Lee, Hee Eun

Abstract Immune effector cell–associated enterocolitis (IEC-EC) has been observed after ciltacabtagene autoleucel (cilta-cel [Carvykti]) chimeric antigen receptor T-cell (CAR-T) therapy. It is associated with dismal outcomes and is poorly characterized. Here, we examined its clinical features, risk factors, and proposed management strategies. Among the 229 consecutive patients who received cilta-cel at Mayo Clinic, 9 (3.9%) presented with a nonresolving, nonbloody, grade 3 diarrhea, often requiring prolonged total parenteral nutrition. Gastrointestinal coinfections were seen in most patients. Median time from CAR-T infusion to symptom onset was 85 days (range, 35-166), and there appeared to be a latency from symptom onset to endoscopic evaluation. Histopathology findings resembling a graft-versus-host disease pattern of mucosal injury were most seen on duodenal biopsies, whereas 2 cases had patterns akin to a T-cell lymphoproliferative disorder (1 CD4+ and 1 CD8+). Independent associated factors for IEC-EC included high-risk disease as defined by the International Myeloma Society and International Myeloma Working Group, prolonged cytokine release syndrome, and antecedent delayed neurotoxicity. Response to first-line therapy comprising IV or oral corticosteroids, bile acid sequestrants, IV immunoglobulin, and antimicrobial-directed therapy was poor, with no durable responses. Biologic therapy appeared to induce durable responses in 3 of the 5 patients (2/2 vedolizumab; 1/3 infliximab); none of the responders had gastrointestinal coinfection. Early gastroenterology input for endoscopic evaluation with the inclusion of duodenal biopsy is a key component for diagnosis. Early institution of biologic therapy after failure of a short course of corticosteroids should be considered.

INTRODUCTION: Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS: Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS: One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION: Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

Abstract Alopecia areata (AA) is the most frequent form of an organ-specific autoimmune disease in humans mediated by NKG2D+ CD8 T cells destroying hair follicles. C3H/HeJ mice naturally develop AA similar to humans, and we found it accompanies the expansion of exhausted phenotype (CD101+ Tim3+) memory CD8 T cells not only in the skin and skin-draining lymph nodes (SDLNs), but also in the liver and lungs. Before the disease induction, we found these CD8 T cells are activated in the lungs and liver, suggesting they are pre-activated in these organs. In the skin, expanded CD8 T cells additionally upregulated CD39, PD-1, and CTLA-4, which produced less IFNg than those in the SDLN, liver and lungs when stimulated. These features suggest that autoreactive CD8 T cells in the skin are exhausted by chronic antigenic stimulation. However, they did not upregulate TOX, a hallmark of T cell exhaustion. Intriguingly, CD44high NKG2D-expressing CD8 T cells appeared in the thymi of aged C3H/HeJ mice before disease induction. These cells express TBET and EOMES without overt expansion of PLZF-expressing T cells. Collectively these features suggest AA is mediated by autoreactive activation CD8 T cells that are not explained by previously known mechanisms. This research was supported by the National Research Foundation of Korea (NRF-2022R1A2C1007692)

3525 Background: Tumor-infiltrating lymphocytes (TILs) are significantly associated with clinical outcomes in patients with colon cancer. However, the potential for a differential effect of TILs on prognosis based on primary tumor sidedness has not been studied. We determined the interaction between TILs and tumor sidedness in relationship to disease-free survival (DFS). Methods: We analyzed data on TIL densities by primary tumor sidedness in 1532 stage III colon carcinomas from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy (NCCTG N0147). TIL densities were dichotomized as low or high (≤3 /HPF) based on an optimized cutoff previously identified for DFS in this cohort. Right-sided tumors were defined as proximal to the splenic flexure. Analysis of TILs and sidedness with DFS were examined using Kaplan-Meier methodology and multivariable Cox regression. Results: Overall, tumors with high vs low TILs had the best DFS [HRadj: 0.58 (95%CI: 0.45-0.74); Padj <0.0001]. The association of TIL densities with 5-yr DFS differed significantly by primary tumor sidedness ( Pinteraction (adj) = 0.045). Among right-sided tumors, high vs low TILs were significantly associated with improved DFS ( Padj <0.0001)[Table]. Among left-sided tumors, however, DFS did not differ significantly for high vs low TILs ( Padj =0.173)[Table]. Similar results for TILs and DFS by sidedness were found for pMMR cancers. We then analyzed our data in low risk (T1-3, N1) and high risk (T4 and/or N2) tumors. Among low risk tumors, high vs low TILs was significantly associated with improved 5-yr DFS only in right-sided tumors ( Padj =0.006) [Table]. Among high risk tumors, high vs low TILs were significantly associated with better DFS in both right-sided ( Padj<0.001) and left-sided ( Padj =0.024) tumors. Conclusions: Overall, tumors with high TIL densities had significantly better DFS in right-sided but not left-sided cancers. Among low risk patients, the association of high TILs with better DFS was limited to right-sided tumors. These findings suggest that TILs should be interpreted by sidedness for prognostication. ClinicalTrials.gov Identifier: NCT00079274 . [Table: see text]

Aims. Mucinous cystic neoplasms (MCNs) are cystic neoplasms with mucinous epithelium surrounded by ovarian-like stroma. Extraovarian MCN occurring in the liver and pancreas have been well characterized. However, only rare case reports of MCN arising outside of these locations have been reported. MCNs arising in unusual locations should enter the differential diagnosis of mucinous intra-abdominal tumors and must be distinguished from more common mimics. Therefore, we aimed to examine a series of MCNs of the retroperitoneum and mesentery to characterize the clinicopathologic features of this entity. Methods and results. Seven MCNs arising in the abdominal mesentery or retroperitoneum were retrospectively identified. A clinicopathologic, histologic, and immunohistochemical (keratin 7, keratin 19, keratin 20, calretinin, inhibin-α, steroidogenic factor-1 (SF-1), estrogen receptor (ER), progesterone receptor (PR), PAX8, CDX2, and CD10) analysis was performed. All 7 MCNs were from females with a median age of 41 years old and a median size of 8 cm. All cases demonstrated mucinous with or without concomitant non-mucinous epithelium overlying spindle cell ovarian-like stroma. Luteinized cells were noted. The epithelium was positive for keratin 7 and keratin 19 in all 7 cases, while the stroma expressed ER, PR, and SF-1 in all cases stained. Calretinin was focally positive in the stroma of 3 of 7 cases, while inhibin-α was focally expressed in 5 of 6 cases. Conclusions. These results highlight the clinicopathologic, histologic, and immunophenotypic similarities between MCNs of the mesentery, retroperitoneum, pancreas, and liver. Overlapping features suggest a common histogenesis for all MCNs, which could include periductal fetal mesenchyme, aberrant migration of primordial germ cells, or abnormal differentiation or metaplasia of the embryonic coelomic epithelium.

Herein we present a patient that underwent a liver transplant due to primary biliary cholangitis (PBC) and after 9 years developed multiple myeloma. Following the cessation of mycophenolate mofetil and 2 weeks after lenalidomide treatment was started, the patient experienced acute cellular rejection. The patient recovered after treatment with corticosteroids, resumption of mycophenolate mofetil, and cessation of lenalidomide. Lenalidomide-associated allograft rejection has been reported in other organs. However, this is the first case report of liver rejection induced by lenalidomide.

Abstract Objectives Sclerosing pneumocytomas are rare pulmonary neoplasms that are typically benign. However, rare patients experience progressive disease, and therapy targeting specific genetic underpinnings could be an attractive therapeutic option. Recent studies have found recurrent AKT 1 mutations in sclerosing pneumocytoma, but little is known about whether oncogenic fusion genes may also be present. Methods To better understand the genetic background, 10 sclerosing pneumocytomas were subjected to next-generation sequencing cancer mutation panel testing (n = 9) and/or RNA sequencing (n = 3). The patients were all women (average age, 47 years; range, 17-74 years). Results Eight patients had solitary sclerosing pneumocytomas, while one had two tumors, and one had many bilateral tumors. Recurrent mutations were noted in genes involved in the mTOR pathway, including AKT1, PIK3R1, and PTEN. AKT1 alterations were particularly common, present in 78%. No recurrent genetic fusions were identified. The patient in our study with multiple bilateral lesions was treated with the mammalian target of rapamycin (mTOR) inhibitor everolimus, with no objective radiographic evidence of treatment response after 4 months. Conclusions Our data further support that abnormal activation of the mTOR pathway is a consistent genetic event in sclerosing pneumocytoma. This warrants further exploration to determine if mTOR pathway inhibitors may be effective in patients with metastatic or recurrent disease.

The absence of neuroendocrine (NE) cells in the intestinal mucosa in autoimmune enteropathy (AIE) has been occasionally reported. However, the status of NE cells has not been studied in detail in AIE. Small bowel and colonic biopsies were retrospectively retrieved from 18 AIE patients (26 baseline [18 small bowel and 8 colon]; and 15 follow-up [11 duodenum and 4 colon] biopsies in 11 patients). Thirty-three common variable immunodeficiency (CVID) patients (30 small bowel and 16 colon), 15 inflammatory bowel disease patients (5 duodenum and 10 colon), 13 immunoglobulinA deficiency patients (13 duodenum and 5 colon), and 10 normal controls (5 colon and 5 duodenum) were selected as control groups. Histologic features (villous atrophy, intraepithelial lymphocytosis, acute inflammation, crypt apoptosis, and absence or presence of goblet cells, Paneth cells and plasma cells) were recorded. Chromogranin immunostain was performed and chromogranin-positive NE cells were counted per 10 consecutive, well-oriented crypts. On the basis of the number of chromogranin-positive NE cells, cases were graded as being absent (≤3 NE cells), markedly decreased (≤15), and intact (>15). The NE cell status correlated with histologic features. The median age of 18 AIE patients was 38.5 years (range: 11 to 74 y) and 14 patients were male. Fourteen of 18 (78%) patients showed loss (absent or markedly decreased) of NE cells in the small bowel and/or colon in the baseline biopsies including 12 (of 18) small bowel and 6 (of 8) colon biopsies. Follow-up biopsy was available in 11 patients. Six of 7 (85%) patients who showed loss of NE cells in the baseline biopsies regained NE cells in the follow-up biopsies, and 1 patient continued to show loss of NE cells. Four patients who showed intact NE cells in the baseline remained unchanged in the follow-up. Among the control groups, 3 of 33 (9%) CVID patients showed loss of NE cells. NE cells were not lost in the biopsies of all 15 and 13 patients with inflammatory bowel disease and immunoglobulinA deficiency, respectively, or the 10 normal controls. In all 41 biopsies (26 baseline plus 15 follow-up) with AIE, NE cell loss was significantly associated with increased crypt apoptosis and loss of goblet cells (P=0.001, both) but not with other histologic findings. In conclusion, our study suggests that NE cells may also be the target cells in AIE and commonly lost in the intestinal crypts in AIE, and consequently loss of NE cells can be used as an adjunct histologic feature for diagnosis of AIE.

4065 Background: Tumor infiltrating lymphocytes (TILs) and tumor budding (linked to epithelial mesenchymal transition) may influence metastatic potential and patient prognosis. We analyzed these features and their relative contribution to survival among low (T1-3 N1) and high (T4 and/or N2) risk groups, defined by the IDEA study, used to inform the duration of adjuvant chemotherapy in stage III colon cancer. Methods: Among 1,532 patients (low risk n=804; high risk n=728) treated in a phase III adjuvant trial of FOLFOX + cetuximab (x 6 months), intraepithelial TIL densities and tumor budding were quantified at microscopy in routine histologic sections. Optimal cutpoints were determined in association with 5-yr disease-free survival (DFS). Relative contribution of variables to DFS was calculated using χ2 from Harrell’s rms R package based on multivariable Cox regression models. Results: In the overall cohort, the tumor budding/TILs combined variable was more robust for predition of DFS than either alone. Budding/TILs was significantly associated with DFS in both low (HRadj, 1.59; 95% CI, 1.02-2.48; p=.0273) and high (HRadj, 2.82; 95% CI, 1.72-4.63; p<.0001) risk patients. We then determined its relative contribution (%) to DFS (Table). Among low risk, budding/TILs ranked second (24.4%) behind KRAS status (45.5%) and ahead of treatment arm (7.2%) and mismatch repair (MMR) status (6.1%). Among high risk, budding/TILs contributed the most to DFS (45.4%) followed by primary tumor sidedness (13.0%), performance status (12.0%), and MMR (10.4%). Conclusions: Tumor budding/TILs provides robust prognostic stratification by risk group to improve anatomic tumor staging. The relative contribution of budding/TILs to DFS was second only to KRAS status in low risk patients, and was the most important predictor of DFS in high risk patients. Evaluation in patients treated with 3 vs 6 mos of adjuvant chemotherapy is warranted. [Table: see text]