfizer, Novartis and Astra Zeneca. Named on patents from Moffitt Cancer Center and Biodesix. D Ollila: Advisory boards and/or Consulting for Philogen, Merck, Novartis and Castle Biosciences. Medical Advisory Bopard - Delcath Systems. Speaker honorarium from Sun Pharma and Pfizer. Institutional research funding from Neracare, Castle Biosciences, Delcath Systems, Philogen and Provectus, GV Long: Consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Evaxion Biotech A/S, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V. and Specialised Therapeutics Australia Pty Ltd. J Zager: Advisory boards and/or Consulting for Philogen, Merck, Novartis and Castle Biosciences. Medical Advisory Board Delcath Systems. Speaker honorarium from Sun Pharma and Pfizer. Institutional research funding from Neracare, Castle Biosciences, Delcath Systems, Philogen and Provectus. A van Akkooi: Advisory Board and Consultancy Honoraria from Amgen, Bristol-Myers Squibb, Novartis, Merck Sharp & Dhome, Merck, Pfizer, Pierre Fabre, Sanofi, Sirius Medical and 4SC. Research grants from Amgen, Merck and Pfizer. All unrelated to current work and paid to institute. The funding bodies had no part in the design of the study, the collection of data, in the analysis of data or in writing the manuscript., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Exciting advances in melanoma systemic therapies have presented the opportunity for surgical oncologists and their multidisciplinary colleagues to test the neoadjuvant systemic treatment approach in high-risk, resectable metastatic melanomas. Here we describe the state of the science of neoadjuvant systemic therapy (NAST) for melanoma, focusing on the surgical aspects and the key role of the surgical oncologist in this treatment paradigm. This paper summarizes the past decade of developments in melanoma treatment and the current evidence for NAST in stage III melanoma specifically. Issues of surgical relevance are discussed, including the risk of progression on NAST prior to surgery. Technical aspects, such as the definition of resectability for melanoma and the extent and scope of routine surgery are presented. Other important issues, such as the utility of radiographic response evaluation and method of pathologic response evaluation, are addressed. Surgical complications and perioperative management of NAST related adverse events are considered. The International Neoadjuvant Melanoma Consortium has the goal of harmonizing NAST trials in melanoma to facilitate rapid advances with new approaches, and facilitating the comparison of results across trials evaluating different treatment regimens. Our ultimate goals are to provide definitive proof of the safety and efficacy of NAST in melanoma, sufficient for NAST to become an acceptable standard of care, and to leverage this platform to allow more personalized, biomarker-driven, tailored approaches to subsequent treatment and surveillance., (© 2022. Society of Surgical Oncology.)

Purpose: After tooth extraction in the posterior maxilla, bone resorption often limits implant placement unless additional grafting procedures are performed. However, it is difficult to predict the amount of bone that will remain after extraction based on current evidence. The purpose of this study was to develop a method for predicting the postextraction alveolar bone height in the posterior maxilla., Patients and Methods: The authors conducted a retrospective cohort study that included all patients who were treated for the extraction and replacement of a maxillary first molar with a dental implant from 2008 to 2019. Potential predictor variables included thirteen pre-extraction radiographic measurements obtained via cone-beam computed tomography. The outcome variable was having more than 6 mm of bone height from the alveolar crest to the sinus floor after extraction. Decision tree analyses were used to search for the best predictors of this outcome using random forest analysis with a maximum of 3 randomly chosen covariates in each candidate tree., Results: A total of 63 patients were included in the study; 55.6% were women, and the mean age was 57.6 ± 14.5 years. In this study population, having a bone height from the furcation to the maxillary sinus floor of <6.7 mm had a 7.1% chance of having >6 mm of bone height postoperatively, whereas those patients with ≥6.7 mm at the same position preoperatively had a 61.9% chance of having >6 mm of bone height postoperatively (P < .001)., Conclusions: This study suggests that patients with <6.7 mm of bone from the furcation to the sinus are at increased risk of having insufficient bone to support a dental implant without additional grafting at the maxillary first molar position. When treating these patients, the surgeon should consider performing a procedure at the time of extraction to increase bone height or explain additional bone grafting is expected for ideal implant placement., (Copyright © 2021. Published by Elsevier Inc.)

Background: Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling., Patients and Methods: In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored., Results: Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009)., Conclusions: Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation., Competing Interests: Competing interests: SL has received honoraria from AstraZeneca, Merck, Eisai, GSK, and Roche. PAK has participated in Advisory Boards/Scientific Advisory Committees for Alkermes, AstraZeneca, Bayer, GSK, Merck, Pfizer, Tesaro, Vertex, and Repare; and has received institutional funding as Principal Investigator from AstraZeneca, Bayer, Eli Lilly, GSK, Merck, Merck KGaA, Pfizer, and Tesaro/GSK. BXW has no conflicts of interest related to this manuscript; financial disclosures that are not related: he has received honoraria from Tessa Therapeutics and AstraZeneca. MSB has no conflicts of interest related to this manuscript; financial disclosures that are not related: he has received institutional research support from Merck, Transgene, Pharmacyclics, Immune Design, Bristol Myers Squibb, Marker Therapeutics, Sorrento, Viewpoint Molecular Targeting, and Genentech; and is an Advisory Board member (unpaid) for TILT Biotherapeutics, Viewpoint Molecular Targeting, and Sorrento. SLG has received personal fees from AstraZeneca, Immunogen, Sermonix, Elvar Therapeutics, and GSK; and has received grants from AstraZeneca, AbbVie, Pfizer, Rigel, Iovance, Tesaro, Genentech/Roche, PharmaMar, and GSK; and has patents for Sermonix (US patent no. 10,905,659 and 10,258.604). FJB has participated in Advisory Boards for Merck, Eisai, and Agenus; and has received research funding from Eisai, Clovis, ImmunoGen, Merck, and Beigene (all outside the submitted work). TLW has no significant conflicts of interest related to this manuscript; financial disclosures that are not related: she has received research support to the institution for clinical trials from AbbVie, AstraZeneca, Clovis Oncology, Mersana, Mirati, Novartis, Roche Genentech, and Tesaro-GSK. LD has received personal fees from AstraZeneca, Genentech/Roche, MorphoTek, Merck, Inovio, Advance Medical, UpToDate, Cue Biopharma, British Journal of Obstetrics and Gynaecology, Parexel, State of California, Elsevier, ASCO, Expert review, ClearView Heath Care, National Cancer Institute, and JB Learning; and has received grants from Genentech/Roche, Cerulean/NextGen, AbbVie, Tesaro, Pfizer, GSK/Novartis, Morab, MorphoTek, Merck, Aduro BioTech, Syndax, Ludwig, LEAP Therapeutics, Eisai, Lycera, Inovio, and Advaxis; she reports other disclosures from Merck, GSK/Novartis and Genentech/Roche. IC has received travel grants from Tesaro; and is an advisor for AstraZeneca and GSK. PSO has no conflicts of interest related to this manuscript; financial disclosures that are not related to the current work: EMD Serono, Symphogen, Providence, and Tessa Therapeutics. GFF participates in an Advisory Board for GSK; has received honoraria from UpToDate; has received reviewer compensation from Journal of Clinical Oncology and Lancet Oncology; and has received payments to institution for clinical trial conduct from Roche, Syros, GSK, Iovance, Sermonix, Comugen, Cellex, Corcept, and Plexxikon. No disclosures were reported by the other authors., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)