The efficacy and safety of short-course radiotherapy followed by sequential chemotherapy and Cadonilimab for locally advanced rectal cancer: a protocol of a phase II study.

BACKGROUND: For patients with locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT), namely, intensifying preoperative treatment through the integration of radiotherapy and systemic chemotherapy before surgery, was commonly recommended as the standard treatment. However, the risk of distant metastasis at 3 years remained higher than 20%, and the complete response (CR) rate was less than 30%. Several clinical trials had suggested a higher complete response rate when combining single-agent immunotherapy with short-course radiotherapy (SCRT). The CheckMate 142 study had shown encouraging outcomes of dual immunotherapy and seemingly comparable toxicity for CRC compared with single-agent immunotherapy in historical results. Therefore, dual immunotherapy might be more feasible in conjunction with the TNT paradigm of SCRT. We performed a phase II study to investigate whether the addition of a dual immune checkpoint inhibitor bispecific antibody, Cadonilimab, to SCRT combined with chemotherapy might further increase the clinical benefit and prognosis for LARC patients. METHODS: This single-arm, multicenter, prospective, phase II study included patients with pathologically confirmed cT3-T4N0 or cT2-4N + rectal adenocarcinoma with an ECOG performance score of 0 or 1. Bispecific antibody immunotherapy was added to SCRT combined with chemotherapy. Patients enrolled would be treated with SCRT (25 Gy in five fractions over 1 week) for the pelvic cavity, followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX and Cadonilimab. The primary endpoint was the CR rate, which was the ratio of the pathological CR rate plus the clinical CR rate. The secondary endpoints included local-regional control, distant metastasis, disease-free survival, overall survival, toxicity profile, quality of life and functional outcome of the rectum. To detect an increase in the complete remission rate from 21.8% to 40% with 80% power, 50 patients were needed. DISCUSSION: This study would provide evidence on the efficacy and safety of SCRT plus bispecific antibody immunotherapy combined with chemotherapy as neoadjuvant therapy for patients with LARC, which might be used as a candidate potential therapy in the future. TRIAL REGISTRATION: This phase II trial was prospectively registered at ClinicalTrials.gov, under the identifier NCT05794750.

Corrigendum: Toxicity profile of combined immune checkpoint inhibitors and thoracic radiotherapy in esophageal cancer: A meta-analysis and systematic review.

[This corrects the article DOI: 10.3389/fimmu.2022.1039020.].

Toxicity profile of combined immune checkpoint inhibitors and thoracic radiotherapy in esophageal cancer: A meta-analysis and systematic review.

Background: Therapies based on the combination of immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) are transforming the treatment landscape of esophageal cancer. Nevertheless, the available data on adverse events (AEs) mainly stemmed from several prospective clinical trials and retrospective studies, in which, AE data are often handled and reported with less rigor than the primary beneficial outcomes of the study. Thus, we conducted a systematic review to investigate the toxicity spectrum of these novel regimens. Method: We searched for all prospective clinical trials investigating the role of ICIs combined with TRT published between January 2010 and August 2022. Study articles and conference proceedings involving esophageal cancers and reporting the overall incidence or details of treatment-related AEs (trAEs) were synthesized to determine the toxicity profile of combination treatment. We compared trAEs between cancer type, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, and between sequential and concurrent administration of ICIs and TRT to identify potentially high-risk patients. Results: We obtained toxicity data from 14 clinical trials involving 863 patients. The pooled overall incidence was 88.97% for any-grade trAEs and 18.48% for high-grade trAEs. The three most frequent non-hematologic any-grade trAEs were reactive cutaneous capillary endothelial proliferation (RCCEP, 63.80%), esophagitis (51.54%), and fatigue (33.63%). Meanwhile, RCCEP (15.69%) was the most common non-hematologic high-grade trAE, followed by nausea (4.91%) and anorexia (3.81%). The occurrence rates of any-grade and high-grade pneumonitis were 10.82% and 0.66%, respectively. In subgroup analysis, the toxicity profiles of PD-1 and PD-L1 inhibitors were mostly similar, except for any-grade pneumonitis (15.20% vs 4.88%, p=0.03) and high-grade leukopenia (6.25% vs 59.09%, p=0.00). In addition, concurrent treatment seemed to have a higher incidence of any-grade trAEs (95.20% vs 70.85%, p=0.03) compared with sequential treatment. ESCC seems to have higher incidence of any-grade hypothyroidism (22.55% vs 8.96%, p=0.049) compared to EAC. Conclusion: Our study is the first systematic review to provide a toxicity profile of trAEs in esophageal cancer patients who received ICIs combined with TRT. Most AEs of this combination treatment are tolerable, although the incidence of any-grade trAEs was higher in the concurrent group. The difference in any-grade pneumonitis between PD-1 and PD-L1 inhibitor groups needs further validation in a large clinical trial.

Resection of Thymic Neuroendocrine Carcinoma Guided by Three-Dimensional Reconstruction: A Case Report.

Primary thymic small cell neuroendocrine carcinoma (SCNEC), which possesses a more aggressive biological behaviour, including invasion of proximal structures, local recurrence, and distant metastasis, is extremely rare. According to a previous literature report, only a few patients with this disease have been reported, compared to patients with distant metastasis of bones, lungs, spleen, liver, and adrenal glands (1, 2). The report data suggest that SCNEC is a highly malignant tumour compared to most other tumours of the human body. In this study, we presented the case of a patient who underwent surgery guided by three-dimensional reconstruction modelling before the operation. We were fully prepared for the resection of this tumour using three-dimensional reconstruction modelling, even after reading the computed tomography (CT) images that showed a closed relationship with the pericardium, the vein of the right middle lung lobe, and the phrenic nerve. All these features demonstrate that SCNEC is highly malignant. To date, there are no procedural reports for three-dimensional reconstruction modelling in malignant thymus tumours.

MiR-522-3p inhibits proliferation and activation by regulating the expression of SLC31A1 in T cells.

We investigated the role of miR-522-3p in thymoma-associated myasthenia gravis (TAMG), and the mechanism of action in T cells. The miR-522-3p expression in normal serum, non-thymoma MG patient serum and TAMG patient serum and tissues was detected by quantitative real-time PCR (qRT-PCR), respectively. We assessed miR-522-3p expression in Jurkat cells and human CD4+ T cells after activation by anti-CD3 and anti-CD28 using qRT-PCR. The viability, proliferation, cycle distribution and the levels of CD25, CD69, interleukin-2 (IL-2) and IL-10 in transfected Jurkat cells were detected by Cell counting kit-8, 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, qRT-PCR, respectively. Targeting relationships of miR-522-3p and SLC31A1 were predicted and validated by bioinformatics analysis and dual-luciferase reporter. The viability, proliferation, cycle distribution and the levels of SLC31A1, CD25, CD69, IL-2 and IL-10 in transfected Jurkat cells were detected by above methods and western blot. The miR-522-3p expression was declined in TAMG and activated T cells. MiR-522-3p inhibitor promoted cell viability, EdU positive cells, cycle progression, and the level of CD25, CD69, IL-2 and IL-10 in Jurkat cells, while the effect of miR-522-3p mimic was the opposite. SLC31A1 was targeted by miR-522-3p, and miR-522-3p inhibited SLC31A1 expression. Overexpressed SLC31A1 reversed the inhibitory effects of miR-522-3p mimic on cell viability, EdU positive cell, cycle progression, and the levels of IL-2 and IL-10 in transfected Jurkat cells. MiR-522-3p expression was down-regulated in TAMG, and miR-522-3p inhibited proliferation and activation by regulating SLC31A1 expression in T cells.

Expression of PGDH correlates with cell growth in both esophageal squamous cell carcinoma and adenocarcinoma.

Esophageal cancer represents the fourth most common gastrointestinal cancer and generally confers a poor prognosis. Prostaglandin-producing cyclo-oxygenase has been implicated in the pathogenesis of esophageal cancer growth. Here we report that prostaglandin dehydrogenase, the major enzyme responsible for prostaglandin degradation, is significantly reduced in expression in esophageal cancer in comparison to normal esophageal tissue. Reconstitution of PGDH expression in esophageal cancer cells suppresses cancer cell growth, at least in part through preventing cell proliferation and promoting cell apoptosis. The tumor suppressive role of PGDH applies equally to both squamous cell carcinoma and adenocarcinoma, which enriches our understanding of the pathogenesis of esophageal cancer and may provide an important therapeutic target.

A comparison of short-term outcomes between Ivor-Lewis and McKeown minimally invasive esophagectomy.

BACKGROUND: Only few comparative studies have been reported on the outcomes of minimally invasive esophagectomy (MIE) with intrathoracic anastomosis (MIE Ivor-Lewis) and MIE with cervical anastomosis (MIE McKeown) for patients with mid and lower esophageal cancer. The objective of this study is to compare the safety, feasibility, and short-term outcomes between two groups. METHODS: Clinical and surgical data of patients with esophageal cancer who underwent either MIE Ivor-Lewis or MIE McKeown between January 2013 and October 2014 were retrospectively analyzed. Demographic characteristics, pathological data, operative procedures, and perioperative outcomes and survival in patients were compared between both groups. RESULTS: Of the 72 patients included in this retrospective analysis, 32 underwent MIE Ivor-Lewis and 40 underwent MIE McKeown. Demographics, pathologic data, inpatient mortality, and surgical morbidity in both cohorts were almost identical. A significant difference was observed in Pulmonary complication (18.8% vs. 42.5%, P=0.032), Anastomotic leakage (9.4% vs. 30%, P=0.032), Anastomotic stenosis (12.5% vs. 35%, P=0.028), recurrent laryngeal nerve (RLN) injury (6.3% vs. 22.5%, P=0.034) between MIE Ivor-Lewis and MIE McKeown groups; however, no difference in operative time (312.6±82.0 vs. 339.4±80.0, P=0.249), blood loss (246.3±82.4 vs. 272.9±136.3, P=0.443), lymph nodes harvested (19.3±8.1 vs. 20.2±7.2, P=0.655) and 90-day mortality (3.1% vs. 5%, P=0.692) was observed between two groups. CONCLUSIONS: The procedure of MIE Ivor-Lewis for esophageal cancer possesses advantages in perioperative outcomes and less complications compared with MIE McKeown.

Dual roles of sulforaphane in cancer treatment.

Sulforaphane (SFN), one of naturally occurring isothiocyanates (ITCs), has huge cancer chemopreventive potential. It modulates cell death, cell cycle, angiogenesis, susceptibility to carcinogens, invasion and metastasis and possesses antioxidant activities. It functions as an inhibitor of phase I enzymes and also as an inducer of phase II detoxification enzymes through different ways. NF-E2- related factor-2(Nrf-2), as well as mitogen-activated protein kinase (MAPK), is regulated by SFN. Intriguingly, strong evidence has showed the dark side of Nrf-2: stable upregulation of Nrf-2-mediated survival pathway would protect cancer cells from a subset of chemotherapeutic agents tested. This suggested that overexpression of Nrf-2 resulted in enhanced resistance of cancer cells to chemotherapeutic agents. Hence, future studies will focus on clarifying the exact time and dose of SFN to modulate the Nrf-2 signal pathway during chemotherapy and the efficacy of coadministration of Nrf-2 modulators during chemotherapy in order to make full use of the beneficial effect of this agent while eliminating the potential side effects.