HITM-SURE: Hepatic immunotherapy for metastases phase Ib anti-CEA CAR-T study utilizing pressure enabled drug delivery.

In recent years, cell therapy technologies have resulted in impressive results in hematologic malignancies. Treatment of solid tumors with chimeric antigen receptor T-cells (CAR-T) has been less successful. Solid tumors present challenges not encountered with hematologic cancers, including high intra-tumoral pressure and ineffective CAR-T trafficking to the site of disease. Novel delivery methods may enable CAR-T therapies for solid tumor malignancies. A patient with liver metastases secondary to pancreatic adenocarcinoma received CAR-T targeting carcinoembryonic antigen (CEA). Previously we reported that Pressure-Enabled Drug Delivery (PEDD) enhanced CAR-T delivery to liver metastases 5.2-fold. Three doses of anti-CEA CAR-T were regionally delivered via hepatic artery infusion (HAI) using PEDD technology to optimize the therapeutic index. Interleukin-2 was systemically delivered by continuous intravenous infusion to support CAR-T in vivo. HAI of anti-CEA CAR-T was not associated with any serious adverse events (SAEs) above grade 3 and there were no on-target/off-tumor SAEs. Following CAR-T treatment, positron emission tomography-CT demonstrated a complete metabolic response within the liver, which was durable and sustained for 13 months. The response was accompanied by normalization of serum tumor markers and an abundance of CAR+ cells found within post-treatment tumor specimens. The findings from this report exhibit biologic activity and safety of regionally infused CAR-T for an indication with limited immune-oncology success to date. Further studies will determine how HAI of CAR-T may be included in multidisciplinary treatment plans for patients with liver metastases. ClinicalTrials.gov number, NCT02850536.

Peripheral T-cell lymphoma arising in the liver.

We report 3 cases of primary hepatic peripheral T-cell lymphoma (PTCL). All patients were men, 50 to 57 years of age, who sought care because of systemic symptoms including fever, fatigue, and weight loss. Physical examination revealed hepatomegaly in 2 patients, associated with jaundice in 1. Two patients had abnormal serum liver enzyme levels and coagulation profiles. Imaging studies demonstrated marked hepatomegaly without focal lesions in 1 patient and multiple discrete tumor masses in 2 patients. Tumor infiltrates in biopsy specimens were heterogeneous with a large cell component in 2 cases. An inflammatory background was present in all cases, complicating the histologic recognition of PTCL Immunohistochemical studies showed that all tumors were of T-cell lineage, and 2 cases had monoclonal T-cell receptor gamma chain gene rearrangements. One patient died of disease shortly after diagnosis, and 2 patients treated with multiagent chemotherapy are in clinical remission with 12 and 84 months of clinicalfollow-up, respectively. PTCL may rarely arise in the liver. These neoplasms respond to chemotherapy, suggesting that this disease is curable if diagnosed at an early stage.

Lymphomas involving the pleura: a clinicopathologic study of 34 cases diagnosed by pleural biopsy.

CONTEXT: Pleural involvement by lymphoma is relatively common. However, there are very few clinicopathologic studies reported in the literature of lymphomas involving the pleura. OBJECTIVE: To characterize the clinicopathologic features of lymphomas involving the pleura. DESIGN: We reviewed the clinicopathologic features of 34 patients with lymphoma involving the pleura proven by biopsy and classified these neoplasms using the World Health Organization classification. RESULTS: There were 22 men and 12 women, with an average age of 62 years (range, 22-82 years). Nine (26.5%) patients had pleural involvement as the only site of disease, 22 (64.7%) had other sites of involvement, and 3 (8.8%) had inadequate staging data. Eighteen (56.2%) of 32 patients with adequate clinical data had a history of lymphoma (including 3 patients with pleural involvement as the only disease site). In 29 (85.3%) cases, a specific diagnosis according to the World Health Organization classification could be made: 17 (58.6%) diffuse large B-cell lymphoma, 5 (17.2%) follicular lymphoma (including a case with areas of diffuse large B-cell lymphoma), 2 (6.9%) small lymphocytic lymphomas/chronic lymphocytic leukemia, 2 (6.9%) precursor T-cell lymphoblastic lymphoma/leukemia, 1 (3.4%) mantle cell lymphoma, 1 (3.4%) posttransplant lymphoproliferative disorder, and 1 (3.4%) classical Hodgkin lymphoma. The other 5 cases were B-cell lymphomas that could not be further classified. Cytologic examination of pleural fluid was performed in 15 cases and was positive for lymphoma in 8 (53.3%) cases. CONCLUSIONS: Most patients with lymphoma involving the pleura have simultaneous evidence of systemic involvement. The most frequent type is diffuse large B-cell lymphoma, followed by follicular lymphoma. Cytologic examination can have negative results in patients with pleural involvement by lymphoma.

Genetic alterations in goblet cell carcinoids of the vermiform appendix and comparison with gastrointestinal carcinoid tumors.

Goblet cell carcinoid is a relatively rare neuroendocrine tumor of the vermiform appendix with poorly understood molecular pathogenesis. We studied the clinicopathologic features and genetic alterations, including allelic loss of chromosomes 11q, 16q, and 18q; sequencing of the K-ras, beta-catenin, and DPC4 (SMAD4) genes; and p53 overexpression and loss of DPC4 by immunohistochemistry; in 16 goblet cell carcinoids. We compared the allelic loss in goblet cell carcinoids to those in 18 gastrointestinal carcinoid tumors. For goblet cell carcinoids, appendiceal perforation was the most common (70%, 7/10) clinical presentation. The mean tumor size was 2.0 +/- 1.5 cm (range, 0.4 to 4.5 cm). The tumor invaded to appendiceal serosa in 50% (8/16) of patients, and two patients had metastasis in lymph nodes or adjoining viscera. With mean follow-up of 24 +/- 14 months (median, 23 mo), 1 of 10 patients had died of disease, and 2 others had tumor recurrence. All four patients with metastases, recurrences, and/or death from disease had serosal involvement at presentation (P =.02). Loss of heterozygosity of chromosome 11q was present in 25% of goblet cell carcinoids, 14% of ileal carcinoid tumors, and 9% of nonileal carcinoid tumors; of chromosome 16q in 38%, 29%, and 0 (P =.02); and of chromosome 18q in 56%, 86%, and 9% (P =.002), respectively. No mutations of K-ras, beta-catenin, or DPC4 genes; p53 overexpression; or loss of staining for DPC4 was present in any tumors. These findings suggest that allelic loss of chromosomes 11q, 16q, and 18q in goblet cell carcinoids and ileal carcinoids may have an important role in the pathogenesis of these tumors.