Maximum Efficacy of Immune Checkpoint Inhibitors Occurs in Esophageal Cancer Patients With a Low Neutrophil-to-Lymphocyte Ratio and Good Performance Status Prior to Treatment.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) play an important role in the treatment of esophageal cancer (EC). However, few patients achieve long-term survival, and some patients develop serious immune-related adverse events (irAEs). Reliable predictive biomarkers of efficacy and safety need to be established in order to improve efficacy. We retrospectively analyzed the outcomes of nivolumab monotherapy on EC at Showa University, Department of Medicine, to identify biomarkers and characteristics of patients who benefit from ICI monotherapy. PATIENTS AND METHODS: Eighty-six patients with EC who received nivolumab monotherapy were included in the present study. Patient characteristics, efficacy, and safety were analyzed. A multivariable analysis evaluated the correlation among overall survival (OS), progression-free survival (PFS), best overall response (BOR), irAEs, and the following variables: sex, age, performance status (PS), neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP) level, albumin level, and body-mass index before treatment. RESULTS: Median PFS was 3.1 months, and median OS was 9.0 months. In multivariable analysis, pretreatment PS, NLR, and sex were significantly correlated with OS and PFS. NLR <3.3 predicted longer survival (median OS 17.5 vs. 6.4 months for NLR ≥3.3; p<0.001). Median OS was 10.6 months for PS 0-1 and 1.3 months for PS 2-3 (p<0.001). NLR remained significantly predictive in the PS 0-1 group. The development of irAEs was significantly associated with increased OS and PFS. CONCLUSION: Patients with low NLR and good PS before treatment may maximize the benefits of ICIs. A low NLR may be an indicator of higher immunocompetence for anti-tumor immunity, suggesting that NLR may be a convenient predictive biomarker in daily practice.

Isobutyric acid enhances the anti-tumour effect of anti-PD-1 antibody.

The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

Anti-EGFR antibody monotherapy for colorectal cancer with severe hyperbilirubinemia: A case report.

BACKGROUND: Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer (CRC). Effective drainage is often impossible before initiating systemic chemotherapy, owing to the liver's diffuse metastatic involvement. Moreover, an appropriate chemotherapeutic approach for the treatment of hyperbilirubinemia is currently unavailable. CASE SUMMARY: The patient, a man in his 50s, presented with progressive fatigue and severe jaundice. Computed tomography revealed multiple hepatic masses with thickened walls in the sigmoid colon, which was pathologically confirmed as a well-differentiated adenocarcinoma. No RAS or BRAF mutations were detected. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was 2. Biliary drainage was impossible due to the absence of a dilated bile duct, and panitumumab monotherapy was promptly initiated. Subsequently, the bilirubin level decreased and then normalized, and the patient's PS improved to zero ECOG score after four cycles of therapy without significant adverse events. CONCLUSION: Anti-EGFR antibody monotherapy is a safe and effective treatment for RAS wild-type CRC and hepatic metastases with severe hyperbilirubinemia.

Nivolumab receptor occupancy on effector regulatory T cells predicts clinical benefit.

Immune checkpoint inhibitor discovery represents a turning point in cancer treatment. However, the response rates of solid tumors remain ~10%-30%; consequently, prognostic and immune-related adverse event (irAE) predictors are being explored. The programmed cell death protein 1 (PD-1) receptor occupancy (RO) of PD-1 inhibitors depends on the number of peripheral blood lymphocytes and their PD-1 expression levels, suggesting that the RO may be related to efficacy and adverse events. As PD-1 inhibition affects each T-cell subset differently, the RO of each cell population must be characterized. However, relevant data have not been reported, and the prognostic relevance of this parameter is not known. In this study, we aimed to clarify the association between the nivolumab RO in each T-cell population and patient prognosis and reveal the development of irAEs in nivolumab-treated patients. Thirty-two patients were included in the study, and the mean follow-up period was 364 days. The nivolumab RO on effector regulatory T cells (eTregs) was significantly lower in the group that presented clinical benefits, and a significant negative association was observed between PD-1 occupancy on eTregs and all-cause mortality. The results suggest that the nivolumab RO on eTregs may be a prognostic factor in PD-1 inhibitor therapy, implying that the inhibition of PD-1/PD-ligand 1 (PD-L1) signaling on eTregs may attenuate antitumor effects.

Butyricimonas is a key gut microbiome component for predicting postoperative recurrence of esophageal cancer.

BACKGROUND: Recently, intestinal bacteria have attracted attention as factors affecting the prognosis of patients with cancer. However, the intestinal microbiome is composed of several hundred types of bacteria, necessitating the development of an analytical method that can allow the use of this information as a highly accurate biomarker. In this study, we investigated whether the preoperative intestinal bacterial profile in patients with esophageal cancer who underwent surgery after preoperative chemotherapy could be used as a biomarker of postoperative recurrence of esophageal cancer. METHODS: We determined the gut microbiome of the patients using 16S rRNA metagenome sequencing, followed by statistical analysis. Simultaneously, we performed a machine learning analysis using a random forest model with hyperparameter tuning and compared the data obtained. RESULTS: Statistical and machine learning analyses revealed two common bacterial genera, Butyricimonas and Actinomyces, which were abundant in cases with recurrent esophageal cancer. Butyricimonas primarily produces butyrate, whereas Actinomyces are oral bacteria whose function in the gut is unknown. CONCLUSION: Our results indicate that Butyricimonas spp. may be a biomarker of postoperative recurrence of esophageal cancer. Although the extent of the involvement of these bacteria in immune regulation remains unknown, future research should investigate their presence in other pathological conditions. Such research could potentially lead to a better understanding of the immunological impact of these bacteria on patients with cancer and their application as biomarkers.

Non-classical Monocytes Enhance the Efficacy of Immune Checkpoint Inhibitors on Colon Cancer in a Syngeneic Mouse Model.

BACKGROUND/AIM: The response rate to immune checkpoint inhibitors (ICIs) is approximately 10%-30% and only in a few cancer types. In the present study, we determined whether non-classical monocytes (NCMs) could enhance ICI efficacy in colon cancer using a syngeneic mouse model. MATERIALS AND METHODS: The MC38 C57BL/6 mouse colon cancer model was used. Cells collected from the bone marrow of C57BL/6 mice were cultured, and NCMs were fractionated by cell sorting and administered via the tail veins to the mice implanted with MC38 cells. The anti-mouse PD-L1 antibody was administered three times, and tumor volume and overall survival were observed. RESULTS: More tumors were eradicated and more complete response occurred, after cotreatment with ICIs and NCMs than after treatment with ICIs alone. Moreover, no efficacy was observed when NCMs were administered alone. CONCLUSION: NCMs enhance ICI efficacy. The underlying mechanisms and clinical applications will be studied in the future.

Novel quantitative immunohistochemical analysis for evaluating PD-L1 expression with phosphor-integrated dots for predicting the efficacy of patients with cancer treated with immune checkpoint inhibitors.

Introduction: Programmed cell death ligand 1 (PD-L1) expression in tumor tissues is measured as a predictor of the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in many cancer types. PD-L1 expression is evaluated by immunohistochemical staining using 3,3´-diaminobenzidine (DAB) chronogenesis (IHC-DAB); however, quantitative and reproducibility issues remain. We focused on a highly sensitive quantitative immunohistochemical method using phosphor-integrated dots (PIDs), which are fluorescent nanoparticles, and evaluated PD-L1 expression between the PID method and conventional DAB method. Methods: In total, 155 patients with metastatic or recurrent cancer treated with ICIs were enrolled from four university hospitals. Tumor tissue specimens collected before treatment were subjected to immunohistochemical staining with both the PID and conventional DAB methods to evaluate PD-L1 protein expression. Results: PD-L1 expression assessed using the PID and DAB methods was positively correlated. We quantified PD-L1 expression using the PID method and calculated PD-L1 PID scores. The PID score was significantly higher in the responder group than in the non-responder group. Survival analysis demonstrated that PD-L1 expression evaluated using the IHC-DAB method was not associated with progression-free survival (PFS) or overall survival (OS). Yet, PFS and OS were strikingly prolonged in the high PD-L1 PID score group. Conclusion: Quantification of PD-L1 expression as a PID score was more effective in predicting the treatment efficacy and prognosis of patients with cancer treated with ICIs. The quantitative evaluation of PD-L1 expression using the PID method is a novel strategy for protein detection. It is highly significant that the PID method was able to identify a group of patients with a favorable prognosis who could not be identified by the conventional DAB method.

Monocyte subsets associated with the efficacy of anti­PD­1 antibody monotherapy.

Immune checkpoint inhibitors (ICIs) are among the most notable advances in cancer immunotherapy; however, reliable biomarkers for the efficacy of ICIs are yet to be reported. Programmed death (PD)-ligand 1 (L1)-expressing CD14+ monocytes are associated with shorter overall survival (OS) time in patients with cancer treated with anti-PD-1 antibodies. The present study focused on the classification of monocytes into three subsets: Classical, intermediate and non-classical. A total of 44 patients with different types of cancer treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) were enrolled in the present study. The percentage of each monocyte subset was investigated, and the percentage of cells expressing PD-L1 or PD-1 within each of the three subsets was further analyzed. Higher pretreatment classical monocyte percentages were correlated with shorter OS (r=-0.32; P=0.032), whereas higher non-classical monocyte percentages were correlated with a favorable OS (r=0.39; P=0.0083). PD-L1-expressing classical monocytes accounted for a higher percentage of the total monocytes than non-classical monocytes with PD-L1 expression. In patients with non-small cell lung cancer (NSCLC), a higher percentage of PD-L1-expressing classical monocytes was correlated with shorter OS (r=-0.60; P=0.012), which is similar to the observation for the whole patient cohort. Comparatively, higher percentages of non-classical monocytes expressing PD-L1 were significantly associated with better OS, especially in patients with NSCLC (r=0.60; P=0.010). Moreover, a higher percentage of non-classical monocytes contributed to prolonged progression-free survival in patients with NSCLC (r=0.50; P=0.042), with similar results for PD-L1-expressing non-classical monocytes. The results suggested that the percentage of monocyte subsets in patients with cancer before anti-PD-1 monotherapy may predict the treatment efficacy and prognosis. Furthermore, more classical monocytes and fewer non-classical monocytes, especially those expressing PD-L1, are involved in shortening OS time, which may indicate the poor efficiency of anti-PD-1 treatment approaches.

Case Report: Combined pembrolizumab, 5-fluorouracil, and cisplatin therapy were remarkably effective in p16-positive squamous cell carcinoma of unknown primary.

Background: Cancer of unknown primary (CUP) is a malignant tumor without a known primary lesion with a frequency of 3-5%. It can be divided into favorable and unfavorable prognosis subsets. While recommended treatments are available for the former group, there is no established treatment for the latter. Here, we report the effective treatment of a 32-year-old woman with p16-positive squamous cell CUP with pembrolizumab plus 5-fluorouracil and cisplatin therapy. Case presentation: A 32-year-old woman presented with metastatic lesions in the liver, lung, bone, cervical region, abdominal region, and pelvic lymph nodes. She was diagnosed with p16-positive squamous cell carcinoma of unknown primary origin. The patient received pembrolizumab plus 5-fluorouracil and cisplatin therapy, which markedly reduced the metastasis and improved her Eastern Cooperative Oncology Group performance status after two courses. Conclusion: This case report highlights the potential of pembrolizumab plus 5-fluorouracil and cisplatin therapy for treating CUP with an unfavorable prognosis. p16 positivity is worth examining for squamous cell carcinoma of unknown primary origin, and if present, this therapy should be considered a promising treatment option.

Turicibacter and Acidaminococcus predict immune-related adverse events and efficacy of immune checkpoint inhibitor.

Introduction: Immune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown. Methods: We investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs). Results: The genera Prevotella and Parabacteroides were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of Catenibacterium (P = 0.022) and Turicibacter (P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of Desulfovibrion (P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of Turicibacter (P = 0.001) and Acidaminococcus (P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of Blautia (P = 0.013) and the unclassified Clostridiales (P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group, Acidaminococcus and Turicibacter (both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast, Blautia (P = 0.021) and Bilophila (P= 0.033) were statistically significantly more common in those without irAEs. Discussion: Our Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy.

A case of bronchial asthma as an immune-related adverse event of pembrolizumab treatment for bladder cancer: A case report.

RATIONALE: Bladder cancer is one of the most common cancers worldwide. The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab, which is an immune checkpoint inhibitor (ICI), has improved survival in bladder cancer. We report a case of bladder cancer that had a high antitumor effect with anti-programmed cell death PD-1 antibody pembrolizumab, an ICI, but asthma occurred an immune-related adverse event (irAE). PATIENT CONCERNS: A 70-year-old female patient was diagnosed as unresectable bladder cancer who was indicated for ICI treatment. DIAGNOSIS: After ICI administration as a treatment for bladder cancer, the patient had a grade 3 asthma attack. Cytotoxic T lymphocyte antigen 4 (CTLA-4) in CD4+ FOX3+ T cells was upregulated in the early phase before the development of asthma attacks. Moreover, T-cell immunoglobulin and mucin domain 3 (TIM-3) was upregulated in all memory T cells among CD4+ T cells. However, no change in the expression of TIM-3 was observed in any CD8+ T-cell subtype. In contrast, the proportion of CD161- T helper 17 cell (Th17) cells increased. INTERVENTIONS: The patient was treated with betamethasone, montelukast, salbutamol nebulization, and a combination of salmeterol (50 µg) and fluticasone (500 µg) (SFC). OUTCOMES: The patient's wheezing resolved, and her peak flow rate reached 100% of the predicted value; therefore, the patient continued treatment with SFC and montelukast and was discharged from the hospital. CONCLUSION: Increases in CTLA-4 and TIM-3 expression in CD4+ T cells (not CD8+), as well as an increase in Th17 cells, may reflect asthma-related inflammation activity. Immune-related adverse events during immune checkpoint inhibitor administration may be predictive markers of antitumor efficacy.

Increased Plasma Soluble PD-1 Concentration Correlates with Disease Progression in Patients with Cancer Treated with Anti-PD-1 Antibodies.

Immune checkpoint inhibitors (ICIs) confer remarkable therapeutic benefits to patients with various cancers. However, many patients are non-responders or develop resistance following an initial response to ICIs. There are no reliable biomarkers to predict the therapeutic effect of ICIs. Therefore, this study investigated the clinical implications of plasma levels of soluble anti-programmed death-1 (sPD-1) in patients with cancer treated with ICIs. In total, 22 patients (13 with non-small-cell lung carcinoma, 8 with gastric cancer, and 1 with bladder cancer) were evaluated for sPD-1 concentration using enzyme-linked immunosorbent assays for diagnostic and anti-PD-1 antibody analyses. sPD-1 levels were low before the administration of anti-PD-1 antibodies. After two and four cycles of anti-PD-1 antibody therapy, sPD-1 levels significantly increased compared with pretreatment levels (p = 0.0348 vs. 0.0232). We observed an increased rate of change in plasma sPD-1 concentrations after two and four cycles of anti-PD-1 antibody therapy that significantly correlated with tumor size progression (p = 0.024). sPD-1 may be involved in resistance to anti-PD-1 antibody therapy, suggesting that changes in sPD-1 levels can identify primary ICI non-responders early in treatment. Detailed analysis of each cancer type revealed the potential of sPD-1 as a predictive biomarker of response to ICI treatment in patients with cancer.

Antibiotic Usage Reduced Overall Survival by over 70% in Non-small Cell Lung Cancer Patients on Anti-PD-1 Immunotherapy.

BACKGROUND/AIM: There is an increasing use of immunotherapy for non-small cell lung cancer (NSCLC) patients. The present study analysed the effect of antibiotic use on the outcome of NSCLC patients undergoing treatment with anti-programmed cell death-1 (anti-PD-1) immunotherapy. PATIENTS AND METHODS: This was a retrospective study of 69 NSCLC patients. Eighteen out of 69 patients received antibiotics within 21 days before or within 21 days after start of anti-PD-1 therapy. RESULTS: Patients treated with anti-PD-1 antibodies receiving antibiotics had greatly decreased objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) compared to those who did not use antibiotics. Multivariate analysis showed that antibiotic treatment of patients on anti-PD-1 antibody therapy was an independent negative predictive factor of PFS; however, it was not a significant independent predictive factor of OS. CONCLUSION: Use of antibiotics within 21 days before and after anti-PD-1 treatment initiation in patients with NSCLC strongly reduced OS and PFS, suggesting the two treatments should not be combined.

Minimal contribution of the hepatic uptake transporter OATP1B1 to the inter-individual variability in SN-38 pharmacokinetics in cancer patients without severe renal failure.

PURPOSE: SN-38, a pharmacologically active metabolite of irinotecan, is taken up into hepatocytes by organic anion transporting polypeptide (OATP) 1B1. The effects of functional OATP1B1 521T>C on the pharmacokinetics of SN-38 remain controversial. Here, we prospectively examined the effects of OATP1B1 function on the area under the plasma total or unbound concentration-time curve (tAUC or uAUC) of SN-38 by assessing OATP1B1 521T>C and the plasma levels of endogenous OATP1B1 substrates, coproporphyrin (CP)-I and III, in cancer patients treated with irinotecan. METHODS: We enrolled cancer patients who were treated with an irinotecan-containing regimen and did not have severe renal failure. The total and unbound concentrations of SN-38 in the plasma were measured by high-performance liquid chromatography. AUC values were calculated and normalized to the actual irinotecan dose (AUC/dose). The OATP1B1 521T>C was analyzed by direct sequencing. Concentrations of the endogenous substrates in plasma before irinotecan treatment (baseline) were determined by liquid chromatography with tandem mass spectrometry. RESULTS: Twenty-two patients with a median estimated glomerular filtration rate of 74.8 mL/min (range 32.6-99.6) were examined. Both tAUC/dose and uAUC/dose were associated with the grade of neutropenia; however, they were not associated with OATP1B1 521T>C or baseline CP-I and III levels. It is worth noting that these baseline concentrations were significantly higher in patients with OATP1B1 521C, supporting functional changes in OATP1B1. CONCLUSION: The contribution of OATP1B1 activity to inter-patient variability in the systemic exposure to SN-38 is likely minimal in patients without severe renal failure.

A case report on severe nivolumab-induced adverse events similar to primary sclerosing cholangitis refractory to immunosuppressive therapy.

INTRODUCTION: Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death. PATIENTS CONCERNS: The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses. DIAGNOSIS: A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct. INTERVENTIONS: Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered. OUTCOMES: The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death. CONCLUSION: This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.

Examination of endobronchial ultrasound-guided transbronchial needle aspiration using a puncture needle with a side trap.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is useful for diagnosing hilar and mediastinal lymph node enlargement; however, specimens obtained are often small and inadequate for pathologic diagnosis. In June 2017, EchoTip ProCore, a puncture needle with a side trap, was launched in Japan. In this single-center prospective interventional study, 57 patients with lymph nodes, intrapulmonary tumor or pleural mass were diagnosed using EBUS-TBNA with EchoTip ProCore between June 2017 and February 2020. EBUS-TBNA was performed for 57 patients and 53 patients had sufficient specimen for histologic diagnosis. The following pathologic subtypes were diagnosed: non-small cell lung cancer, 22; small cell lung cancer, 8; cancer of unknown primary, 2; neuroendocrine tumor (G2) recurrence, 1; lymphoma, 2; metastatic renal cell carcinoma, 3; thymoma recurrence, 1; sarcoidosis, 4; tuberculosis, 1; and non-malignancy, 9. In addition, the cytology showed Class V in 31 out of 57 cases (54.4%). In total, a definitive pathological diagnosis was obtained in 50 out of 57 cases (87.7%). The only complication was pneumonia caused by BAL simultaneously combined with EBUS-TBNA in one patient. Among 13 patients with inadequate specimens or without malignancy, only one patient was subsequently diagnosed with malignancy, and the median follow-up period was 300 days. EBUS-TBNA using EchoTip ProCore can obtain a sufficient specimen size for pathologic diagnosis.

Rare Nivolumab-associated Super Hyper Progressive Disease in Patients With Advanced Gastric Cancer.

BACKGROUND/AIM: Rapid tumor growth after administration of immune checkpoint inhibitors is designated hyper progressive disease (HPD). In this study, besides the conventional HPD category, we proposed the "super HPD" category where the disease is naturally rapidly growing. PATIENTS AND METHODS: Patients treated for advanced gastric cancer with irinotecan or nivolumab as a third-line treatment were retrospectively compared. RESULTS: Eighteen and 26 patients were treated with irinotecan or nivolumab, respectively. There were 3 HPD cases (16.7%) in the irinotecan group, 6 cases (23.1%) in the nivolumab group, and the frequency of HPD was not significantly different. Two cases satisfied the super HPD definition only in the nivolumab group. When one of them was analyzed immunologically, the number of regulatory T cells was found to be increased, resulting in a low neutrophil-to-lymphocyte ratio. CONCLUSION: Our proposed super HPD was likely to represent a true HPD, with a frequency of 7.7%.

The Prognostic Impact of Eosinophils and the Eosinophil-to-Lymphocyte Ratio on Survival Outcomes in Stage II Resectable Pancreatic Cancer.

OBJECTIVES: The relationship between eosinophils and cancer prognosis is unknown. Therefore, we analyzed the relationship between circulating eosinophils and the survival of stage IIA and IIB pancreatic cancer patients who underwent surgical resection. METHODS: This study included a retrospective cohort of 67 consecutive patients. Patients were categorized into two different groups based on the optimal cutoff for pretreatment levels of each biomarker, according to the receiver operating characteristic curves. RESULTS: The Kaplan-Meier method showed that low eosinophil (P = 0.0403), high neutrophil (P = 0.0066), and high monocyte (P = 0.0003) counts were associated with short overall survival (OS). Low lymphocyte-to-monocyte ratio (P = 0.0194) and eosinophil-to-lymphocyte ratio (ELR) (P = 0.0413) were associated with reduced OS. In multivariate analysis, histological differentiation (P = 0.0014), high neutrophils (P = 0.047), high monocytes (P = 0.029), and low eosinophils (P < 0.0001) were correlated with poorer OS. Histological differentiation (P = 0.033), low lymphocyte-to-monocyte ratio (P = 0.029), and low ELR (P = 0.005) were correlated with poor OS and were significant independent prognostic factors of poor outcomes. CONCLUSIONS: Low eosinophils and low ELR were significant independent prognostic factors of poor outcomes.

A high number of PD-L1+ CD14+ monocytes in peripheral blood is correlated with shorter survival in patients receiving immune checkpoint inhibitors.

PURPOSE: Targeting of anti-programmed cell death protein-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) is a standard therapeutic strategy for various cancers. The aim of the present study was to investigate the prognostic effect of pretreatment PD-L1 expression levels in peripheral blood mononuclear cell (PBMC) subsets for patients with several cancer types receiving anti-PD-1 blockade therapies. PATIENTS AND METHODS: Thirty-two patients undergoing anti-PD-L1 blockade therapy, including 15 with non-small cell lung cancer, 14 with gastric cancer, 1 with melanoma, 1 with parotid cancer, and 1 with bladder cancer, were recruited for the present study. PD-L1 expression levels in CD3+, CD4+, CD8+, CD45RA+ and CCR7+ T cells; CD20+ B cells; CD14+ and CD16+ monocytes were measured via flow cytometry before treatment. The percentages of PD-L1+ cells in respective PBMC subsets were compared with respect to different clinicopathological conditions and the association with overall survival (OS) was assessed. RESULTS: The percentages of PD-L1+ with CD3+, CD4+ and CD8+ T cells including naïve and memory T cell subsets, or CD20+ B cells during pretreatment were not markedly correlated with the OS of patients (p > 0.05); however, the percentage of the PD-L1+ CD14+ monocyte subset was significantly correlated with OS (p = 0.0426). CONCLUSION: Increase in pretreatment expression levels of PD-L1 on CD14+ monocytes is associated with the OS of patients treated with immune checkpoint inhibitors. Further evaluation of large sample size and each specific cancer type might clarify the predictive role of PBMC in patients.

High levels of human epididymis protein 4 mRNA and protein expression are associated with chemoresistance and a poor prognosis in pancreatic cancer.

Pancreatic cancer is associated with an exceedingly poor prognosis, warranting the development of novel therapeutic strategies and discovery of prognostic predictors. Given that chemoresistance­related molecules are reportedly associated with the poor prognosis of pancreatic cancer, the present study aimed to identify molecules that could be efficacious therapeutic targets for pancreatic cancer. First, 10 patient­derived xenografts (PDXs) were established from patients with pancreatic cancer. Subsequently, after treating tumor tissue generated from the PDXs with standard drugs, next­generation sequencing (NGS) was performed using these tissues. The results of NGS analysis and immunohistochemical analysis on 80 pancreatic cancer tissues revealed that human epididymis protein 4 (HE4) expression in the anticancer drug­treated PDX group was higher than that in the untreated PDXs. In addition, chemoresistance ability was observed in tumor cell lines overexpressing HE4. Furthermore, Kaplan­Meier analysis of tumor tissues from 80 patients with pancreatic cancer was performed and it was found that patients with a high HE4 expression level had a poor survival rate compared with those who had a low HE4 expression level. Multivariate analysis also indicated the high expression level of HE4 was an independent poor prognostic biomarker. Thus, it was concluded that high gene and protein expression levels of HE4 mediate chemoresistance and are independent prognostic factors for pancreatic cancer.