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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., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Recent advances in chemotherapy have made significant progress in conversion surgery (CS) for unresectable pancreatic cancer (uPC). However, the success rate and efficacy of CS have not been fully demonstrated in patients with uPC treated with FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP)., Patients and Methods: We retrospectively reviewed the records of 318 patients with uPC who received FFX or GnP as first-line chemotherapy. The efficacy in the CS group, defined as undergoing complete resection after chemotherapy, was analyzed, and compared with the non-CS group; then, contributing factors to achieving CS were extracted. We also analyzed differences in the efficacy of CS between locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC)., Results: Overall, CS was achieved in 4.3% of cases, eight patients (13.3%) with LAPC and five (2.1%) with MPC. Contributing factors to CS were LAPC, no liver metastasis, CA19-9 ≤37, and chemotherapy response. After adjusting for these, overall survival was significantly better in the CS group than in the non-CS group [median of 32.9 vs. 11.3 months; adjusted hazard ratio (HR)=0.32; 95% confidence interval (CI)=0.14-0.70; p<0.01]. Median relapse-free survival duration after CS was 19.1 and 18.1 months in the LAPC-CS and MPC-CS group, respectively (p=0.84). The median post-conversion survival was 27.6 months in the entire CS group, 43.8 months in the LAPC-CS group and 21.3 months in the MPC-CS group., Conclusion: CS was achieved in 13.3% of LAPC and 2.1% of MPC cases. If possible, CS can markedly improve prognosis, even in MPC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The aim of the study was to evaluate gemcitabine plus nanoparticle albumin-bound paclitaxel (GnP) and FOLFIRINOX for recurrent pancreatic cancer (rPC) after resection., Patients and Methods: Forty-four patients with rPC and 211 with de novo metastatic pancreatic cancer (mPC) who received GnP or FOLFIRINOX as first-line chemotherapy were retrospectively analyzed., Results: On crude analysis, the median overall survival (OS) was significantly longer in the rPC group than in the mPC group (14.0 vs. 10.6 months, respectively; p=0.02). However, the difference was not significant on adjusted analysis using the Cox proportional hazards model (adjusted p=0.90). Patients receiving FOLFIRINOX (n=10) and GnP (n=34) in the rPC group had comparable OS (medians, 12.2 vs. 14.4 months, respectively; p=0.82) even after adjusting for covariates using the Cox model (adjusted p=0.18)., Conclusion: The outcomes of patients in the rPC and mPC groups were comparable following chemotherapy. Both FOLFIRINOX and GnP may be reasonable options for treating rPC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: Patients with triple-negative breast cancer (TNBC) who have not achieved pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) were considered for adjuvant capecitabine. This study was to explore the utility of the Neo-Bioscore in guiding post-surgical therapy in TNBC., Patients and Methods: The Neo-Bioscore was calculated for patients with non-metastatic primary breast cancer who received NAC at National Cancer Center Hospital East, Japan., Results: A total of 329 patients were evaluated. The Neo-Bioscore stratified prognosis after NAC better than clinical or pathological stage. The Neo-Bioscore performed well in the selection of patients with TNBC with excellent prognoses despite non-pCR; no death was observed in patients who had a Neo-Bioscore of 2, the lowest score in those with TNBC., Conclusion: The Neo-Bioscore can improve the prognostic stratification of patients after NAC for breast cancer over clinical and pathological staging and may enable the identification of patients with non-pCR TNBC who can avoid additional adjuvant chemotherapy., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Albumin-bilirubin (ALBI) grade is an indicator of liver dysfunction and is useful for predicting postoperative prognosis of hepatocellular carcinomas. However, the significance of ALBI grade in non-small cell lung carcinoma (NSCLC) has not been elucidated., Patients and Methods: We analyzed 947 patients with pStage IA-IIIA NSCLC. We divided patients into ALBI grade 1 and grade 2/3 groups. We then analyzed the association of ABLI grade with clinicopathological characteristics and prognosis in NSCLC by using propensity-score matching., Results: ALBI grade 2/3 was significantly associated with older age, male sex, advanced pT status, and histological type. Even after propensity-score matching, ALBI grade 2/3 patients had significantly worse cancer-specific survival (CSS) than ALBI grade 1 patients (5-year CSS: 87.3% versus 92.8%; p=0.0247). In multivariate analysis, ALBI grade 2/3 was an independent predictor of CSS (HR=1.9; 95%CI=1.11-3.11; p=0.0177)., Conclusion: ALBI grade was an independent prognostic factor in surgically resected NSCLC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Although neurokinin-1 receptor antagonists are approved chemotherapy drugs in Japan, no nationwide surveys have been performed to validate chemotherapy-induced nausea and vomiting (CINV) guidelines in clinical practice. This study evaluated CINV in patients with haematological malignancies starting first-time chemotherapy., Patients and Methods: A nationwide CINV survey on patients with haematological malignancies was conducted at 118 institutions. Patients undergoing moderately emetic chemotherapy (n=17) and highly emetic chemotherapy (HEC; n=180) were compared., Results: Forty-one patients undergoing HEC received triple antiemetics. Female gender and young age were risk factors for early-phase nausea, while female gender remained a risk factor for late-phase nausea and vomiting. Among 125 patients receiving CHOP (doxorubicin, cyclophosphamide, vincristine, prednisone)-like regimens, complete response and complete control were increased in patients receiving triple antiemetics, compared to those with double antiemetics., Conclusion: Guideline compliance was very low. Although not statistically significant, there was a trend for reduced CINV and improved disease control for triple versus double antiemetics, suggesting that triple antiemetics should be considered for HEC, especially in young female patients with non-Hodgkin lymphoma receiving CHOP-like regimens., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The effects of oxidative stress on various carcinomas were reported in previous studies, but those in intrahepatic cholangiocarcinoma (ICC) have not been fully elucidated. The purpose of this study was, thus, to reveal the effects of oxidative DNA damage and repair enzymes on ICC., Materials and Methods: The levels of 8-hydroxydeoxyguanosine (8-OHdG) and 8-OHdG DNA glycosylase (OGG1) were immunohistochemically evaluated in specimens resected from 63 patients with ICC., Results: Low OGG1 expression was related to tumour depth T4 (p=0.04), venous invasion (p=0.0005), lymphatic vessel invasion (p=0.03), and perineural invasion (p=0.03). Compared to the high-OGG1-expression group, patients with low OGG1 expression had a significantly poorer prognosis (overall survival: p=0.04, recurrence-free survival: p=0.02). Unlike for OGG1, the expression levels of 8-OHdG showed no association with prognosis., Conclusion: Oxidative DNA damage and DNA repair enzymes may be closely related to ICC progression., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: This study was performed to evaluate the influence of the body mass index (BMI) on disease-free survival and overall survival (DFS and OS) in patients with resected non-small cell lung cancer (NSCLC)., Patients and Methods: Overall, 546 of 780 (70%) patients with stage I to III NSCLC who underwent surgical resection were randomly selected. The patients were subdivided into three groups: low BMI (<18.5 kg/m 2 ), normal BMI (18.5 to <25.0 kg/m 2 ), and high BMI (≥25.0 kg/m 2 ). Cox proportional hazards regression analyses were performed to identify variables associated with survival., Results: In all patients, a low BMI was an independent prognostic factor for both DFS and OS (p=0.0175 and p=0.0134, respectively). In patients with stage I, a low BMI was also an independent prognostic factor for both DFS and OS (p=0.0066 and p<0.0001, respectively)., Conclusion: A low BMI was an independent prognostic factor after surgical resection of stage I NSCLC. Molecular targeted therapies, such as epidermal growth factor receptor inhibitors, anaplastic lymphoma kinase-tyrosine kinase inhibitors, and immune checkpoint inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-L1) pathway have greatly improved the clinical course for patients with non-small cell lung cancer (NSCLC), especially advanced-stage NSCLC (1-7). However, lung cancer remains the leading cause of cancer-related death worldwide (8). Even in patients with stage I to IIIA NSCLC, the clinical course is unsatisfactory despite the fact that surgical resection is the main treatment option (9). Therefore, it is important to identify useful, simple, and inexpensive prognostic markers in patients with resectable NSCLC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The incidence of delayed chemotherapy-induced nausea and vomiting (CINV), especially nausea, in gynecologic cancer patients who receive paclitaxel and carboplatin (TC) chemotherapy is unclear. We assessed risk factors for delayed CINV in these patients, and examined whether it was controlled with combination antiemetic therapy., Materials and Methods: Data were pooled from two prospective studies, and compared between the two antiemetic prophylaxis groups using inverse probability of treatment weighted (IPTW) analysis., Results: Among the 182 evaluable patients (mean age: 56.2 years), three antiemetics gave better overall control than two for delayed nausea (42.9% vs. 57.4%,) and vomiting (13.8% vs. 34.5%). Risk factor for delayed nausea was age [odds ratio (OR)=0.953; p=0.0898[and use of two antiemetics (vs. three antiemetics) for delayed vomiting (OR=0.304; p=0.0732)., Conclusion: A combination of three antiemetics controls delayed CINV among patients who undergo TC chemotherapy. Identification of risk factors can facilitate personalized treatments., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: To investigate the role of programmed cell death-ligand 2 (PD-L2) expression as a predictive biomarker for response to anti-programmed cell death-1 (PD-1) drugs in patients with non-small cell lung cancer (NSCLC)., Patients and Methods: Ten patients who had undergone curative lung resection and received the anti-PD-1 drugs for the recurrence were enrolled. The cut-off value for PD-L2 (antibody clone 176611) expression on tumor cells was set at 50%. Tumor response was evaluated according to immune-related response criteria., Results: Seven patients (70.0%) were positive for PD-L2. The response rates were 28.6% (2/7) and 33.3% (1/3) in patients with PD-L2-positive and PD-L2-negative NSCLC, respectively. Disease control was obtained in 2 patients despite the programmed cell death-ligand 1 (PD-L1)-negativity (antibody clone 22C3: 0%, antibody clone SP142: 0%), and these tumors expressed PD-L2 (≥1%)., Conclusion: PD-L2 expression may be a target of immunotherapy in patients with PD-L1-negative NSCLC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: A combination of immune-checkpoint inhibitors that target the programmed cell death 1 (PD1)/programmed cell-death ligand 1 (PDL1) pathway and indoleamine 2,3-dioxygenase 1 (IDO1) is a promising treatment for non-small-cell lung cancer. Herein, we investigated clinical features of IDO1 + /PDL1 + primary lung adenocarcinoma., Materials and Methods: IDO1 and PDL1 expression in 388 resected primary lung adenocarcinoma samples was evaluated using immunohistochemistry, and the radiological features of patients with IDO1 + /PDL1 + lung adenocarcinoma were analyzed., Results: Of 388 specimens, 229 (59.0%) were IDO1 + , 131 (33.8%) were PDL1 + , and 109 (28.1%) were IDO1 + /PDL1 + In multivariate analysis, vascular convergence and the absence of surrounding ground glass opacity were significantly associated with IDO1 + /PDL1 + tumors. Fisher's exact test showed high consolidation/tumor ratio was also significantly associated with IDO1 + /PDL1 + tumors. Moreover, maximum standardized uptake in 18 F-fluorodeoxyglucose positron-emission tomography/computed tomography was significantly higher in patients with IDO1 + /PDL1 + tumors than in those with IDO1 - or PDL1 - tumors., Conclusion: IDO1/PDL1 co-expression was significantly related to radiological invasiveness and malignancy in lung adenocarcinoma. This study may help select patients likely to benefit from combination therapy using immune-checkpoint inhibitors., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: To investigate the radiological features on computed tomography (CT) of brain metastasis (BM) from epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC)., Patients and Methods: Thirty-four patients with NSCLC with BMs who underwent surgical resection of the BMs at the Department of Neurosurgery, Kyushu University from 2005 to 2016 were enrolled in the study. The EGFR statuses of the 34 BMs were investigated. Radiological features, including the number, size, and location of the tumor, were delineated by CT., Results: Patients with EGFR-mutated BMs had significantly higher frequencies of multiple metastases than those with the non-EGFR-mutated type (p=0.042). BMs harboring mutations in EGFR were more frequently observed in the central area of the brain compared to those without mutations in EGFR (p=0.037)., Conclusion: Careful follow-up of patients with EGFR-mutated NSCLC may be necessary given the high frequencies of multiple BMs and their location in the central area of the brain., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: This study aimed to clarify the predictive impact of visceral fat on response to bevacizumab in patients with metastatic colorectal cancer (mCRC)., Patients and Methods: Pretreatment computed tomography was used to measure visceral fat area (VFA) and patients with mCRC receiving first-line chemotherapy with/without bevacizumab were divided by median VFA value into two groups: high VFA and low VFA., Results: In the bevacizumab-treated group, patients with low VFA had significantly shorter overall survival (OS) than patients with high VFA in univariate (median=21.1 vs. 38.9 months; hazard ratio=1.70, 95% confidence interval=1.06-2.70, p=0.03) and multivariate analysis (hazard ratio=1.85, 95% confidence interval=1.15-3.03, p=0.01). No significant differences were seen in OS between groups treated with chemotherapy alone. The VFA had a marginally significant modifying effect on the relationship between bevacizumab and OS (p for interaction=0.07)., Conclusion: Our findings provide the first evidence that a low VFA might be a negative predictive marker for response to bevacizumab in patients with mCRC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Jumonji domain-containing 2B, JMJD2B, has been shown to play an important role in the pathogenesis of lung cancer cells. However, the significance of JMJD2B in patients with lung cancer remains to be elucidated., Patients and Methods: Seventy-eight patients with resected adenocarcinoma, whose data regarding oncogenic drivers in lung cancer were available, were included in the study. Immunohistochemical analysis was performed with a specific antibody for JMJD2B to investigate JMJD2B expression and the significance of JMJD2B expression in survival after surgery was evaluated., Results: Among the 78 patients, 50 (64%) exhibited JMJD2B immunopositivity. The overall survival (OS) of the 50 JMJD2B-positive patients after surgery was significantly inferior to that of the JMJD2B-negative patients (five-year survival=56.7% vs. 92.6%; log-rank: p=0.01). Multivariate analysis showed that JMJD2B positivity was an independent prognostic factor., Conclusion: JMJD2B may be a novel prognostic factor for resected lung adenocarcinoma., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: This study investigated the prevalence of chemotherapy-induced nausea and vomiting (CINV) in patients with hepatobiliary-pancreatic (HBP) cancer in a prospective nationwide survey., Patients and Methods: One hundred patients with HBP cancer (biliary tract cancer; n=70, hepatocellular carcinoma; n=20, and pancreatic cancer; n=10) who received chemotherapy for the first time were analyzed. Medical personnel were surveyed to examine the accuracy of their predicted frequency of CINV., Results: The compliance rate with the Japanese guideline with highly emetogenic chemotherapy was 36/89 (40%). Although the prevalence of CINV in patients with HBP cancer was significantly lower than that of the total 1,910 patients with cancer, the prevalence of delayed CINV in patients with HBP cancer was as high as 28%. The survey results suggested that the medical staff tended to overestimate the incidence of CINV., Conclusion: CINV appears to be controlled under management according to the guidelines, but delayed nausea remains prevalent and requires further investigation., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: To elucidate the causes of cancer death in Japanese families with Lynch syndrome (LS)., Methods: The distributions of cancer deaths in 485 individuals from 67 families with LS (35, 30, and two families with MutL homologue 1 (MLH1), MSH2, and MSH6 gene mutations, respectively), obtained from the Registry of the Japanese Society for Cancer of the Colon and Rectum were analyzed., Results: Among 98 cancer deaths of first-degree relatives of unknown mutation status, 53%, 19%, 13% (among females), 7% (among females) and 5% were due to colorectal, gastric, uterine, ovarian, and hepatobiliary cancer, respectively. The proportion of deaths from extra-colonic cancer was significantly higher in families with MSH2 mutation than in those with MLH1 mutation (p=0.003)., Conclusion: In addition to colonic and uterine cancer, management and surveillance targeting gastric, ovarian and hepatobiliary cancer are considered important for Japanese families with LS. Extra-colonic cancer in families with MSH2 mutation might require for more intensive surveillance., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

We describe a very rare case of recurrent hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT). A 47-year-old female underwent LDLT for HCC within Milan criteria, receiving a left liver lobe from her 38-year-old husband with an incompatible blood type. Thirty months after LDLT, however, enhanced computed tomography (CT) showed a tumor in her left adrenal gland; after another six months, enhanced CT and positron-emission tomography detected a frontal head bone tumor; enhanced CT performed 54 months after LDLT revealed a recurrent HCC in the liver graft. Each of these three tumors was surgically resected. Two months after hepatic partial resection, an enhanced CT showed another HCC in her liver graft, which was treated with local ablation therapy. One year after the last ablation treatment, the recipient is doing well without evidence of recurrence. At the time of detection of each of these tumors, the patient's serum concentration of hepatitis B virus surface antigen was elevated. Pathological examination showed that the resected tumors were moderately differentiated HCCs. Genotyping by microsatellite analysis confirmed their origin to be metastases of the primary HCC., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: The aim of the present study was to evaluate the feasibility of, and compliance with a regimen using split-dose cisplatin and vinorelbine (split-CV) as adjuvant chemotherapy in patients with completely resected non-small cell lung cancer (NSCLC)., Patients and Methods: The treatment schedule included cisplatin at 40 mg/m(2) and vinorelbine at 25 mg/m(2) administered intravenously on days 1 and 8, every three weeks for four cycles., Results: This study included 22 patients (male/female; 12/10) with a median age of 67 (range 50-76) years; 10 had clinical stage II and 12 stage III; 21 had ECOG 0 and 1 patient ECOG 1; 15 patients had adenocarcinoma, 5 squamous cell and 2 adenosquamous carcinoma; 18 patients had undergone lobectomy, 3 pneumonectomy and 1 segmentectomy. Seventeen out of 22 patients (77%) received the planned 4 cycles. The main adverse events were grade 3/4 neutropenia (76%) and anemia (12%). The average total doses of cisplatin and vinorelbine were 285 mg/m(2) and 177 mg/m(2), respectively., Conclusion: The split-CV regimen is well-tolerated as adjuvant chemotherapy for completely resected NSCLC.