Salvage surgery for advanced non-small cell lung cancer following previous immunotherapy: a retrospective study.

BACKGROUND: The development of systemic chemotherapy including immune checkpoint inhibitors (ICIs) has provided patients with unresectable advanced non-small cell lung cancer (NSCLC) an opportunity to undergo surgical intervention after initial treatment. However, no consensus regarding the indication for salvage surgery in these patients has been reached. METHODS: We conducted a retrospective study of patients who underwent salvage surgery for advanced NSCLC (cStage IIIA-IVB) after treatment with ICIs from January 2018 to December 2022 at Aizu Medical Center and Fukushima Medical University Hospital. We evaluated the patients' clinical data, calculated disease-free survival (DFS) and overall survival (OS), and assessed the survival benefit using the Kaplan-Meier method. RESULTS: Thirteen patients underwent salvage surgery after immunotherapy. All patients achieved downstaging after initial chemotherapy. Eleven patients underwent lobectomy, and one patient underwent extirpation of intra-abdominal lymph nodes. The mean surgery time and intraoperative blood loss were 242.2 min and 415.1 g, respectively. The mean drainage period was 4.2 days (range, 2-9 days). Grade ≥ 3 postoperative complications were confirmed in three patients. The 2-year DFS rate was 71.2%, and the 2-year OS rate was 76.2%. A pathological complete response compatible with ypStage 0 was achieved in four (30.8%) patients. Patients with ypStage 0 and I achieved significantly better OS than those with ypStage ≥ II (p = 0.044), and patients without severe complications achieved significantly better DFS and OS than those with severe complications (p = 0.001 and p < 0.001, respectively). CONCLUSIONS: Salvage surgery after chemotherapy including ICIs is a feasible and effective treatment option for patients with advanced NSCLC, especially those who acquire downstaging to pathological stage 0 or I. However, severe perioperative complications might affect patient survival. A prospective study is urgently needed to evaluate the efficacy of salvage surgery.

[Clinical Features of Endocrine Disorders with Immune Checkpoint Inhibitor in Patients with Non-Small Cell Lung Cancer].

Immune checkpoint inhibitors(ICIs)could cause immune-related adverse events(irAEs), of which endocrine disorders are relatively common. Symptoms include fatigue, anorexia, and shock, making diagnosis and treatment difficult. This study aimed to analyze the characteristics of patients with non-small cell lung cancer concomitant with endocrine disorders as irAEs. In total, 83 patients who were administered ICIs for advanced or postoperative recurrent non-small cell lung cancer between February 2016 and February 2021 were identified. We retrospectively studied the clinical course and findings of 7 patients who developed endocrine disorders after treatment. Four patients had hypopituitarism, and 3 patients had thyroid dysfunctions. There were 6 male patients and 1 female patient. Regarding anticancer agents, 5 patients received ICI alone, and 2 patients received ICI plus cytotoxic chemotherapies. The patients received treatment from the irAE treatment team in our hospital, and 5 of 7 patients could were able to be readministered ICIs. Endocrine disorders as irAEs require collaboration with specialized departments for early diagnosis and treatment.

Wnt/ß-Catenin Signaling and Resistance to Immune Checkpoint Inhibitors: From Non-Small-Cell Lung Cancer to Other Cancers.

Lung cancer is the leading cause of cancer-related deaths worldwide. The standard of care for advanced non-small-cell lung cancer (NSCLC) without driver-gene mutations is a combination of an anti-PD-1/PD-L1 antibody and chemotherapy, or an anti-PD-1/PD-L1 antibody and an anti-CTLA-4 antibody with or without chemotherapy. Although there were fewer cases of disease progression in the early stages of combination treatment than with anti-PD-1/PD-L1 antibodies alone, only approximately half of the patients had a long-term response. Therefore, it is necessary to elucidate the mechanisms of resistance to immune checkpoint inhibitors. Recent reports of such mechanisms include reduced cancer-cell immunogenicity, loss of major histocompatibility complex, dysfunctional tumor-intrinsic interferon-γ signaling, and oncogenic signaling leading to immunoediting. Among these, the Wnt/ß-catenin pathway is a notable potential mechanism of immune escape and resistance to immune checkpoint inhibitors. In this review, we will summarize findings on these resistance mechanisms in NSCLC and other cancers, focusing on Wnt/ß-catenin signaling. First, we will review the molecular biology of Wnt/ß-catenin signaling, then discuss how it can induce immunoediting and resistance to immune checkpoint inhibitors. We will also describe other various mechanisms of immune-checkpoint-inhibitor resistance. Finally, we will propose therapeutic approaches to overcome these mechanisms.

Ectopic adrenocorticotropic hormone-secreting carcinoid with solitary cryptococcosis in the lungs.

BACKGROUND: Carcinoid tumors can on rare occasions ectopically produce adrenocorticotropic hormone (ACTH), causing Cushing's syndrome, and patients could become immunocompromised. Care must therefore be taken regarding infectious complications. In particular, ACTH-producing pulmonary carcinoid is not easy to diagnose by itself, and when combined with pulmonary nodules as infectious foci, each is very difficult to diagnose. CASE: The patient was a 71-year-old woman with refractory diabetes. She showed clinical symptoms of Cushing's syndrome during treatment for diabetes and ectopic ACTH production was suspected based on biochemical and imaging tests. Nodules were identified in the left lung apex and lingual segment. Examination of resected nodules revealed that the nodule in the apex was pulmonary cryptococcosis, while the nodule in the lingual segment represented typical carcinoid. After surgery, clinical symptoms, laboratory findings, and diabetes all improved. CONCLUSION: We present this very instructive case in terms of the difficulty of diagnosing ACTH-producing tumors, the possibility of infection complicating the immunodeficiency caused by ACTH-producing tumors, and the surgical strategy.

[Resistance Mechanisms to Immune Checkpoint Inhibitor and Its Overcome with Focus on ß-Catenin in Lung Cancer].

Although the indications for immune checkpoint inhibitors are expanding rapidly, the disease will eventually progress in many patients. Elucidating and overcoming the resistant mechanisms to immune checkpoint inhibitors is a major challenge. WNT/ß-catenin pathway has long been known as one of the mechanisms involved in cell proliferation and epithelial-mesenchymal transition in cancer development. Recently, it has become clear that WNT/ß-catenin pathway also plays a role in cancer immune escape, as reported in melanoma. We have also studied WNT/ß-catenin pathway as a mechanism of immune escape in lung cancer. In this article, we review how WNT/ß-catenin pathway is involved in immune escape and resistance to immune checkpoint inhibitors, mainly in non-small cell lung cancer. In addition, we discuss how to overcome the tumor immune mechanism caused by WNT/ß-catenin pathway in the context of current combination therapies and therapies in development.

[ß-Catenin Expression in Non-Small Cell Lung Cancer and Therapeutic Effect of Immune Checkpoint Inhibitors].

Recently, ß-catenin mediated immune escape mechanism has been reported in several cancers. We investigated whether ß-catenin is associated with resistance to immune checkpoint inhibitor therapy in non-small cell lung cancer. Non-small cell lung cancer patients expressing high levels of ß-catenin showed poor progression-free survival and overall survival after single agent anti-PD-1 therapy. They had less infiltration of CD8-positive cells and antigen-presenting cells. Microarray analysis also showed low gene expression of CD8A and IFNG. siRNA knockdown of CTNNB1 in the ß-catenin-positive lung cancer cell line LK-2 tended to decrease CTNNB1 and ATF3 expression and increase CCL4 expression. The results suggest that ß- catenin suppresses tumor infiltration by antigen-presenting cells and confers resistance to immune checkpoint inhibitors in non-small cell lung cancer via downregulation of CCL4 production.

Lung adenocarcinoma coexisting with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia manifesting as multiple pulmonary nodules: A case report.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), a rare condition, is characterized by pathological proliferation of neuroendocrine cells. Some of them are localized to the airway mucosa, and others locally infiltrate to form tumorlets and nodules. Here, we present a patient with lung adenocarcinoma accompanied by DIPNECH, making the latter difficult to distinguish from multiple pulmonary metastases. The patient, a 72-year-old Japanese woman, was diagnosed as having stage IVA lung adenocarcinoma because she had multiple nodules in both lungs. Mutation of epidermal growth factor receptor gene having been found in the primary tumor, treatment with osimertinib was started. This resulted in shrinkage of the primary tumor, but not the multiple pulmonary nodules. To determine whether these lung nodules were indeed lung metastases, we performed right upper lobectomy with lymphadenectomy and wedge resection of the right lower lobe. On pathological examination, the primary tumor was diagnosed as invasive adenocarcinoma, whereas the multiple pulmonary nodules were diagnosed as DIPNECH manifesting as tumorlets. Therefore, the final diagnosis was stage IA1 lung adenocarcinoma accompanied by DINPECH. The patient had no recurrences 1 year after the operation without any additional treatment. This is a rare case of lung adenocarcinoma accompanied by DIPNECH presenting as multiple pulmonary nodules. DIPNECH should be included in the differential diagnosis of multiple pulmonary nodules.

The clinical significance of tertiary lymphoid structure and its relationship with peripheral blood characteristics in patients with surgically resected non-small cell lung cancer: a single-center, retrospective study.

INTRODUCTION: The presence of tertiary lymphoid structure (TLS) in tumor tissues has been reported to be a factor associated with a good prognosis in several types of cancers. However, the relationship between TLS formation and peripheral blood findings remains unclear. The purposes of the study were to evaluate the effect of the presence of TLS on survival and determine the peripheral blood characteristics associated with TLS formation in non-small cell lung cancer (NSCLC) patients. METHODS: A total of 147 consecutive NSCLC patients who underwent lung resection at Fukushima Medical University Hospital between 2013 and 2017 were enrolled. TLS expression was evaluated, and the relationships between clinical parameters and outcomes were analyzed. Peripheral blood mononuclear cells (PBMCs) were further analyzed by mass cytometry to characterize the TLS-positive microenvironment. RESULTS: Forty-six patients had high TLS expression, and the remaining 101 patients had low TLS expression. In stage II to IV patients (n = 35), disease-free survival was longer in the high TLS expression group (p = 0.027). A low neutrophil to lymphocyte ratio (NLR) < 2.75 in the peripheral blood was associated with high TLS expression (p = 0.003). Citrus analysis after mass cytometry assay showed that the number of cells expressing HLA-DR and CD9 in PBMCs was lower in the high TLS expression group. CONCLUSION: High TLS expression is associated with a good prognosis after surgery in stage II and III NSCLC patients. In the peripheral blood, a low NLR and few antigen-presenting cells indicate the presence of TLS in the tumor microenvironment.

CTLA-4 Expression in Tumor-infiltrating Lymphocytes Is Irrelevant to PD-L1 Expression in NSCLC.

BACKGROUND/AIM: Treatments containing ipilimumab have shown a good outcome in patients with non-small cell lung cancer (NSCLC) regardless of the PD-L1 tumor proportion score (TPS). However, the association between PD-L1 TPS and the expression of CTLA-4 in tumor-infiltrating lymphocytes is unknown. PATIENTS AND METHODS: Fifty-five NSCLC patients who underwent surgery in our hospital were included in this study. We measured the proportions of CTLA-4+ regulatory T cells, and CTLA-4+ CD8 T cells, and statistically analyzed their correlations with the PD-L1 TPS. RESULTS: Statistical correlations were found neither between the proportion of CTLA-4+ regulatory T cells to CD8 T cells and the PD-L1 TPS (p=0.2859) nor between the proportion of CTLA-4+ cells in CD8 T cells and the PD-L1 TPS (p=0.1919). CONCLUSION: The proportions of CTLA-4+ regulatory T cells to CD8 T cells and CTLA-4+ cells in CD8 T cells were irrelevant to the PD-L1 TPS in NSCLC patients.

A patient with ALK-positive lung adenocarcinoma who survived alectinib-refractory postoperative recurrence for 4 years by switching to ceritinib.

Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements are found in ~ 5% of patients with non-small cell lung cancer (NSCLC). Several tyrosine kinase inhibitors (TKIs) have been developed for treatment of so-called ALK-positive NSCLC. In cases of tumor progression during treatment with second-generation ALK-TKIs, such as alectinib, brigatinib, or ceritinib, National Comprehensive Cancer Network guidelines propose a switch to lorlatinib, a third-generation ALK-TKI, or to cytotoxic chemotherapy. However, they do not mention switching to other second-generation ALK-TKIs. Here, we present a rare case of a 53-year-old Japanese woman, who had never smoked, with ALK-positive lung adenocarcinoma who survived alectinib-resistant postoperative recurrence for 4 years by switching to ceritinib. She underwent curative resection for lung adenocarcinoma, but the cancer recurred at the bronchial stump and mediastinal lymph nodes. After platinum-doublet chemotherapy, the patient still had a single growing liver metastasis, but the tumor was found to harbor EML4-ALK rearrangement. Therefore, the patient started to take ALK-TKIs. Alectinib was the second ALK-TKI used to treat this patient. Alectinib shrank the liver metastasis, which was surgically resected. The tumor relapsed again during continued treatment with alectinib, which was switched to ceritinib. Ceritinib was effective for the relapsed tumor and treatment continued well for 4 years. This case report suggests that, in case of tumor progression during treatment with a second-generation ALK-TKI, switching to another second-generation ALK-TKI may be one of the treatment options. Further analyses are warranted to find robust markers to determine which ALK-TKI is best for each patient.

Triazoyl-phenyl linker system enhancing the aqueous solubility of a molecular probe and its efficiency in affinity labeling of a target protein for jasmonate glucoside.

In methods employing molecular probes to explore the targets of bioactive small molecules, long or rigid linker moieties are thought to be critical factors for efficient tagging of target protein. We previously reported the synthesis of a jasmonate glucoside probe with a highly rigid linker consisting of a triazoyl-phenyl (TAzP) moiety, and this probe demonstrated effective target tagging. Here we compare the TAzP probe with other rigid or flexible probes with respect to target tagging efficiency, hydrophobic parameters, aqueous solubility, and dihedral angles around the biaryl linkage by a combination of empirical and calculation methods. The rigid biaryl linkage of the TAzP probe has a skewed conformation that influences its aqueous solubility. Such features that include rigidness and good aqueous solubility resulted in highly efficient target tagging. These findings provide a promising guideline toward designing of better linkers for improving molecular probe performance.

Hybrid stereoisomers of a compact molecular probe based on a jasmonic acid glucoside: syntheses and biological evaluations.

12-O-ß-D-glucopyranosyl jasmonic acid (JAG) shows unique biological activities, including leaf-closing of Samanea saman. It is expected that the mode of action for such regulation is distinct from that of other jasmonates. We developed high-performance compact molecular probes (CMPs) based on JAG that can be used for the FLAG-tagging of JAG target. We synthesized four hybrid-type JAG-CMP stereoisomers (7, ent-7, 8, and ent-8), which are composed of (-)-12-OH-JA (2)/D-galactopyranoside, (-)-2/L-galactopyranoside, (+)-ent-2/d-galactopyranoside, and (+)-ent-2/L-galactopyranoside moieties, respectively, and we examined their biological features, such as the stereospecific induction of shrinkage, rate of the cellular response, and dependence on potassium channel activity. These features of the JAG-CMPs were completely consistent with those of the original JAG. These results indicate the biological equivalence of JAG and the JAG-CMPs. During the course of such biological evaluations, it was revealed that the biological activity of the CMPs is greatly dependent on the d/l-stereochemistry of a glycon moiety. To the best of our knowledge, this is the first study suggesting that the d/l-stereochemistry of the glycon moiety significantly affects the biological activity of the associated glycoside.

"Click-made" biaryl-linker improving efficiency in protein labelling for the membrane target protein of a bioactive compound.

We report on the design, synthesis and assessment of a novel biaryl-linked (BArL) molecular probe for the exploration of low-abundant target proteins for bioactive compounds based on the activity based protein profiling (ABPP) approach. Surprisingly, the performance of the BArL probe was better than that of the stepwise tagging approach that is considered to be the most effective method used in ABPP study.

Recent advances on bioorganic chemistry of plant metabolites controlling nyctinasty.

Leguminous plants open their leaves during the daytime and close them at night as if sleeping, a type of movement that follows circadian rhythms, and is known as nyctinastic movement. This phenomenon is controlled by two endogenous bioactive substances that exhibit opposing activities: Leaf-Opening Factor (LOF), which opens the leaves, and Leaf-Closing Factor (LCF), which closes them. The authors have carried out chemical biological research using these bioactive substances as molecular probes in order to clarify the mechanisms of nyctinastic movement. Here, we report on the detection and identification of the target proteins of these compounds using original methodology.

Synthesis and bioactivity of potassium beta-D-glucopyranosyl 12-hydroxy jasmonate and related compounds.

Albizzia saman, a leguminous plant, is known to open its leaves in the daytime and sleep at night with the leaves folded. beta-D-Glucopyranosyl 12-hydroxyjasmonate (1) was isolated as an endogenous chemical factor controlling this leafmovement. We developed a concise synthesis of optically pure (-)-1 in 9 steps from (+)-2 with a total yield of 58%. Similarly, such analogs of 1 as epi-LCF (13), enantiomer (14), and galactoside (19) were synthesized for a structure activity relationship (SAR) study. The results of this SAR study strongly suggest that the mechanism for the leaf-closing activity of 1 would be different from that of methyl jasmonate, and also suggest the involvement of a different kind of target protein which recognizes the trans-isomer of a jasmonate derivative.