Citations

Case: A 20-year-old man sustained a comminuted bone-patellar tendon-bone donor-site fracture 17 days after a contralateral anterior cruciate ligament revision reconstruction. Successful fixation was achieved by using a tricortical iliac crest allograft bone plug with mesh plate osteosynthesis. At 6 months of follow-up, the patient had full range of motion without pain. Conclusion: Patellar fractures after bone-patellar tendon-bone harvest may be treated successfully with mesh plate osteosynthesis and a tricortical iliac crest allograft bone plug. This unique fixation option addresses bone loss and restores the extensor mechanism while avoiding autograft donor site morbidity.

269 Background: Metastatic visceral involvement in prostate cancer patients conveys a poor prognosis. Survival patterns of site-specific visceral metastasis are poorly understood. Here, we sought to investigate survival patterns in prostate cancer patients according to their first detected site of visceral metastasis. Methods: Retrospectively, we identified 200 patients with visceral metastatic prostate cancer. Patients were divided into three groups according to first site detected with visceral metastases; first-site lung metastases, first-site brain metastases, and first-site liver metastases. Visceral metastases were detected on either conventional imaging (CT/MRI), metabolic imaging (C-11 choline), or PSMA PET-CT scan. Follow up duration of our study was 80 months. Results: Clinicopathological variables are shown. The K-M curve of overall survival of the entire cohort suggests better survival patterns in patients with first-site lung metastases compared to patients with first-site brain or liver metastases (p<0.0001). In subset analysis of patients with CRPC, the K-M curve of overall survival, which demonstrates better survival outcomes in patients with first-site lung metastases in comparison with patients with first-site brain or liver metastases (p<0.0001). Conclusions: Our data suggests that prostate cancer patients with visceral metastatic disease have different survival patterns according to the first site detected with visceral metastasis. In our cohort, patients with first-site lung metastasis demonstrated better survival outcomes than patients with first-site brain or liver metastasis. Further studies are warranted. [Table: see text]

Importance Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) shows frequent and durable responses to programmed cell death 1 blockade. While most of these tumors are sporadic and observed in older patients, first-line pembrolizumab data are limited to findings from the KEYNOTE-177 trial (A Phase III Study of Pembrolizumab [MK-3475] vs Chemotherapy in Microsatellite Instability-High [MSI-H] or Mismatch Repair Deficient [dMMR] Stage IV Colorectal Carcinoma). Objective To investigate outcome with first-line pembrolizumab monotherapy in mostly older patients with dMMR mCRC at a multisite clinical practice. Design, Setting, and Participants This cohort study included consecutive patients with dMMR mCRC who received pembrolizumab monotherapy between April 1, 2015, and January 1, 2022, at Mayo Clinic sites and the Mayo Clinic Health System. Patients were identified from review of electronic health records at the sites, which included the evaluation of digitized radiologic imaging studies. Intervention Patients with dMMR mCRC received first-line pembrolizumab, 200 mg, every 3 weeks. Main Outcomes and Measures The primary study end point was progression-free survival (PFS), which was analyzed using the Kaplan-Meier method and a multivariable stepwise Cox proportional hazards regression model. Clinicopathological features, including metastatic site and molecular data ( BRAF V600E and KRAS ), were also analyzed along with tumor response rate, which was determined using Response Evaluation Criteria in Solid Tumors, version 1.1. Results The study cohort included 41 patients (median [IQR] age at treatment initiation, 81 [76-86] years; 29 females [71%]) with dMMR mCRC. Of these patients, 30 (79%) had the BRAF V600E variant and 32 (80%) were classified as having sporadic tumors. Median (range) follow-up was 23 (3-89) months. Median (IQR) number of treatment cycles was 9 (4-20). Overall response rate was 49% (20 of 41 patients), including 13 patients (32%) with complete responses and 7 (17%) with partial responses. Median (IQR) PFS was 21 (95% CI, 6-39) months. Liver as a site of metastasis was associated with significantly poorer PFS vs nonliver metastasis (adjusted hazard ratio, 3.40; 95% CI, 1.27-9.13; adjusted P = .01). Complete and partial responses were observed in 3 patients (21%) with liver metastasis vs 17 patients (63%) with nonliver metastases. Treatment-related grade 3 or 4 adverse events were observed in 8 patients (20%), 2 of whom discontinued therapy; there was 1 treatment-related death. Conclusions and Relevance This cohort study found a clinically significant prolongation of survival in older patients with dMMR mCRC who were treated with first-line pembrolizumab in routine clinical practice. Furthermore, liver vs nonliver metastasis was associated with poorer survival in this patient population, which suggests that the metastatic site has implications for survival outcome.

57 Background: Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) show frequent and durable responses to programmed cell death -1 (PD-1) blockade. While the majority of these tumors are sporadics and observed in elderly patients, first-line data are limited to the KEYNOTE-177 study. Here, we report a consecutive series of elderly patients with dMMR mCRC treated with pembrolizumab in routine clinical practice that includes analysis of clinical outcome based on metastatic site. Methods: Patients with dMMR mCRC received first-line pembrolizumab (200 mg every 3 weeks) (N = 41) at Mayo Clinic and Mayo Clinic Health System (2015-2022). Clinicopathological features including metastatic site and molecular data ( BRAFV600E, KRAS) were analyzed in relationship to tumor response rate (RECIST version 1.1). Furthermore, these variables were also analyzed in relationship to patient progression-free survival (PFS) using Kaplan-Meier methodology and multivariable stepwise Cox regression. Results: Among patients with dMMR mCRC, 29/41 (70.7%) were female, 30 (78.9%) harbored BRAFV600E, and 32 (80%) were sporadic. Median age at start of treatment was 80.6 years (IQR of 75.9, 85.9) and median number of treatment cycles was 9 (IQR: 4, 20). At a median follow-up of 23 months (range, 3.0 to 88.5), patient median PFS was 21.3 months (95% CI: 6.4, 38.5). An overall response was observed in 48.8% (20 of 41) of patients including 13 (31.7%) complete (CR) and 7 (17.1%) partial responses (PR). The median duration of response was 42.2 months (95%CI: 8.6, NR). Patients with metastases that included liver had significantly poorer PFS compared to those with non-liver metastases (HRadj 3.40 (95%CI: 1.27-9.13); Padj= 0. 01). In this regard, responses (CR, PR) to pembrolizumab were observed in 3 (21.4%) patients with liver metastasis compared to 17 (62.9%) of those with non-liver metastases. Treatment-related grade 3 or 4 adverse events were observed in 9 (22.0%) patients of whom two discontinued therapy, and there was one treatment-related death. Conclusions: First-line therapy with pembrolizumab for dMMR mCRC significantly prolonged survival in an elderly patient population with manageable toxicity in routine clinical practice. Moreover, the survival benefit of pembrolizumab was significantly attenuated in patients with liver vs non-liver metastases.

Clinical trial participants do not reflect the racial and ethnic diversity of people with cancer. ASCO and the Association of Community Cancer Centers collaborated on a quality improvement study to enhance racial and ethnic equity, diversity, and inclusion (EDI) in cancer clinical trials. The groups conducted a pilot study to examine the feasibility, utility, and face validity of a two-part clinical trial site self-assessment to enable diverse types of research sites in the United States to (1) review internal data to assess racial and ethnic disparities in screening and enrollment and (2) review their policies, programs, procedures to identify opportunities and strategies to improve EDI. Overall, 81% of 62 participating sites were satisfied with the assessment; 82% identified opportunities for improvement; and 63% identified specific strategies and 74% thought the assessment had potential to help their site increase EDI. The assessment increased awareness about performance (82%) and helped identify specific strategies (63%) to increase EDI in trials. Although most sites (65%) were able to provide some data on the number of patients that consented, only two sites were able to provide all requested trial screening, offering, and enrollment data by race and ethnicity. Documenting and evaluating such data are critical steps toward improving EDI and are key to identifying and addressing disparities more broadly. ASCO and Association of Community Cancer Centers will partner with sites to better understand their processes and the feasibility of collecting screening, offering, and enrollment data in systematic and automated ways.

Abstract Structural changes on the surface of the class I Ag binding domain resulting from point mutations localized inside the Ag binding cleft of the H-2Kb and Kf glycoproteins were revealed using mAb. Both the loss and gain of antibody binding sites found among naturally occurring K glycoproteins resulted from single amino acid substitutions at a variety of different positions buried within the Ag binding groove. Each of the amino acid replacements analyzed represented naturally occurring diversity known to exist among the functional class I Ag-presenting molecules of the mouse. The binding of the affected mAb was not significantly altered in Kb molecules expressed by transfected T2 cells. Because T2 cells have been shown to express Kb molecules that are either largely devoid of bound peptides or bind a vastly different set of low affinity peptides, it is unlikely that the detected structural changes were caused by alterations in the spectrum of peptides bound by the class I variant glycoproteins. Similarly, a class I point mutant, Kb-97R, that also has been shown previously to bind a very different set of peptides in comparison to the parental Kb molecule also displays normal antibody binding properties. We conclude from these studies that structural diversity within the Ag binding cleft indirectly influences the external surface of the Ag-presenting domain of the class I H chain. Significantly, this surface is the interface between the T cell receptor and MHC molecules and may make contributions to the fine specificity of allorecognition.

Abstract Optimum function of HLA-DR molecules in transgenic mice requires efficient interaction between the class II molecules on APCs and CD4 on T cells. Residues 110 and 139 of the second domain of class II molecules are considered to be critical for recognition of CD4. We generated an HLA-DR4β(NT) transgene construct in which positions 110 and 139 were altered to resemble endogenous mouse H2 Aβ molecules. This construct was introduced into (B10 × SWR) embryos, and DR4β(NT) transgenic mice were produced. The transgene was transferred into B10.RFB3 (Eβ0 Eαp) mice. The transgene-encoded DR4β molecules paired with endogenous Eα chains to form stable DR4β/Eα dimers expressed on the cell surface. The hybrid dimers showed similar Ag-binding specificity to HLA-DR4 molecules and positively selected CD4+ T cells in vivo. Immunization of HLA-DR4β(NT) transgenic mice with DR4-restricted peptides induced T cell proliferation in vitro. While the purified T cells from DR4β(NT) transgenic mice responded strongly to the HA(307–319) presented by M12C3 transfectants expressing altered DR4β/Eα heterodimers, the response to the same peptides presented by transfectants expressing wild-type DR4β/Eα molecules was substantially reduced. Taken together, these data confirmed in vitro studies on the importance of these residues in CD4-MHC class II interaction. The altered HLA-DR4β transgenic mice were able to overcome the species barrier and generate efficient HLA-DR4-restricted CD4-specific immune responses. Thus, residues 110 and 139 were critical for the interaction of class II with CD4 T cells during thymic selection as well as peripheral immune responses.

Abstract The ability of OVA-specific H-2Kb-restricted CTL to recognize the defined OVA258-276 peptide in the context of the Kbm mutants and variants of these mutants was examined to determine how specific variations in the Ag recognition site-influenced peptide presentation to these CTL. L cells expressing Kb or Kbm10 were equally capable of presenting the OVA peptide to Kb-restricted, OVA-specific bulk CTL, whereas L cell clones expressing Kbm8 or Kbm1 showed little to no capacity to present this peptide. L cell transfectants expressing Kbm3 and Kbm23 consistently demonstrated an intermediate to low level of presentation to bulk OVA-specific CTL. Dissection of the Kbm8 mutant revealed that cells expressing Kbm8-22 (Tyr----Phe) and/or Kbm8-24 (Glu----Ser) presented the OVA peptide significantly less well than the Kb-presenting molecule. Presentation of OVA by cells expressing Kbm8-23,30 (Met----Ile) (Asp----Asn), Kbm8-23 (Met----Ile), and Kbm8-30 (Asp----Asn) was equivalent to Kb presentation. Another mutation designated as Kbm5, that has a substitution at position 116 (Tyr----Phe), demonstrated an intermediate to high ability to present OVA258-276 to an OVA-specific CTL line. The Kbm3, Kbm11, and Kbm23 mutants were unable to present the OVA peptide to this same CTL line. Dissection of these mutants showed that the substitution at position 77 (Asp----Ser), which is shared by all three mutants, was responsible for their inability to present the peptide. A second Kb-restricted CTL line was able to recognize OVA in the context of the Asp----Ser substitution at position 77. The results of this analysis suggest that the OVA258-276 peptide interacts with multiple regions within the Ag recognition site of the Kb class I protein.