Duodenal metastasis from primary lung adenocarcinoma: A rare case report.

Duodenal metastases from pulmonary adenocarcinoma are rare. Early detection, diagnosis, and treatment are crucial for improving the prognosis of patients with duodenal metastases from primary lung cancer, which often go unnoticed due to their low incidence and diagnostic challenges. Here, we present the case of a 64-year-old man with an unusual occurrence of duodenal metastases from pulmonary adenocarcinoma, admitted with symptoms of cholangitis. Radiological findings revealed a mass in the D2-D3 segments of the duodenum. Endoscopic ultrasound with biopsy was performed, and immunohistochemical analysis confirmed that the mass was a duodenal metastasis of pulmonary adenocarcinoma.

Sudden Intrauterine Unexplained Death (SIUD) and Oxidative Stress: Placental Immunohistochemical Markers.

BACKGROUND: Intrauterine fetal death and perinatal death represent one of the most relevant medical scientific problems since, in many cases, even after extensive investigation, the causes remain unknown. The considerable increase in medical legal litigation in the obstetrical field that has witnessed in recent years, especially in cases of stillborn births, has simultaneously involved the figure of the forensic pathologist in scientific research aimed at clarifying the pathophysiological processes underlying stillbirth. METHODS: our study aims to analyze cases of sudden intrauterine unexplained death syndrome (SIUD) to evaluate the role of oxidative stress in the complex pathogenetic process of stillbirth. In particular, the immunohistochemical expression of specific oxidative stress markers (NOX2, NT, iNOS, 8-HODG, IL-6) was evaluated in tissue samples of placentas of SIUDs belonging to the extensive case series (20 cases), collected from autopsy cases of the University of Ferrara and Politecnica delle Marche between 2017 and 2023. RESULTS: The study demonstrated the involvement of oxidative stress in intrauterine fetal deaths in the placenta of the cases examined. In SIUD, the most expressed oxidative stress markers were NOX2 and 8-HODG. CONCLUSIONS: The study contributes to investigating the role of oxidative stress in modulating different pathways in unexplained intrauterine fetal death (SIUD) tissues.

[Molecular markers of M. tuberculosis virulence in lung tissue (experimental study)]. / Molekulyarnye markery virulentnosti M. tuberculosis v tkani legkikh (eksperimental'noe issledovanie).

More than a quarter of the world's population is infected with Mycobacterium tuberculosis. However, only about 10% of those infected develop active TB. This indicates a key role for innate immunity in limiting M. tuberculosis replication. Most often, bacteria can regulate the expression of host-specific molecules and weaken host immunity. OBJECTIVE: To use a biological model, in order to determine significant molecular immunohistochemical markers characterizing the virulence of the "Buryat" and "Omsk" subtypes of the M. tuberculosis Beijing genotype in lung tissue. MATERIAL AND METHODS: Lung samples of the C57BL/6 male mice were obtained during experimental infection with M. tuberculosis strains: the reference laboratory strain H37Rv, multidrug-resistant clinical strains 396 (highly lethal and hypervirulent «Buryat¼ genotype Beijing 14717-15) and 6691 (low-lethal and low-virulent "Omsk" genotype Beijing 1071-32) on days 14, 21, 60 and 120. They were studied by histological and immunohistochemical methods. The relative areas of expression of IL-6, IL-12A, iNOS, and TNF-α in the lung tissue of model animals were established. RESULTS: A study of strain 396 showed that both disease progression and damage to lung tissue are associated with a highly reactive immune response and increased synthesis of iNOS and strain characteristics that block the production of TNF-α. On the contrary, for strain 6691 a low reactivity of the immune response was revealed, with statistically significantly lower values of the relative area of expression of NOS and TNF-α during all observation periods (days 14-120). All animals that survived to day 120 showed a similar morphological picture with differences in cytokine levels, indicating a nonlinear relationship between proinflammatory factors and the damage substratum. CONCLUSION: The progression of the disease and damage of lung tissue were associated with a highly reactive immune response and increased synthesis of iNOS, strain properties that block the TNF-α production. Thus, iNOS and TNF-α can act as molecular markers characterizing the virulence of the "Buryat" and "Omsk" subtypes of M. tuberculosis in lung tissue.

Diffuse large B-cell lymphoma-induced intussusception: A case report and literature review.

Adult intussusception necessitates early surgical intervention. We emphasis the significance of considering diffuse large B-Cell lymphoma in differential diagnoses for adult intussusception, particularly in the colon, to ensure precise diagnosis and optimal management.

Extramammary Paget disease. Part I. epidemiology, pathogenesis, clinical features, and diagnosis.

Extramammary Paget disease (EMPD) is a rare skin cancer of apocrine-rich skin that mimics common inflammatory and infectious dermatoses, leading to delays in diagnosis and increased patient morbidity. Better clinical recognition of this entity, multidisciplinary patient assessment, and deeper understanding of the underlying pathophysiology are essential to improve patient care and disease outcomes. It is important to distinguish primary intraepithelial/micro-invasive EMPD from invasive EMPD or cases with adenocarcinoma arising within EMPD. This 2-part continuing medical education series provides a complete picture of EMPD. Part 1 of this continuing medical education series reviews the epidemiology, oncogenesis, clinical and histopathologic presentation, workup, and prognosis of this rare cancer.

Lupus Erythematosus Tumidus as a Distinct Uncommon Subtype of Cutaneous Lupus Erythematosus: A Case Report and Review.

Lupus erythematosus tumidus (LET) is an uncommon but distinct photosensitive subtype of cutaneous lupus erythematosus (CLE). It differs from discoid and subacute cutaneous lupus erythematosus (SCLE) clinically and pathologically. LET is marked by extreme photosensitivity and carries a much lower risk of progression to systemic disease. The differential diagnosis of LET includes polymorphic light eruption (PMLE) and Jessner's lymphocytic infiltration of the skin (JLIS) because of subtle alterations in the histopathology and the paucity of immunopathologic markers in LET. We report herein a case of LET with positive immunoglobulin (Ig) deposits on direct immunofluorescence (DIF) testing. LET resolved completely with strict sun avoidance and treatment with topical corticosteroids, without the sequelae of atrophy, scarring, or dyspigmentation.

Decoding Early Mycosis Fungoides: Histopathologic and Immunohistochemical Clues.

INTRODUCTION: Primary cutaneous lymphomas, notably mycosis fungoides (MF), present diagnostic challenges in recognizing early mycosis fungoides (eMF) due to their diverse clinical and histopathologic manifestations. The aim of our study was to use adjunctive histopathologic and immunohistochemical methods in eMF cases to make an early diagnosis and to facilitate differentiation from other dermatoses. METHODS: This retrospective study analyzed 35 cases of eMF diagnosed at a single center. Demographic and clinicopathologic data were collected, and histopathologic features were assessed. Comparative analyses were conducted with conditions mimicking eMF, including large plaque parapsoriasis (LPP), psoriasis, and chronic dermatitis. Immunohistochemistry for T-cell markers (CD3, CD4, CD8, CD2, CD7) was performed. RESULTS: With the scoring we applied in our study, a sensitivity of 91.43% (95% CI; 76.94% to 98.20%) and specificity of 85.71% (95% CI; 69.74% to 95.19%) for distinguishing eMF from LPP. Epidermotropism emerged as a crucial histopathologic marker, with a notable absence in most cases of cutaneous dermatitis (81.6% and 80% for CD and psoriasis, respectively) (P < 0.001). Immunohistochemistry revealed a T-helper phenotype (CD4+/CD8-) in the majority of eMF cases (78.1%), while CD4+/CD8+ and CD8+/CD4- patterns were less common (28.5% and 8.5%, respectively). CONCLUSION: This study underscores the complexities in distinguishing eMF from inflammatory skin diseases, advocating for a comprehensive diagnostic approach.

The Relationship of Grade, Stage and Tobacco Usage in Head and Neck Squamous Cell Carcinoma With p53, PIK3CA and MicroRNA Profiles.

BACKGROUND:  Head and neck squamous cell carcinoma (HNSCC) has multiple epigenetic modifications including post-transcriptional regulation by microRNAs (miRNAs) as well as alterations in molecular pathways due to mutations. Examining these miRNAs and location-specific molecular alterations is essential to understanding the intricacies of HNSCC and directing focused diagnoses and treatments. AIM:  To investigate tobacco-related changes in the expression of miRNAs and proteins with clinicopathological parameters of HNSCC and disease-modifying personal habits like tobacco and alcohol use. METHODOLOGY:  The study concentrated on oropharyngeal cancers using immunohistochemistry and reverse transcription-polymerase chain reaction. Expression of microRNAs mir15a, mir20b, mir21, mir31, mir33b, mir146a, mir155, mir218, mir363 and mir497 and immunohistochemical expression of P53 and PIK3CA were correlated with grade, stage and personal habits like tobacco and alcohol intake. RESULTS:  mir21 and mir15a are under-expressed in higher grades with a trend towards statistical significance (P-value of 0.094 and 0.056 by one-way analysis of variance (ANOVA) on ΔCT values). mir155 and mir146a are overexpressed in stage IV tumours while mir 31 is under-expressed in stage IV tumours but statistical significance was not reached. mir497 showed overexpression in tobacco users, but these results were limited by many tumours not showing any amplification for the miRNA and statistical significance was not reached. There was no statistically significant association found between immunohistochemical expression of p53 and PIK3CA with grade, stage or personal habits. CONCLUSION:  Through the deciphering of complex miRNA patterns and their relationships with clinicopathology, this study attempted to increase our understanding of HNSCC. Some candidate miRNAs showing probable association with grade, stage and personal habits were identified, but larger studies are needed to confirm or refute the importance of these miRNAs.

Application of Aquaporins as Markers in Forensic Pathology: A Systematic Review of the Literature.

The study of aquaporins (AQPs) in various forensic fields has offered a promising horizon in response to the need to have reliable elements for the identification of the manner of death and for the individuation of forensic markers for the timing of lesions and vitality of injury. In the literature, various tissues have been studied; the most investigated are the lungs, brain, kidneys, skin, and blood vessels. A systematic literature review on PubMed following PRISMA 2020 guidelines enabled the identification of 96 articles. In all, 34 of these were enrolled to identify Aquaporin-like (AQP-like) forensic markers. The analysis of the literature demonstrated that the most significant markers among the AQPs are as follows: for the brain, AQP4, which is very important in brain trauma and hypoxic damage; AQP3 in the skin lesions caused by various mechanisms; and AQP5 in the diagnosis of drowning. Other applications are in organ damage due to drug abuse and thrombus dating. The focus of this review is to collect all the data present in the literature about the forensic application of AQPs as forensic markers in the most important fields of application. In the current use, the individuation, validation, and application of markers in forensic investigation are very useful in real forensic applications in cases evaluated in court.

An Extremely Rare Case of Poorly Differentiated Thyroid Carcinoma Arising in Malignant Struma Ovarii and Concurrent Papillary Thyroid Carcinoma: A Case Study.

Ovarian tumors can be classified by their origin - epithelial tumors, germ cell tumors, and stromal tumors. Malignant struma ovarii (MSO) are 0.01% of all ovarian tumors. In order to be classified as a struma ovarii, more than 50% of the teratoma consists of thyroid tissue. The thyroid tissue in the struma ovarii exhibits the same histological and physiological properties as that of the cervical thyroid tissue. Poorly differentiated thyroid carcinoma (PDTC) is an extremely rare occurrence when arising from an MSO. Including this case report, there are only 10 reports of PDTC in the setting of MSO. Of these cases, this patient is the only one who presented with concurrent primary thyroid carcinoma (PTC). This case study examines how invaluable intra-professional collaboration is for appropriate diagnosis, along with attention to detail of identifying markers in pathology sections and use of the appropriate immunohistochemical analysis.

STUDY OF THE INFLUENCE OF LINDANE AND SODIUM BICHROMATE ON THE MYOCARDIUM.

OBJECTIVE: Aim: The aim of the research is to study the immunohistochemical markers of the endothelium of blood vessels and myocardial ventricles under chronic exposure to sodium bichromate and lindane, as well as in conjunction with damaging biochemical agents contained in the blood. PATIENTS AND METHODS: Materials and Methods: The object of the experiment was outbred white mice (males). The study was carried out in 3 groups: 1st group - control, 2nd group - exposure to sodium bichromate 5 mg/kg, 3rd group - exposure to organochlorine pesticide lindane 100 mg/kg. In this experiment authors used the next methods: immunohistochemical method., biochemical research, statistical analysis. RESULTS: Results: The data obtained from an experimental study show that the level of cardiomarkers in blood plasma is characterized by different changes when exposed to these two compounds. Basically, the predominance of the effect of sodium bichromate on the LDH level is noted as compared to the effect of lindane; on the CK-MB level, their effects were the same, i.e., there is an increase in their level in blood plasma. CONCLUSION: Conclusions: Thus, long-term exposure to sodium bichromate leads to the activation of angiogenesis, destruction of the integrity of the endothelium, and this, in turn, leads to reparative changes located around in the myocardial cells.

Correlations between Immune Response and Etiopathogenic Factors of Medication-Related Osteonecrosis of the Jaw in Cancer Patients Treated with Zoledronic Acid.

Impairment of the immune response in MRONJ (medication-related osteonecrosis of the jaws) is one of the still unclear etiopathogenic mechanisms of this condition encountered in cancer patients treated with bisphosphonates, with negative effects on the patient's quality of life. The aim of the present study was to correlate the immune response with etiopathogenic factors via immunohistochemical evaluation of the maxillary tissues in zoledronic acid osteonecrosis. The retrospective study included a group of 51 patients with various types of cancers, diagnosed with stage 2 or 3 MRONJ at zoledronic acid and treated surgically. Immunohistochemical expressions of αSMA, CD3, CD4, CD8, CD20, CD79α, CD68, CD204, and tryptase were evaluated. Immunohistochemical markers expressions were statistically analyzed according to the duration of the treatment, the trigger factor, the location of the MRONJ, and the healing status. Analysis of the immune response included T lymphocytes, B lymphocytes, plasma cells, macrophages, and mast cells. The duration of treatment significantly influenced the immunohistochemical expression of most markers (p < 0.05). For an increasing trend in treatment duration, a decreasing trend in marker score was observed, suggesting an inverse correlation. The expression of the markers was different depending on the trigger factor, on MRONJ localization (maxilla/mandible), and the healing status, being more intense in patients cured per primam compared to those who had relapses. The patient's immune response was negatively influenced by the duration of the treatment, the trigger factor, the location of the lesion in the mandible, and the recurrence of MRONJ.

Oxidative Stress Markers in Human Brain and Placenta May Reveal the Timing of Hypoxic-Ischemic Injury: Evidence from an Immunohistochemical Study.

During pregnancy, reactive oxygen species (ROS) serve as crucial signaling molecules for fetoplacental circulatory physiology. Oxidative stress is thought to sustain the pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE). A retrospective study was performed on the brains and placentas of fetuses and newborns between 36-42 weeks of gestation (Group_1: Fetal intrauterine deaths, Group_2: Intrapartum deaths, Group_3: Post-partum deaths, Control group sudden neonatal death); all groups were further divided into two subgroups (Subgroup_B [brain] and Subgroup_P [placenta]), and the study was conducted through the immunohistochemical investigations of markers of oxidative stress (NOX2, 8-OHdG, NT, iNOS), IL-6, and only on the brain samples, AQP4. The results for the brain samples suggest that NOX2, 8-OHdG, NT, iNOS, and IL-6 were statistically significantly expressed above the controls. iNOS was more expressed in the fetal intrauterine death (Group_1) and less expressed in post-partum death (Group_3), while in intrapartum death (Group_2), the immunoreactivity was very low. IL-6 showed the highest expression in the brain cortex of the fetal intrauterine death (Group_1), while intrapartum death (Group_2) and post-partum death (Group_3) showed weak immunoreactivity. Post-partum death (Group_3) placentas showed the highest immunoreactivity to NOX2, which was almost double that of the fetal intrauterine death (Group_1) and intrapartum death (Group_2) placentas. Placental tissues of fetal intrauterine death (Group_1) and intrapartum death (Group_2) showed higher expression of iNOS than post-partum death (Group_3), while the IL-6 expression was higher in the fetal intrauterine death (Group_1) than the post-partum death (Group_3). The AQP4 was discarded as a possible marker because the immunohistochemical reaction in the three groups of cases and the control group was negative. The goal of this study, from the point of view of forensic pathology, is to provide scientific evidence in cases of medical liability in the Obstetric field to support the clinical data of the timing of HIE.

SLUG and SNAIL as Potential Immunohistochemical Biomarkers for Renal Cancer Staging and Survival.

Renal cell carcinoma (RCC) is the deadliest urological neoplasm. Up to date, no validated biomarkers are included in clinical guidelines for the screening and follow up of patients suffering from RCC. Slug (Snail2) and Snail (Snail1) belong to the Snail superfamily of zinc finger transcriptional factors that take part in the epithelial-mesenchymal transition, a process important during embryogenesis but also involved in tumor progression. We examined Slug and Snail immunohistochemical expression in patients with different stages of renal cell carcinomas with the aim to investigate their potential role as staging and prognostic factors. A total of 166 samples of malignant renal cell neoplasms were analyzed using tissue microarray and immunohistochemistry. Slug and Snail expressions were evaluated qualitatively (presence or absence), in nuclear and cytoplasmic cell compartments and compared in relation to clinical parameters. The Kaplan-Meier survival analysis showed the impact of the sarcomatoid component and Slug expression on the survival longevity. Cox regression analysis separated Slug as the only independent prognostic factor (p = 0.046). The expression of Snail was associated with higher stages of the disease (p = 0.004), especially observing nuclear Snail expression (p < 0.001). All of the tumors that had metastasized showed nuclear immunoreactivity (p < 0.001). In clear cell RCC, we showed a significant relationship between a high nuclear grade and nuclear Snail expression (p = 0.039). Our results suggest that Slug and Snail could be useful immunohistochemical markers for staging and prognosis in patients suffering from various RCCs, representing potential targets for further therapy strategies of renal cancer.

Recurrent Metastatic Colorectal Adenocarcinoma to the Thyroid Gland Presenting With Vocal Cord Paralysis and Inspiratory Stridor.

The most common sites for metastases of colorectal cancer include the liver, lungs, brain, and regional lymph nodes. However, a limited number of reported cases describe colon cancer metastasis to the thyroid gland. Metastatic colorectal adenocarcinoma to the thyroid gland is rare. The majority of these cases with colon cancer metastases to the thyroid gland are diagnosed years after initial treatment of colon cancer. The discovery is usually made after routine surveillance imaging, and often patients have minimal or absent symptoms. We report a case of a recurrence of metastatic colorectal adenocarcinoma to the thyroid gland presenting with vocal cord paralysis and inspiratory stridor.

Duodenal Metastasis From Primary Lung Adenocarcinoma: A Diagnostic and Therapeutic Challenge.

Distant metastasis from primary lung cancer is mostly seen in the liver, brain, adrenal glands and bones. Small bowel, specifically duodenum is a relatively unusual site for distant metastasis from lung carcinoma. This case reports a rare scenario of upper gastrointestinal bleeding caused by duodenal metastasis by a primary lung adenocarcinoma. A 43-year-old woman presented to the emergency department with complaints of progressive hemoptysis for the past three weeks. Esophagogastroduodenoscopy (EGD) revealed a 2.5 cm x 2.5 cm fungating villous mass-like structure in the first portion of the duodenum, with a normal-appearing esophagus and stomach. Biopsies were performed, which were histologically consistent with poorly differentiated malignant. The immunohistochemical (IHC) staining was consistent with metastatic disease from primary lung adenocarcinoma. Due to its rarity, there are no solidified guidelines for the management of duodenal metastasis from lung carcinoma. Our case was challenging due to the extensive metastasis and low functional status of the patient and was ultimately managed with home hospice.

New Insights and Evidence on "Food Intolerances": Non-Celiac Gluten Sensitivity and Nickel Allergic Contact Mucositis.

The clinical examination of patients often includes the observation of the existence of a close relationship between the ingestion of certain foods and the appearance of various symptoms. Until now, the occurrence of these events has been loosely defined as food intolerance. Instead, these conditions should be more properly defined as adverse food reactions (AFRs), which can consist of the presentation of a wide variety of symptoms which are commonly identified as irritable bowel syndrome (IBS). In addition, systemic manifestations such as neurological, dermatological, joint, and respiratory disorders may also occur in affected patients. Although the etiology and pathogenesis of some of them are already known, others, such as non-celiac gluten sensitivity and adverse reactions to nickel-containing foods, are not yet fully defined. The study aimed to evaluate the relationship between the ingestion of some foods and the appearance of some symptoms and clinical improvements and detectable immunohistochemical alterations after a specific exclusion diet. One hundred and six consecutive patients suffering from meteorism, dyspepsia, and nausea following the ingestion of foods containing gluten or nickel were subjected to the GSRS questionnaire which was modified according to the "Salerno experts' criteria". All patients underwent detection of IgA antibodies to tissue transglutaminase, oral mucosal patch tests with gluten and nickel (OMPT), and EGDS, including biopsies. Our data show that GSRS and OMPT, the use of APERIO CS2 software, and the endothelial marker CD34 could be suggested as useful tools in the diagnostic procedure of these new pathologies. Larger, multi-center clinical trials could be helpful in defining these emerging clinical problems.

DIAGNOSTIC UTILITY OF IMMUNOHISTOCHEMICAL EXPRESSION OF KI!67, P63 AND AMACR IN PROSTATE INTRAEPITHELIAL NEOPLASIA.

OBJECTIVE: The aim: To determine malignant transformation and progression ability of high grade and low grade prostate intraepithelial neoplasia with the help of immunohistochemical method. PATIENTS AND METHODS: Materials and methods: The results of examination of 93 patients with PIN (50 patients with high grade PIN and 43 patients with low grade PIN) were assessed comparatively using immunohistochemical markers. Semiquantitative method was used to evaluate !"-67, #63 and AMACR tissue expression with four grades from "+" to "++++" or from 1 to 4 points: '+' - low reaction, '++' - poor reaction, '+++' - moderate reaction and '++++" - intense reaction. RESULTS: Results: There were statistically significant differences in immunohistochemical expression rates between HGPIN and LGPIN. Patients with HGPIN had higher Ki-67 and AMACR expression rate and lower p63 expression rate than patients with LGPIN. Intense and moderate Ki-67 expression was detected in HGPIN more often, in 24 % and 11 % respectively. Low and moderate AMACR expression was determined in HGPIN more often, in 28 % and 5 % respectively. Low and not evident p63 expression was observed in HGPIN more often, in 36 % and 8 % respectively. CONCLUSION: Conclusions: HGPIN has common morphological peculiarities with prostate adenocarcinoma. Immunohistochemical detection of Ki-67, p63 and AMACR is aimed to differentiate among patients with PIN a group of high malignant transformation risk.

Significance of immunohistochemical markers in women with breast cancer.

Background and Aims: This study aimed to investigate the importance of immunohistochemical (IHC) markers and other prognostic variables in the definition of breast cancer. Patients and Methods: Two hundred female patients who underwent breast cancer surgery were classified into two groups according to age: young women (≤45 years; n = 104) and older women (≥65 years; n = 96). Molecular subtypes and local stages were determined. The Kaplan-Meier method was used to estimate the survival curves. The relationships among categorical variables were analyzed using the Chi-square test. Results: The difference between the tumor diameter and distribution of Ki-67 levels was significant (P = 0.001, P < 0.05). T stage, local stage, histological grade, estrogen receptor status, lymphovascular invasion status, axillary nodal state, human epidermal growth factor receptor 2 status, and distribution of molecular subtypes were correlated (P < 0.05). The mean disease-free survival rates (DFS) at 1, 2, and 5 years were found 92.9%, 86.5%, and 70.1%, respectively, in the young female group. The DFS rates of older patients were 96.7%, 95.4%, and 84.6%, respectively. Conclusion: This study showed that young age was associated with poor prognostic features at the IHC marker level.

PCSK9 regulates the efficacy of immune checkpoint therapy in lung cancer.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) secreted by tumors was reported as a deleterious factor that led to the reduction of lymphocyte infiltration and the poorer efficacy of ICIs in vivo. This study aimed to explore whether PCSK9 expression in tumor tissue could predict the response of advanced non-small cell lung cancer (NSCLC) to anti-PD-1 immunotherapy and the synergistic antitumor effect of the combination of the PCSK9 inhibitor with the anti-CD137 agonist. One hundred fifteen advanced NSCLC patients who received anti-PD-1 immunotherapy were retrospectively studied with PCSK9 expression in baseline NSCLC tissues detected by immunohistochemistry (IHC). The mPFS of the PCSK9lo group was significantly longer than that of the PCSK9hi group [8.1 vs. 3.6 months, hazard ratio (HR): 3.450; 95% confidence interval (CI), 2.166-5.496]. A higher objective response rate (ORR) and a higher disease control rate (DCR) were observed in the PCSK9lo group than in the PCSK9hi group (54.4% vs. 34.5%, 94.7% vs. 65.5%). Reduction and marginal distribution of CD8+ T cells were observed in PCSK9hi NSCLC tissues. Tumor growth was retarded by the PCSK9 inhibitor and the anti-CD137 agonist alone in the Lewis lung carcinoma (LLC) mice model and further retarded by the PCSK9 inhibitor in combination with the CD137 agonist with long-term survival of the host mice with noticeable increases of CD8+ and GzmB+ CD8+ T cells and reduction of Tregs. Together, these results suggested that high PCSK9 expression in baseline tumor tissue was a deleterious factor for the efficacy of anti-PD-1 immunotherapy in advanced NSCLC patients. The PCSK9 inhibitor in combination with the anti-CD137 agonist could not only enhance the recruitment of CD8+ and GzmB+ CD8+ T cells but also deplete Tregs, which may be a novel therapeutic strategy for future research and clinical practice.