Lipid Peroxidation Regulators GPX4 and FSP1 as Prognostic Markers and Therapeutic Targets in Advanced Gastric Cancer.

Gastric cancer is one of the most common cancers worldwide, and new therapeutic strategies are urgently needed. Ferroptosis is an intracellular iron-dependent cell death induced by the accumulation of lipid peroxidation, a mechanism different from conventional apoptosis and necrosis. Therefore, induction of ferroptosis is expected to be a new therapeutic strategy. Glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) have been identified as the major inhibitors of ferroptosis. Herein, we performed immunohistochemistry for GPX4, FSP1, and 4-HNE using tissues from patients with gastric cancer and investigated the relationship between these factors and prognosis. Patients with high GPX4 expression or high GPX4 expression and low 4-HNE accumulation tended to have a poor prognosis (p = 0.036, 0.023), whereas those with low FSP1 expression and high 4-HNE accumulation had a good prognosis (p = 0.033). The synergistic induction of cell death by inhibiting GPX4 and FSP1 in vitro was also observed, indicating that the cell death was non-apoptotic. Our results indicate that the expression and accumulation of lipid peroxidation-related factors play an important role in the clinicopathological significance of gastric cancer and that novel therapeutic strategies targeting GPX4 and FSP1 may be effective in treating patients with gastric cancer who have poor prognosis.

Nivolumab Rechallenge After Immune-related Adverse Events in Patients With Unresectable Advanced or Recurrent Esophageal Cancer.

BACKGROUND/AIM: Rechallenge with immune checkpoint inhibitors following immune-related adverse events (irAEs) during the treatment of certain cancers reportedly has good efficacy. However, the subsequent clinical course of esophageal cancer remains unclear. This study investigated the nature of irAEs and the efficacy of a nivolumab rechallenge for patients with esophageal cancer. PATIENTS AND METHODS: This study retrospectively analyzed 44 patients with unresectable advanced or recurrent esophageal cancer who were treated with nivolumab as a second-line or later regimen and developed irAEs between February 2020 and May 2022. The cohort was divided into continuation, rechallenge, and discontinuation groups based on nivolumab administration after the occurrence of irAEs. The proportion of each group was investigated according to the type of irAEs. The progression-free and overall survival periods were retrospectively analyzed for each group. RESULTS: Among patients with skin-related irAEs, 78.6% continued nivolumab administration, 14.3% rechallenged, and 7.1% discontinued nivolumab. Among patients with gastrointestinal disorders, 30.8% continued, 46.2% rechallenged, and 23.1% discontinued nivolumab. Among patients with interstitial pneumonia, none continued, 55.6% rechallenged, and 44.4% discontinued nivolumab. In those with endocrine disorders, 83.3% continued, none rechallenged, and 16.7% discontinued nivolumab. The median progression-free survival after irAE occurrence in the continuation, rechallenge, and discontinuation groups was 210, 333, and 72.5 days, respectively (p=0.022), while the median overall survival after irAE occurrence was 714, 848, and 223 days, respectively (p=0.008). CONCLUSION: Rechallenge with nivolumab may be considerably effective, depending on the type and severity of irAEs, and may improve the prognosis of patients with unresectable advanced or recurrent esophageal cancer.

Determination of the Minimum Sample Amount for Capillary Electrophoresis-Fourier Transform Mass Spectrometry (CE-FTMS)-Based Metabolomics of Colorectal Cancer Biopsies.

The minimum sample volume for capillary electrophoresis-Fourier transform mass spectrometry (CE-FTMS) useful for analyzing hydrophilic metabolites was investigated using samples obtained from colorectal cancer patients. One, two, five, and ten biopsies were collected from tumor and nontumor parts of the surgically removed specimens from each of the five patients who had undergone colorectal cancer surgery. Metabolomics was performed on the collected samples using CE-FTMS. To determine the minimum number of specimens based on data volume and biological interpretability, we compared the number of annotated metabolites in each sample with different numbers of biopsies and conducted principal component analysis (PCA), hierarchical cluster analysis (HCA), quantitative enrichment analysis (QEA), and random forest analysis (RFA). The number of metabolites detected in one biopsy was significantly lower than those in 2, 5, and 10 biopsies, whereas those detected among 2, 5, and 10 pieces were not significantly different. Moreover, a binary classification model developed by RFA based on 2-biopsy data perfectly distinguished tumor and nontumor samples with 5- and 10-biopsy data. Taken together, two biopsies would be sufficient for CE-FTMS-based metabolomics from a data content and biological interpretability viewpoint, which opens the gate of biopsy metabolomics for practical clinical applications.

[A Case of Suspected Pure Red Cell Aplasia Due to Nivolumab Treatment for Unresectable Esophageal Cancer].

Immune checkpoint inhibitor(ICI)combination therapy is the first-line of treatment for unresectable or recurrent esophageal cancer. The frequency and mechanism of immune-related adverse events(irAEs)associated with ICI are still unclear and may require differentiation from other diseases. The present study examined a patient with unresectable, advanced esophageal cancer treated with cisplatin plus 5-fluorouracil(CF)plus nivolumab as the first-line treatment. CF therapy was discontinued after 1 course owing to adverse events. Nivolumab was continued, but progressive anemia stemming from pure red cell aplasia(PRCA), an irAE of nivolumab administration, was observed. Nivolumab was discontinued, but later, interstitial pneumonia also developed, and pulse steroid therapy was begun. After steroid tapering, both the PRCA and interstitial pneumonia improved. At present, about 6 months have elapsed since the last nivolumab administration without any PRCA recurrence or evidence of tumor progression.

[A Case of Locally Advanced Unresectable Esophageal Cancer Treated with Nivolumab and Ipilimumab Therapy Followed by Surgery].

In cases of unresectable, locally advanced esophageal cancer, conversion surgery may be considered if chemotherapy produces favorable results and surgical resection is indicated. The use of immune checkpoint inhibitors in chemotherapy for esophageal cancer has expanded, and has increased the number of cases in which conversion surgery becomes possible. The patient in the present report had received a diagnosis of Stage Ⅳa esophageal carcinoma, and a prior nephroureterectomy discouraged the administration of platinum-based agents. Nivolumab and ipilimumab were administered as induction chemotherapy. Despite the achievement of stable disease, the patient's esophageal stricture deteriorated, necessitating surgical intervention. The resected specimen revealed that fewer than 50% of malignant cells remained viable and residual cancer cells were noticeably absent, particularly in the enlarged lymph nodes. We herein present the details of this case and discuss the literature concerning surgery following immune checkpoint inhibitor therapy.

[A Case of Unresectable Thoracic Esophageal Cancer Responding Well to Multimodal Therapy Including 5-FU plus CDDP plus Pembrolizumab].

A 51-year-old male presented with swelling on the left side of his neck. A diagnosis of thoracic esophageal cancer(Lt type 5a, squamous cell carcinoma, T3N4[16LN]M1[skin, bone, retroperitoneum, lung], cStage Ⅳb)was made, and treatment with a combination of 5-FU plus CDDP and pembrolizumab was initiated. After the 1st round of chemotherapy, there was an increase in metastases in the left cervical lymph node and skin, along with the development of back pain because of an L3 lumbar spine metastasis. Palliative radiotherapy(Σ24 Gy/6 Fr)was administered for all lesions. Subsequently, pembrolizumab was administered for the persistent decline in white blood cell and neutrophil counts. After 6 courses of pembrolizumab, computed tomography(CT)revealed an absence of lesions. Positron emission tomography/CT demonstrated no significant accumulation, prompting a diagnosis of complete response(CR). The patient is currently under pembrolizumab therapy and continues to remain in a state of CR.

Spatial and Quantitative Analysis of Tumor-Associated Macrophages: Intratumoral CD163-/PD-L1+ TAMs as a Marker of Favorable Clinical Outcomes in Triple-Negative Breast Cancer.

Tumor-associated macrophages (TAMs) and abnormalities in cancer cells affect cancer progression and response to therapy. TAMs are a major component of the tumor microenvironment (TME) in breast cancer, with their invasion affecting clinical outcomes. Programmed death-ligand 1 (PD-L1), a target of immune checkpoint inhibitors, acts as a suppressive signal for the surrounding immune system; however, its expression and effect on TAMs and the clinical outcome in breast cancer are unknown. In this study, we used high-throughput multiple immunohistochemistry to spatially and quantitatively analyze TAMs. We subjected 81 breast cancer specimens to immunostaining for CD68, CD163, PD-1, PD-L1, CD20, and pan-CK. In both stromal and intratumoral areas, the triple-negative subtype had significantly more CD68/CD163, CD68/PD-L1, and CD163/PD-L1 double-positive cells than the estrogen receptor (ER)/progesterone receptor (PR) subtype. Interestingly, a higher number of CD68+/PD-L1+/CK-/CD163- TAMs in the intratumoral area was correlated with a favorable recurrence rate (p = 0.048). These findings indicated that the specific subpopulation and localization of TAMs in the TME affect clinical outcomes in breast cancer.

The impact of lymphadenectomy on lymph node recurrence after performing various treatments for esophageal squamous cell carcinoma.

BACKGROUND: Treatment for regional lymph node recurrence after initial treatment for esophageal squamous cell carcinoma (ESCC) differs among institutions. Though some retrospective cohort studies have shown that lymphadenectomy for cervical lymph node recurrence is safe and leads to long-term survival, the efficacy remains unclear. In this study, we investigated the long-term outcomes of patients who underwent lymphadenectomy for regional recurrence after treatment for ESCC. PATIENTS AND METHODS: We retrieved 20 cases in which lymphadenectomy was performed for lymph node recurrence after initial treatment for ESCC in our hospital from January 2003 to December 2016. Initial treatments included esophagectomy, endoscopic resection (ER) and chemoradiotherapy/chemotherapy (CRT/CT). Overall survival (OS) and recurrence-free survival (RFS) after lymphadenectomy were calculated by the Kaplan-Meier method. We also used a univariate analysis with a Cox proportional hazards model to determine factors influencing the long-term outcomes. RESULTS: The five-year OS and RFS of patients who underwent secondary lymphadenectomy for recurrence after initial treatment were 50.0% and 26.7%, respectively. The five-year overall survival rates of patients who received esophagectomy, ER and CRT/CT as initial treatments, were 40.0%, 75.0% and 50.0%, respectively. The five-year OS rates of patients with Stage I and Stage II-IVB at initial treatments were 83.3% and 33.3%, respectively. CONCLUSIONS: Lymphadenectomy for regional recurrence after initial treatment for ESCC is effective to some degree. Patients with regional recurrence after initial treatment for Stage I ESCC have a good prognosis; thus, lymphadenectomy should be considered for these cases.

A Case of Breast Cancer in a Patient with a Congenital Pectoralis Muscle Defect.

Congenital pectoral muscle defects are very rare, and when accompanied by limb defects, they are called Poland syndrome. A woman in her 70s, 4 years after partial mastectomy for breast cancer, underwent mastectomy for a local recurrence. During the operation, the pectoralis major and minor muscles were found to be defective. However, the patient did not have any limb defects. Although congenital pectoral muscle defects are very rare, it would be better to confirm defects of the pectoral muscle by preoperative diagnostic imaging such as CT because the postoperative treatment may be affected.

[A Case of Advanced Esophagogastric Junction Cancer Responding to Combined Modality Therapy].

The patient was a 75-year-old man with advanced esophagogastric junction cancer.He received 2 courses of neoadjuvant chemotherapy with DCS followed by lower esophagectomy and total gastrectomy via the left thoracoabdominal approach. Pathological examination revealed EGJ adenocarcinoma(pT3N4M0, pStage Ⅳa).He was followed up after the surgery and was diagnosed with pulmonary portal lymph node and No.1 07 node recurrences 4 years and 8 months after the surgery, respectively.He received 2 courses of TS-1 monotherapy and chemoradiotherapy, resulting in a complete response(CR).He has remained in CR until June 2019.

Recurrent Early Coronary Stent Thrombosis under Chronic Disseminated Intravascular Coagulation.

A 62-year-old Japanese man presented with chest pain indicating that acute myocardial infarction had occurred. Eleven years earlier, he underwent a splenectomy due to idiopathic portal hypertension. Coronary angiography revealed diffuse stenosis, with calcification in the left anterior descending coronary artery (LAD). We performed a primary percutaneous coronary intervention (PCI). We deployed two drug-eluting stents with sufficient minimal cross-sectional stent area by intravascular ultrasound and thrombolysis in myocardial infarction (TIMI) 3 flow. The initial laboratory examination revealed chronic disseminated intravascular coagulation (DIC). On the 8th hospital day, he developed chest pain indicating early coronary stent thrombosis, although he had been prescribed dual antiplatelet therapy. We performed an emergent second PCI, and the TIMI flow grade improved from 0 to 3. Clopidogrel was replaced with prasugrel. On the 18th hospital day, we detected a repeated coronary stent thrombosis again. We performed a third PCI and the TIMI flow grade improved from 0 to 3. After anticoagulation therapy with warfarin, the DIC was improved and his condition ran a benign course without the recurrence of stent thrombosis for 1 month. Contrast-enhanced CT showed portal vein thrombosis. This patient's case reveals the possibility that the condition of chronic DIC can lead to recurrent stent thrombosis. Stent thrombosis is infrequent, but remains a serious complication in terms of morbidity and mortality. Although stent thrombosis is multifactorial, the present case suggests that DIC is a factor in stent thrombosis. To prevent stent thrombosis after PCI under DIC, anticoagulation might be a treatment option in addition to antiplatelet therapy.