Indocyanine green perfusion assessment of the gastric conduit in minimally invasive Ivor Lewis esophagectomy.

BACKGROUND: Anastomotic leak is a serious complication following esophagectomy. The aim of the study was to report our experience with indocyanine green fluorescence angiography (ICG-FA)-PINPOINT® assisted minimally invasive Ivor Lewis esophagectomy (MILE) and assess factors associated with anastomotic leak. METHODS: We reviewed consecutive patients undergoing MILE from 2013 to 2018. Intraoperative real-time assessment of gastric conduit was performed using ICG-FA with PINPOINT®. Perfusion was categorized as good perfusion (brisk ICG visualization to conduit tip) or non-perfusion (any demarcation along the conduit). RESULTS: 100 patients (81 males, median age 68 [60-72]) underwent MILE for malignancy in 96 patients and benign disease in 4 patients. There were six anastomotic leaks all managed with endoscopic stent placement. There was no intraoperative mortality and no 30-day mortality in leak patients. Patients with a leak were more likely to be overweight with BMI > 25 (100% versus 53%, p = 0.03), have pre-existing diabetes (50% versus 13%, p = 0.04), and have higher intraoperative estimated blood loss (260 mL [95-463] versus 75 mL [48-150], p = 0.03). Anastomotic leaks occurred more frequently in the non-perfusion (67%) versus the good perfusion category (33%, p = 0.03). By multivariable analysis, diabetes (odds ratio [OR] 6.42; p = 0.04) and non-perfusion (OR 6.60; p = 0.04) were independently associated with leak. CONCLUSION: Intraoperative use of ICG-FA may be a useful adjunct to assess perfusion of the gastric conduit with non-perfusion being independently associated with a leak. While perfusion plays an important role in anastomotic integrity, development of a leak is multifactorial, and ICG-FA should be used in conjunction with the optimization of patient and procedural components to minimize leak rates. Prospective, randomized studies are required to validate the interpretation, efficacy, and application of this novel technology in minimally invasive esophagectomies.

Intrahepatic cholangiocarcinoma as a rare secondary malignancy after allogeneic hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia: A case report.

Secondary malignancies are a significant cause of non-relapse mortality in patients who undergo allogeneic HCT. However, secondary liver cancer is rare, and ICC following HCT has never been reported in the literature. Secondary solid cancers typically have a long latency period, and cholangiocarcinoma is classically a malignancy occurring in older individuals. Here, we report the first case of secondary ICC, which presented just 3 years after HCT in a young adult with a history of childhood ALL. A 26-year-old male with history of precursor B-cell ALL presented with asymptomatic elevated liver function tests 3 years after HCT. Laboratories were indicative of biliary obstruction. ERCP showed focal biliary stricturing of the common and left hepatic ducts. MRCP revealed left intrahepatic duct dilatation, suggestive of intrahepatic obstructing mass. Additional workup lead to a clinical diagnosis of ICC. The patient underwent left hepatectomy with extrahepatic bile duct resection and portal lymphadenectomy. Surgical pathology was consistent with moderately differentiated cholangiocarcinoma. Our case illustrates a rare SMN following HCT for ALL. It is the first case report of ICC occurring as a secondary cancer in this patient population. Although cholangiocarcinoma is characteristically diagnosed in the older population, it must remain on the differential for biliary obstruction in post-HCT patients.

T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer.

We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×1011 HLA-C*08:02-restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02.

Immunologic Recognition of a Shared p53 Mutated Neoantigen in a Patient with Metastatic Colorectal Cancer.

Adoptive cell therapy (ACT) with T cells targeting neoantigens can mediate durable responses in patients with metastatic cancer. Cell therapies targeting common shared antigens for epithelial cancers are not yet broadly available. Here, we report the identification and characterization in one patient of T-cell receptors (TCRs) recognizing mutated p53 p.R175H, which is shared among a subset of patients with cancer. Tumor-infiltrating lymphocytes were screened for recognition of mutated neoantigens in a patient with metastatic colorectal cancer. HLA-A*0201-restricted recognition of mutated p53 p.R175H was identified, and the minimal peptide epitope was HMTEVVRHC. Reactive T cells were isolated by tetramer sorting, and three TCRs were identified. These TCRs mediated recognition of commercially available ovarian cancer, uterine carcinoma, and myeloma cell lines, as well as an NIH patient-derived esophageal adenocarcinoma line that endogenously expressed p53 p.R175H and HLA-A*0201. They also mediated recognition of p53 p.R175H+ colon, breast, and leukemia cell lines after transduction with a retrovirus encoding HLA-A*0201. This work demonstrates that common shared mutated epitopes such as those found in p53 can elicit immunogenic responses and that the application of ACT may be extended to patients with any cancer histology that expresses both HLA-A*0201 and the p53 p.R175H mutation.

Characterization of an Immunogenic Mutation in a Patient with Metastatic Triple-Negative Breast Cancer.

Purpose: The administration of autologous tumor-infiltrating lymphocytes (TILs) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There are limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic nonsynonymous mutations in a patient with triple-negative breast cancer (TNBC) to identify and isolate mutation-reactive TILs for possible use in adoptive cell transfer.Experimental Design: A TNBC metastasis was resected for TIL generation and whole-exome sequencing. Tandem minigenes or long 25-mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen-presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNγ ELISPOT. The nature of the T-cell response against a unique nonsynonymous mutation was characterized.Results: We identified 72 nonsynonymous mutations from the tumor of a patient with TNBC. CD4+ and HLA-DRB1*1501-restricted TILs isolated from this tumor recognized a single mutation in RBPJ (recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples.Conclusions: Breast cancers can express naturally processed and presented unique nonsynonymous mutations that are recognized by a patient's immune system. TILs recognizing these immunogenic mutations can be isolated from a patient's tumor, suggesting that adoptive cell transfer of mutation-reactive TILs could be a viable treatment option for patients with breast cancer. Clin Cancer Res; 23(15); 4347-53. ©2017 AACR.