Citations

373 Background: Recent studies have demonstrated encouraging outcomes with neoadjuvant ICIs in pts with localized deficient mismatch repair (dMMR) and/or microsatellite instability-high (MSI-H) GEC, prompting discussions around the feasibility of nonoperative management (NOM). However, current evidence is largely from phase 1 and 2 clinical trials with limited sample sizes. Thus, the efficacy and safety of neoadjuvant ICI in this pt population remain subject to ongoing debate. Methods: We conducted a systematic review and meta-analysis of prospective and retrospective studies evaluating neoadjuvant ICIs in pts with localized dMMR/MSI-H GEC according to the PRISMA guidelines. The primary outcomes were pathological complete response (pCR) and complete clinical response (cCR) rates. cCR was defined as no evidence of residual disease on tumor-specific imaging and on endoscopy with biopsy. Secondary outcomes included major pathologic response (MPR) rates and the incidence of grade 3–4 immune-related adverse events (irAEs). Proportions with 95% confidence intervals (CI) were used to pool event rates for occurrence of cCR, pCR, MPR and grade 3-4 irAEs. The DerSimonian and Laird random-effects model was used. NOM was assessed as part of the qualitative analysis. Results: 20 studies comprising 396 pts treated with neoadjuvant ICIs were included. Three studies utilized double ICI blockade (PD-1/ PD-L1 inhibitor plus CTLA-4 inhibitor), while the remaining studies primarily utilized monotherapy with a PD-1 inhibitor, with or without chemotherapy. Overall, 320 (81.0%) underwent surgical resection. The pooled pCR rate was 41.6% (95% CI, 33.1%–50.8%), cCR 63.8% (95% CI, 45.6%–78.8%), and MPR 64.2% (95% CI, 49.1%–76.9%). The pooled incidence of grade 3–4 irAEs was 5.1% (95% CI, 0.6%–12.2%). Subgroup analysis showed higher pCR with ≥3 months versus <3 months of ICI (50.2% [95% CI 42.2–58.3] vs 28.4% [18.9–40.2]; χ²=8.69, p=0.003). Forty-four pts were managed with NOM, two experienced early local regrowth over median follow-up ranging from 11.5 to 28 months. Conclusions: Neoadjuvant ICI therapy appears to be a safe and effective therapeutic strategy for pts with localized dMMR/MSI-H GEC. Neoadjuvant ICI exposure for ≥3 months seems to yield higher pCR rates than <3 months. The high and prolonged cCR rates support the nonoperative strategy in selected patients with dMMR/MSI-H GEC.

Abstract Purpose: Polatuzumab vedotin (polatuzumab) was approved for up-front treatment of diffuse large B-cell lymphoma in combination with chemoimmunotherapy (Pola-R-CHP) based on the POLARIX trial. However, when stratified by cell of origin (COO), polatuzumab seems to have greater efficacy in activated B-cell than germinal center B-cell (GCB) subtype disease. Most studies of polatuzumab used RNA expression to assess COO, whereas in routine clinical practice, the immunohistochemistry-based Hans algorithm is used. Experimental Design: To assess the impact of COO by immunohistochemistry on polatuzumab efficacy, we conducted a multicenter real-world study of adults with large B-cell lymphoma (LBCL) receiving polatuzumab from 2015 to 2024, split by receipt of polatuzumab in first-line versus relapsed/refractory settings. The primary endpoint was overall response rate (ORR) to polatuzumab-based treatment in GCB versus non-GCB relapsed/refractory LBCL. Results: Of 740 patients, 305 received polatuzumab in the first-line setting and 435 in the relapsed/refractory setting. In the relapsed/refractory cohort, the ORR in non-GCB versus GCB LBCL was 59.7% versus 36.3% [OR, 2.6; 95% confidence interval (CI), 1.77–3.84; P &lt; 0.0001], with a complete response rate of 35.7% versus 17.7% (OR, 2.6; 95% CI, 1.66–4.02; P &lt; 0.0001). Progression-free survival was longer for patients with non-GCB versus GCB COO (HR, 0.64; 95% CI, 0.5–0.83; P = 0.0006). In the first-line cohort, ORR, complete response rate, and progression-free survival were similar in non-GCB versus GCB LBCL, as hypothesized based on outcomes in the Pola-R-CHP arm of POLARIX, suggesting that the addition of polatuzumab overcomes the adverse risk of non-GCB COO in patients receiving R-CHOP. Conclusions: Based on these data, COO classification by the Hans algorithm is a strong predictor of polatuzumab efficacy in LBCL, informing real-world treatment decisions.

Background: Polatuzumab vedotin (Pola) is an antibody drug conjugate targeting CD79b that incorporates the microtubule disrupting monomethyl auristatin E payload. Pola was approved in 2023 for the upfront treatment of diffuse large B cell lymphoma (DLBCL) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (polaRCHP) based on the POLARIX trial. However, the activity of pola appears to vary based on DLBCL cell of origin (COO) subtype, with greater efficacy in activated B cell (ABC) DLBCL compared to germinal center B cell (GCB) DLBCL (Russler-Germain Blood 2023). When outcomes in POLARIX are stratified by COO, polaRCHP demonstrated progression free survival (PFS) and overall survival (OS) benefits over RCHOP in patients with ABC but not GCB subtype DLBCL (PFS HR 0.34 ABC vs 1.03 GCB, OS HR 0.27 ABC vs 1.64 GCB; Morschhauser ASH 2023 and FDA data). Most prospective studies of pola used gene expression to assess COO, which is not readily clinically available. This study aims to examine if COO subtype by Hans algorithm (based on CD10, BCL6, and MUM1 expression by immunohistochemistry) is predictive of pola responses and outcomes in patients with large B cell lymphoma (LBCL). Methods: We conducted a retrospective, multicenter observational study of adults with LBCL who received pola (monotherapy or in combination) from 2015-2024 with Hans algorithm COO data and response assessment available. Patients were stratified by receipt of pola in the frontline vs relapsed/refractory (R/R) setting. The primary endpoint was overall response rate (ORR) to pola-based treatment in GCB vs non-GCB subtypes. Secondary endpoints included complete response rate (CRR), PFS, and OS. For time to event endpoints, patients responding to pola who received CAR T or stem cell transplantation prior to progression were censored at time of cellular therapy. Demographics were summarized by descriptive statistics. Comparative and survival analyses used Chi squared/Fischer exact tests and Kaplan Meier analysis. Data cutoff was July 1, 2024. Results: 718 patients were included. Median follow-up was 15 months (interquartile range [IQR] 8-32). Median age at LBCL diagnosis was 66 years (IQR 56-74); 62% were men; 69 (10%) had double hit lymphoma (DHL); 129 (18%) had underlying low grade lymphoma. Pola was used in the frontline setting in 293 (41%) patients, of whom 139 (47%) had GCB vs 154 (53%) non-GCB COO. Of the 426 patients receiving pola for R/R LBCL (including one patient receiving pola retreatment), 224 (53%) had GCB vs 202 (47%) non-GCB COO. Among patients receiving pola-based regimens in the R/R setting (GCB vs non-GCB: pola monotherapy = 7% vs 4%, pola + R = 26% vs 26%, pola + BR = 55% vs 61%, pola + other = 12% vs 9%; p = 0.44), the ORR in GCB vs non-GCB LBCL was 36% vs 61% (p &lt; 0.001), while CRR in GCB vs non-GCB was 17% vs 36% (p &lt; 0.001). COO remained a significant component of logistic multivariate regression models of ORR (p &lt; 0.001) and CRR (p &lt; 0.001) when incorporating IPI at original LBCL diagnosis, histology, DHL status, and refractory status to frontline therapy. Despite this, no significant PFS or OS differences by COO were seen, potentially due to approximately 1/4 patients being censored due to receiving subsequent cellular therapy (e.g. CAR T) prior to progression. In patients receiving frontline pola-based regimens (of which 275 [94%] included an anthracycline), ORR and CRR were similar in GCB vs non-GCB (ORR 89% vs 88% p &gt; 0.5; CRR 76% vs 77% p &gt; 0.5). While PFS and OS were similar between COO groups in the frontline cohort, follow-up and cohort size were limited. Conclusion: Based on this real-world evidence, COO classification by Hans algorithm is a strong predictor of the activity of pola-containing therapy in R/R LBCL, with significantly higher ORR and CRR in patients with non-GCB compared to GCB COO LBCL. This aligns with the cumulative existing evidence. ORR and CRR to pola-containing therapy in the frontline setting did not differ significantly by COO subtype, but longer follow-up of larger cohorts is needed to clarify the predictive role of COO by Hans algorithm in this setting, especially considering the PFS advantage with polaRCHP in POLARIX was not associated with significant differences in ORR or CRR. Overall, clinicians should consider factoring COO subtype into treatment decisions regarding pola-containing regimens, and studies of pola-based therapies should stratify patients and report outcomes by COO subtype.

Background: Follicular dendritic cell sarcoma (FDCS) is a rare low- to intermediate-grade sarcoma, typically presenting as a slowly growing, painless mass composed of spindle-shaped cells in a whorled pattern. First described in 1986, FDCS has since been identified in several hundred cases. FDCS originates from mesenchymal dendritic cells and is distinct from other histiocytic neoplasms. Its management aligns more with soft tissue sarcomas. Epidemiologically, FDCS is exceedingly rare, constituting less than 0.4% of soft tissue sarcomas. Methods: With IRB approval, we identified patients with biopsy-proven FDCS treated at Mayo Clinic. Chart review extracted clinical characteristics, laboratory testing, treatment data, and clinical outcomes, compiled into Excel. Data analysis was performed through RStudios. Descriptive statistics of patient characteristics, such as gender and stage of disease, were summarized in tables. We compared overall survival (OS) through Kaplan Meier curves, stratifying patients into cohorts based on topics of interest, such as differences in survival in nodal vs. extranodal disease or differences in survival among different chemotherapy regimens. Results: Forty patients met the inclusion criteria, of biopsy proved FCDS. Median age at diagnosis was 57.7 years (SD 14). Men comprised 45% of patients. Locations of malignancy were abdomen and pelvis (32.5%), thoracic and pulmonary regions (32.5%), lymph nodes and neck (20.0%), musculoskeletal (2.5%), and other locations (12.5%). Primary therapies included surgical resection (42.5%), systemic chemotherapy (32.5%), no treatment (10.0%), radiation (2.5%), with data missing for 12.5% of cases. Concurrent or preceding Castleman's Disease was seen in 7.5% (3/40) of patients; one case preceded FCDS, and two were concurrent. Of these patients with Castleman's Disease, one was resected and the other two were not. Two cases were unicentric, and one was multicentric. First-line systemic chemotherapy was most often gemcitabine and docetaxel, with 9/40 patients receiving this regimen. Ifosfamide and doxorubicin were utilized in 3/40 patients. 2/4 patients had received doxorubicin alone. 2/4 patients had received CHOP. The response rate for patients with gemcitabine and docetaxel was complete response for 2/9 (22%) patients, partial response for 2/9 (22%), stable disease for 2/9 (22%), progressive disease for 1/9 (11%), and missing for 2/9 (22%), giving an overall response rate of 67%. For ifosfamide and doxorubicin, one patient had partial response (33%), another had stable disease (33%), and the last patient's data was missing (33%), adding up to a 66% overall response rate. For CHOP, one patient had progressive disease, and the other had partial response. For doxorubicin, both patients had stable disease. At a median follow-up of 29.5 months (IQR 9.2-75.2 months), the median OS was 160.68 months for the group with both nodal and extranodal disease versus 39.95 months for the extranodal disease-only group. The median OS of the nodal disease alone was not reached, with an estimated 2-year OS of 75%. To evaluate the impact of various primary therapies on outcomes in patients with advanced disease, we conducted a survival analysis by therapy used (no treatment, radiation, surgical resection, and systemic chemotherapy). Patients receiving no treatment had a median survival time of 28.9 months, while those treated with radiation had a median survival time of 19.3 months. Patients undergoing surgical resection had an undetermined median survival time, but notably, 80% were alive at the end of the time period analyzed in this study with a median follow-up time of 60.7 months. Those receiving systemic chemotherapy had a median survival time of 30.7 months. Conclusions: This project is one of the largest known single-center studies dedicated to FDCS. We show that the incidence of preceding or concurrent Castleman's Disease is relatively low. Gemcitabine and docetaxel was the most utilized chemotherapy regimen, but there weren't enough data to conclude if this regimen had a better response rate compared to others. Surgical resection of advanced disease is associated with superior outcomes. When systemic therapy is needed, the median survival was lower.

Summary: This article reviews the state of the art for arthroplasty of the metacarpophalangeal and proximal interphalangeal joints. Arthritis that affects these joints can result in significant pain and compromised function. The authors review indications for arthroplasty for each joint, types of implants to consider, technical considerations, patient expectations, and outcomes and complications.

OBJECTIVEThe use of nerve transfers versus nerve grafting for neonatal brachial plexus palsy (NBPP) remains controversial. In adult brachial plexus injury, transfer of an ulnar fascicle to the biceps branch of the musculocutaneous nerve (Oberlin transfer) is reportedly superior to nerve grafting for restoration of elbow flexion. In pediatric patients with NBPP, recovery of elbow flexion and forearm supination is an indicator of resolved NBPP. Currently, limited evidence exists of outcomes for flexion and supination when comparing nerve transfer and nerve grafting for NBPP. Therefore, the authors compared 1-year postoperative outcomes for infants with NBPP who underwent Oberlin transfer versus nerve grafting.METHODSThis retrospective cohort study reviewed patients with NBPP who underwent Oberlin transfer (n = 19) and nerve grafting (n = 31) at a single institution between 2005 and 2015. A single surgeon conducted intraoperative exploration of the brachial plexus and determined the surgical nerve reconstruction strategy undertaken. Active range of motion was evaluated preoperatively and postoperatively at 1 year.RESULTSNo significant difference between treatment groups was observed with respect to the mean change (pre- to postoperatively) in elbow flexion in adduction and abduction and biceps strength. The Oberlin transfer group gained significantly more supination (100° vs 19°; p < 0.0001). Forearm pronation was maintained at 90° in the Oberlin transfer group whereas it was slightly improved in the grafting group (0° vs 32°; p = 0.02). Shoulder, wrist, and hand functions were comparable between treatment groups.CONCLUSIONSThe preliminary data from this study demonstrate that the Oberlin transfer confers an advantageous early recovery of forearm supination over grafting, with equivalent elbow flexion recovery. Further studies that monitor real-world arm usage will provide more insight into the most appropriate surgical strategy for NBPP.