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Abstract Intraperitoneal (IP) chemotherapy with paclitaxel (PTX) for gastric cancer (GC) with peritoneal metastasis (PM) is considered a promising treatment approach, however, there are no useful biomarkers to predict the efficacy of IP therapy. We examined the association between intra-peritoneal exosomes, particularly exosomal micro-RNAs (exo-miRNAs), and IP-chemo sensitivity. MKN45 cells that were cultured with intra-peritoneal exosomes from patients who did not respond to IP therapy with PTX (IPnon-respond group) exhibited resistance to PTX compared with exosomes from responding patients (IPrespond group) (p = 0.002). A comprehensive search for exo-miRNAs indicated that miR-493 was significantly up-regulated in exosomes from the IPnon-respond group compared with those collected from the IPrespond group. The expression of miR-493 in PTX-resistant MKN45 cells (MKN45PTX-res) was higher compared with that in MKN45. In addition, MKN45PTX-res cells exhibited lower MAD2L1 gene and protein expression compared with MKN45. Finally, miR-493 enhancement by transfection of miR-493 mimics significantly down-regulated MAD2L1 expression in MKN45 cells and reduced PTX sensitivity. Our results suggest that intra-peritoneal exo-miR-493 is involved in chemoresistance to PTX by downregulating MAD2L1 in GC with PM. Exo-miR-493 may be a biomarker for chemoresistance and prognosis of GC patients with PM and may also be a promising therapeutic target.

Background: The L-type amino acid transporter (LAT1) exhibits significantly increased expression within tumor cells across various neoplasms. However, the clinical significance of LAT1 expression in patients with pleural mesothelioma (PM) remains unclear. Methods: Eighty patients diagnosed with PM between June 2007 and August 2022, were eligible for this study. LAT1, alanine-serine-cysteine transporter 2 (ASCT2), Ki-67, and VEGFR2 were evaluated by immunohistochemistry. Inflammatory and nutritional indices were also correlated with different variables, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score (GPS). Results: LAT1 was highly expressed in 57.5 % of patients with PM. Among the 80 patients included in this study, 65 (81.3 %) received chemotherapy, either alone or followed by surgical resection, while 15 (18.7 %) opted for best supportive care. The level of LAT1 significantly correlated with cell proliferation and ASCT2. Factors such as performance status, histology, LAT1 expression, PNI, ALI, and GPS were significant prognostic indicators for progression-free survival (PFS), while Ki-67, LAT1, NLR, SII, PNI, ALI, and GPS were identified as significant predictors for overall survival (OS). LAT1 expression emerged as an independent prognostic factor for predicting PFS and OS in all patients, as well as in the subgroup of 65 patients receiving chemotherapy. Notably, high LAT1 expression proved to be a significant predictor of outcome, particularly in the subgroup with high PLR and SII. Conclusion: LAT1 was a significant predictor of outcomes in patients with PM and was more predictive of worse outcomes in patients with high inflammatory and low nutritional status.

Abstract Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p

Abstract Background Molecular abnormalities in the Wnt/β‐catenin pathway confer malignant phenotypes in lung cancer. Previously, we identified the association of leucine‐rich repeat‐containing G protein‐coupled receptor 6 (LGR6) with oncogenic Wnt signaling, and its downregulation upon β‐catenin knockdown in non‐small cell lung cancer (NSCLC) cells carrying CTNNB1 mutations. The aim of this study was to explore the mechanisms underlying this association and the accompanying phenotypes. Methods LGR6 expression in lung cancer cell lines and surgical specimens was analyzed using quantitative RT‐PCR and immunohistochemistry. Cell growth was assessed using colony formation assay. Additionally, mRNA sequencing was performed to compare the expression profiles of cells subjected to different treatments. Results LGR6 was overexpressed in small cell lung cancer (SCLC) and NSCLC cell lines, including the CTNNB1‐mutated NSCLC cell lines HCC15 and A427. In both cell lines, LGR6 knockdown inhibited cell growth. LGR6 expression was upregulated in spheroids compared to adherent cultures of A427 cells, suggesting that LGR6 participates in the acquisition of cancer stem cell properties. Immunohistochemical analysis of lung cancer specimens revealed that the LGR6 protein was predominantly overexpressed in SCLCs, large cell neuroendocrine carcinomas, and lung adenocarcinomas, wherein LGR6 overexpression was associated with vascular invasion, the wild‐type EGFR genotype, and an unfavorable prognosis. Integrated mRNA sequencing analysis of HCC15 and A427 cells with or without LGR6 knockdown revealed LGR6‐related pathways and genes associated with cancer development and stemness properties. Conclusions Our findings highlight the oncogenic roles of LGR6 overexpression induced by aberrant Wnt/β‐catenin signaling in lung cancer.

Abstract Background The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first‐line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non‐small cell lung cancer (NSCLC). Methods Our study comprised 288 patients with advanced NSCLC who received RD as the second‐line treatment after first‐line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum‐based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis. Results Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression‐free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD‐L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment. Conclusion Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second‐line RD treatment in patients with advanced NSCLC.

Abstract Circulating tumor DNA (ctDNA) provides molecular information on tumor heterogeneity. The prognostic usefulness of ctDNA after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are limited. Therefore, the present study evaluated ctDNA during osimertinib administration as a second-line or more setting to identify the relationship between EGFR mutation levels and outcomes in patients with advanced non-small cell lung cancer (NSCLC). Forty patients with EGFR T790M-positive NSCLC receiving osimertinib after prior EGFR-TKI treatment were registered. Plasma samples were collected at osimertinib pretreatment, after 1 month of treatment, and at the time of progressive disease (PD). ctDNA analysis was performed by digital polymerase chain reaction. The detection rate of copy numbers of exon 19 deletion, L858R, and T790M in plasma samples was significantly lower 1 month after osimertinib than at pretreatment, and significantly higher at PD than at 1 month, whereas that of C797S was significantly higher at PD than at 1 month. No statistically significant difference was observed in the copy numbers of exon 19 deletion, L858R, T790M, and C797S between complete response or partial response and stable disease or PD. The detection of T790M at PD after osimertinib initiation was a significant independent prognostic factor for predicting shorter prognosis, and the presence of major EGFR mutations at pretreatment and PD was closely linked to worse survival after osimertinib initiation. Molecular testing based on ctDNA is helpful for predicting outcomes of osimertinib treatment in T790M-positive NSCLC after previous EGFR-TKI treatment.

Abstract Background Vascular endothelial growth factor (VEGF) has been identified as one of the resistant mechanisms to epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs). However, the relationship between the efficacy of osimertinib and protein expression of VEGF family members in patients with advanced non‐small cell lung cancer (NSCLC) harboring EGFR mutations remains unclear. Methods A total of 76 patients with advanced NSCLC with EGFR major mutations (del19 or L858R) receiving first‐line osimertinib were eligible as the osimertinib (Osi) group, whereas 43 patients receiving first‐ or second‐generation EGFR‐TKIs were compared with the control group. The expression of vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial growth factor C (VEGF‐C) in the tumor specimens was analyzed using immunohistochemistry. Results VEGFR2 and VEGF‐C were highly expressed in 65.8% and 51.3% of patients, respectively, in the Osi group, and 69.7% and 76.7%, respectively, in the control group. High VEGFR2 and VEGF‐C levels were significantly associated with poor performance status (PS) and female sex, respectively. In the Osi group, patients with co‐high expression of VEGFR2 and VEGF‐C showed significantly worse progression‐free survival (PFS) and overall survival (OS) than those without co‐high expression. In del19, VEGFR2 was a significant predictor of PFS and OS and independent predictor of OS in multivariate analysis. In L858R, co‐high expression of VEGFR2 and VEGF‐C was identified as a significant predictor of PFS and OS and independent predictor of PFS. Conclusion VEGFR2 and VEGF‐C are highly expressed in EGFR‐mutant NSCLC cells. Increased expression of VEGFR2 was identified as a significant prognostic factor in patients with EGFR del19 mutation who received osimertinib, whereas co‐high expression of VEGFR2 and VEGF‐C was a significant predictor for those with EGFR L858R mutation.

Abstract Background Factors predicting the response to pembrolizumab plus platinum and pemetrexed combination therapy (Pemb‐Plt‐PEM) in nonsquamous non‐small cell lung cancer (non‐sq NSCLC) are unclear. We investigated the Glasgow Prognostic (GP) score, neutrophil‐to‐lymphocyte ratio (NLR), and body mass index (BMI) as predictors of response to initial treatment with combination therapy in individuals with advanced non‐sq NSCLC. Methods We retrospectively reviewed 236 patients who received initial treatment with combination therapy for non‐sq NSCLC at 13 institutions between December 2018 and December 2020. The usefulness of the GP score, NLR, and BMI as prognostic indicators was assessed. Cox proportional hazard models and the Kaplan–Meier method were used to compare progression‐free survival (PFS) and overall survival (OS). Results The response rate was 51.2% (95% CI: 44.9–57.5%). The median PFS and OS after beginning Pemb‐Plt‐PEM were 8.8 (95% CI: 7.0–11.9) months and 23.6 (95% CI: 18.7–28.6) months, respectively. The NLR independently predicted the efficacy of Pemb‐Plt‐PEM—the PFS and OS were more prolonged in individuals with NLR

Background: ALK-tyrosine kinase inhibitors (ALK-TKIs) are effective for treating non-small-cell lung cancer with ALK gene rearrangement; however, resistance is inevitable. Brigatinib is a unique ALK-TKI that is effective against many resistance mutations. However, data on factors associated with its efficacy and resistance mechanisms are limited. Objectives: This study will evaluate the efficacy and safety of brigatinib in the real world and explore factors related to its efficacy, safety, and resistance mechanisms. Design: Prospective observational study. Ethics: This study is approved by the Ethics Committee of Wakayama Medical University. Written informed consent will be obtained from all patients before study-related procedures. Methods and analysis: This study comprises three cohorts. Cohorts A, B, and 0 will enroll patients receiving alectinib as the first ALK-TKI, receiving alectinib as the first ALK-TKI and subsequently cytotoxic agents and/or lorlatinib after alectinib, and without a history of ALK-TKI, respectively. Overall, 100, 30, and 50 patients will be enrolled in Cohorts A, B, and 0, respectively. Circulating tumor DNA before starting brigatinib and at disease progression will be analyzed in all cohorts using a hypersensitive next-generation sequencing (NGS) PGDx Elio plasma resolve panel. Serum protein levels will be analyzed using the Milliplex xMAP assay system with a Luminex 200 (Luminex, Austin, USA). The enrollment period is 31 months and the patients will be observed for 2 years after enrollment. Archived tissues will be collected for NGS analysis, gene expression analysis, and immunohistochemistry staining 1 year after completion of registration. Quality of life and safety evaluation using electronic patient-reported outcomes will be investigated. Discussion: This study will elucidate predictors of ALK-TKI efficacy and resistance mechanisms and evaluate the efficacy and safety of brigatinib in a real-world setting. The results will provide crucial information for establishing treatment strategies, discovering novel biomarkers, and developing new therapeutic agents. Trial registration: UMIN000042439.

Abstract Purpose To compare different response criteria using computed tomography (CT) and positron emission tomography (PET) in measuring response and survival in the early phase after programmed death-1 (PD-1) blockade monotherapy in patients with advanced non-small cell lung cancer (NSCLC). Methods A total of 54 patients with advanced NSCLC who had 2-deoxy-2-[fluorine-18]-fluoro-D-glucose PET or CT at baseline, and 4 and 9 weeks after PD-1 blockade, were registered. Therapeutic response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), the immune-modified RECIST (irRECIST), the PET Response Criteria in Solid Tumors (PERCIST), the immune-modified PERCIST (iPERCIST), and the European Organization for Research and Treatment of Cancer (EORTC) criteria for dichotomous groups, such as responders vs. non-responders and controlled vs. uncontrolled diseases. Cohen’s κ was used to evaluate the concordance among the different criteria. Results The concordance between CT and PET response criteria was fair or slight for responders vs. non-responders, but the agreement between iPERCIST and irRECIST was moderate for controlled vs. uncontrolled diseases. The agreement between EORTC and PERCIST or iPERCIST in detecting responders was higher in the application of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) than in the standardized uptake value corrected for lean body mass (SUL)peak. To distinguish controlled from uncontrolled disease, RECIST, irRECIST, and PET criteria (PERCIST, iPERCIST, and EORTC) defined by MTV or TLG were found to be significant predictors of progression-free survival. To distinguish responders from non-responders, iPERCIST by SULpeak or EORTC by TLG were identified as significant indicators. The EORTC criteria using TLG for the detection of responders or uncontrolled diseases had a significantly higher predictive value for response assessment. Conclusions The EORTC criteria based on TLG for the early detection of responders and uncontrolled disease were effective as a response assessment at 4 weeks after the PD-1 blockade. When SULpeak was not used but MTV or TLG was, the agreement between EORTC and PERCIST or iPERCIST was almost perfect.

Key Clinical Message Although partial hepatic necrosis often occurs following endovascular treatment for bleeding associated with hepatic trauma, it is relatively rare that additional treatment is required. However, invasive procedures such as hepatic resection should sometimes be considered when infection occurs over massive hepatic necrosis. Abstract Although partial hepatic necrosis following endovascular treatment for bleeding associated with hepatic trauma is occasionally experienced, it is relatively rare for the necrotic area of the liver to require additional treatment. However, invasive procedures such as hepatic resection should sometimes be considered when infection occurs over massive hepatic necrosis.

Abstract Aim Tumor-infiltrating lymphocytes (TILs) in the tumor and stroma are expected to accurately predict the efficacy of programmed death-1 (PD-1) blockade therapy. However, little is known about the prognostic significance of TILs in first-line PD-1 therapy. We assessed TILs in patients with advanced or metastatic non-small cell lung cancer (NSCLC) treated with pembrolizumab in the palliative setting. Methods Multiplex immunohistochemistry staining of TILs (CD4, CD8, Foxp3, and PD-1) and immunohistochemical staining of CK and PD-L1 in the tumor and stroma was performed in tumor specimens of 107 NSCLC patients and correlated with clinical outcomes, as a single-center retrospective study. TILs and programmed death ligand-1 (PD-L1) were assessed on biopsies (N = 93) or surgical resections (N = 14) before first-line pembrolizumab. Results A low number of stromal CD4 TILs were significantly associated with bone metastasis and poor performance status (PS). The median progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with a high number of stromal CD4 TILs (336 days and 731 days, respectively) than in those with low infiltration (204 days and 333 days, respectively). Patients with a high number of intratumoral CD8 TILs (731 days) yielded significantly better OS than those with low infiltration (333 days), but not for PFS. Multivariate analysis confirmed that stromal CD4 TILs were independent predictors of PFS, but not OS. Furthermore, intratumoral CD8 TILs were independent predictors of better OS. In the survival analysis of key subgroups, stromal CD4 TILs were identified as significant predictors of survival in patients with non-adenocarcinomatous histology and PD-L1 ≥ 50%. Conclusion Stromal CD4 TILs were identified as a significant marker for predicting the PFS after pembrolizumab therapy, especially in patients with non-adenocarcinoma and high PD-L1 expression. In addition, intratumoral CD8 TILs were identified as significant predictors of OS.

Abstract Purpose The aim of this study was to assess the effectiveness and tolerability of atezolizumab plus carboplatin and etoposide combination chemotherapy in elderly patients with extensive‐disease (ED) small‐cell lung cancer (SCLC). Methods This retrospective study evaluated 65 SCLC patients who received atezolizumab, carboplatin, and etoposide for ED‐SCLC in nine study institutions between August 2019 and September 2020. Clinical efficacy, assessed according to response rate and survival, and toxicity were compared between the elderly (n = 36 patients; median age: 74 years [range: 70–89 years]) and the non‐elderly group (n = 29 patients; median age: 67 years [range: 43–69 years]). Results The response rate was 73.8% (80.5% in the elderly group and 65.5% in the non‐elderly group). There was no significant difference in both the median progression‐free survival (5.5 months vs. 4.9 months, p = 0.18) and the median overall survival (15.4 months vs. 15.9 months, p = 0.24) between the elderly group and the non‐elderly group. The frequencies of grade ≥3 hematological adverse events in the elderly patients were as follows: decreased white blood cells, 36.1%; decreased neutrophil count, 61.1%; decreased platelet count, 8.3%; and febrile neutropenia, 8.3%. One treatment‐related death due to lung infection occurred in the elderly group. Conclusion Despite hematologic toxicities, especially decreased neutrophil count, atezolizumab, carboplatin, and etoposide combination chemotherapy demonstrates favorable effectiveness and acceptable toxicity in elderly patients. Thus, atezolizumab plus carboplatin and etoposide could be the preferred standard treatment modality for elderly patients with ED‐SCLC.

Abstract Nivolumab, an immune checkpoint inhibitor is the first-line therapy for platinum-resistant recurrent/metastatic head and neck cancer, and highly effective for some patients. However, no factors have been identified that could predict response or prognosis after nivolumab administration. We retrospectively investigated the association between tumor infiltrating lymphocytes (TILs) of initial pathology and prognosis in patients treated with nivolumab. Twenty-eight patients with human papilloma virus and Epstein–Barr virus unrelated head and neck squamous cell carcinoma were enrolled. CD8+cells, FoxP3+cells and FoxP3−CD4+cells in the tumoral and peritumoral stromal area and PD-L1 were measured. In result, FoxP3−CD4+TIL, FoxP3+TIL, and CD8+TIL were not correlated with survival in either intratumoral and stromal area. In univariate analysis, objective response was significant prognostic factor both in progression-free survival and overall survival (p = 0.01, 0.006, respectively). PD-L1 was also significant prognostic factor both in progression-free survival and overall survival (p = 0.01, 0.01, respectively). ECOG Performance status was a significant prognostic factor in overall survival (p = 0.0009). In the combined analysis of stromal CD8+TIL and PD-L1, PD-L1 positive with high stromal CD8+TIL subgroups had a better prognosis than PD-L1 negative with low stromal CD8+TIL subgroups in progression-free survival (p = 0.006). Although these results require a further investigation, PD-L1 and ECOG Performance status and the combination of stromal CD8+TIL and PD-L1 positivity have potential as useful prognostic markers in patients of virus unrelated head and neck squamous cell carcinoma treated with nivolumab.

Abstract Background Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62LlowCD4+ T cells (effector T cells; %Teff) and CD4+CD25+FOXP3+ T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method. Here, we investigated the applicability of the formula (K-index) to predict the response to treatment with another ICI to expand its clinical applicability. Furthermore, we developed a simpler assay method based on whole blood (WB) samples to overcome the limitations of the PBMC method, such as technical difficulties, in obtaining the K-index. Methods The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer. Results This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation,

Abstract Background There are numerous indications for minimally invasive surgery. However, the laparoscopic approach for extended pelvic surgery is currently provided by only a few institutions specializing in cancer treatment, primarily because of technical difficulties that arise in cases involving a narrow pelvis and rigid forceps. We report a case of robot-assisted total pelvic exenteration for rectal cancer involving the prostate. We assessed the feasibility of robot-assisted total pelvic exenteration and compared the short-term outcomes of other conventional and minimally invasive approaches. Case presentation A 67-year-old man was referred to our hospital after positive fecal blood test results. The initial diagnosis was clinical T4bN2aM0, Stage IIIC rectal cancer involving the prostate. The patient underwent neoadjuvant chemoradiotherapy. Consequently, robot-assisted total pelvic exenteration with an ileal conduit and end colostomy creation were performed. The total operative duration was 9 h and 20 min. The durations of robot console usage by the colorectal and urological teams were 2 h 9 min and 2 h 23 min, respectively. The patient was discharged on postoperative day 21. The pathological diagnosis was T4b (prostate) N0M0, Stage IIC. The resection margin was 2.5 mm. During reassessment at 2 years after resection, no evidence of recurrence was observed. Conclusions Robot-assisted total pelvic exenteration was performed for a patient with advanced rectal cancer without serious complications. Robot-assisted total pelvic exenteration may provide the advantages of minimally invasive surgery, particularly in the enclosed space of the pelvis.

Abstract Background In this study, we developed a simple method for evaluating achievement degree of lung dose optimization in individual patients with locally advanced non‐small cell lung cancer (NSCLC) treated with intensity modulated radiotherapy (IMRT). Methods Data of 28 patients with stage IIB to IIIC NSCLC were retrospectively analyzed. All patients were treated with IMRT and a simulated three‐dimensional conformal radiotherapy (3D‐CRT) plan created for them. Dose‐volume parameters of lung were analyzed for their correlation with radiation pneumonitis (RP). Results Over a median follow‐up of 14 months, grade 1 pneumonitis was diagnosed in 14 patients (50%), grade 2 pneumonitis in 11 (39%), and grade 3 pneumonitis in one (4%). Two patients did not develop pneumonitis. None of the patients developed grade 4 or 5 pneumonitis. Regarding dose‐volume parameter ratios between IMRT and simulated 3D‐CRT, receiver operating characteristic analysis showed that mean lung dose (MLD)IMRT/MLD3D‐CRT had the largest area under curve (0.750). Cumulative 6‐month incidences of grade 2 or greater RP were 78.4% versus 19.5% (MLDIMRT/MLD3D‐CRT, ≥1.0 or less); this difference was significant (p

Abstract Background The effect of first‐line chemotherapy on overall survival (OS) may be significantly influenced by subsequent therapy for patients with extensive disease small cell lung cancer (ED‐SCLC). Therefore, we evaluated the relationship between progression‐free survival (PFS), post‐progression survival (PPS), and OS of ED‐SCLC patients treated with atezolizumab plus carboplatin and etoposide as first‐line therapy. Methods We analyzed the data of 57 patients with relapsed ED‐SCLC treated with atezolizumab plus carboplatin and etoposide (AteCE) as first‐line chemotherapy between August 2019 and September 2020. The respective correlations between PFS‐OS and PPS‐OS following first‐line AteCE treatment were examined at the individual patient level. Results Spearman's rank correlation analysis and linear regression analysis showed that PPS strongly correlated with OS (r = 0.93, p

Abstract Background The modified nutritional geriatric risk index (mGNRI) was developed as a novel index and provides a more appropriate prognostic index than the original GNRI, which was reported to be a useful index for predicting prognoses for various malignancies. This study investigated the prognostic significance of the mGNRI compared with that of the GNRI in patients with pancreatic cancer and the association with psoas muscle volume (PMV) for survival outcomes. Methods This retrospective study included 137 patients who had undergone pancreatectomy for pancreatic cancer. The enrolled patients were grouped as high mGNRI (≥ 85.3) or low mGNRI (

Abstract Background We conducted a multicenter, retrospective study on the efficacy and safety of naldemedine in thoracic cancer patients using opioids in clinical practice. Methods We retrospectively evaluated thoracic cancer patients treated with naldemedine at 10 institutions in Japan. Clinical data of patients administered naldemedine between June 2017 and August 2019 were extracted from electronic medical records. Inclusion criteria were as follows: (i) patients hospitalized for at least seven days before and after naldemedine administration, and (ii) those whose frequency of defecation was entered in the medical records. Results Forty patients were analyzed, and defecation frequency was observed for at least seven days before and after naldemedine administration. The response rate was 65.0% (95% CI: 50.2%–79.7%). The number of defecations increased significantly after naldemedine administration in the overall population, as well as among only those who defecated

Abstract Background This retrospective study was performed to evaluate the efficacy and toxicity of high-dose stereotactic body radiotherapy (SBRT) using a CyberKnife® for patients with stage I peripheral non-small cell lung cancer (NSCLC). Methods Ninety-six patients with stage I peripheral NSCLC who were treated with SBRT using a CyberKnife® from August 2010 to June 2019 were identified and included in this study. Local control (LC), local progression-free survival (LPFS), progression-free survival (PFS), overall survival (OS), and late toxicity were evaluated. Potential risk factors associated with LC, LPFS, PFS, or OS were investigated by univariate analyses. Results Data of 96 patients were examined. The prescribed dose to the tumor was 54 Gy in 3 fractions in 91 patients and 60 Gy in 3 fractions in 5 patients. The median follow-up duration was 27 months. The 2-year LC, LPFS, PFS, and OS rates were 97%, 88%, 84%, and 90%, respectively. The T factor was significantly correlated with LC, LPFS, and PFS. The 2-year LC rate for patients with T1a/T1b and T1c/T2a disease was 100% and 90%, respectively (p

Strigolactones (SLs) regulate angiosperm development and promote symbiosis with arbuscular mycorrhizae. Here the authors show that bryosymbiol, an SL present in bryophytes and angiosperms, promotes AM symbiosis in Marchantia paleacea suggesting an ancestral function of SLs as rhizosphere signals.

Abstract Anti-programmed death-1 (PD-1) blockade is a standard treatment for advanced non-small-cell lung cancer (NSCLC). However, no appropriate modality exists for monitoring its therapeutic response immediately after initiation. Therefore, we aimed to elucidate the clinical relevance of 18F-FDG PET/CT versus CT in predicting the response to PD-1 blockade in the early phase. This prospective study included a total of 54 NSCLC patients. 18F-FDG PET/CT was performed at 4 weeks and 9 weeks after PD-1 blockade monotherapy. Maximum standardized uptake values (SULmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were evaluated. Among all patients, partial metabolic response and progressive metabolic disease after PD-1 blockade were observed in 35.2% and 11.1% on SULmax, 22.2% and 51.8% on MTV, and 27.8% and 46.3% on TLG, respectively, whereas a partial response (PR) and progressive disease (PD), respectively, based on RECIST v1.1 were recognized in 35.2% and 35.2%, respectively. The predictive probability of PR (MTV: 57.9% vs. 21.1%, p = 0.044; TLG: 63.2% vs. 21.1%, p = 0.020) and PD (MTV: 78.9% vs. 47.3%, p = 0.002; TLG: 73.7% vs. 21.1%, p = 0.007) detected based on RECIST at 4 weeks after PD-1 blockade initiation was significantly higher using MTV or TLG on 18F-FDG uptake than on CT. Multivariate analysis revealed that metabolic response by MTV or TLG at 4 weeks was an independent factor for response to PD-1 blockade treatment. Metabolic assessment by MTV or TLG was superior to morphological changes on CT for predicting the therapeutic response and survival at 4 weeks after PD-1 blockade.

Abstract Background Biomarker assessments for nivolumab monotherapy efficacy in previously treated patients with non‐small cell lung cancer (NSCLC) remain unclear. We evaluated whether body mass index (BMI) and Glasgow prognostic score (GPS) are useful for assessing the efficacy of nivolumab alone as a second‐line treatment in patients with pretreated NSCLC. Methods Data of 99 patients treated with second‐line nivolumab monotherapy for NSCLC between January 2016 and December 2019 were evaluated for prognostic values of BMI and GPS to assess their usefulness in predicting progression‐free survival (PFS) and overall survival (OS). Results The Eastern Cooperative Oncology Group‐performance status (PS) independently predicted the second‐line nivolumab monotherapeutic effect; good PS (0–1) correlated with significantly longer PFS (4.3 vs. 1.9 months, log‐rank; p = 0.0004) and OS (17.7 vs. 4.6 months, log‐rank; p

Abstract Background Adjuvant chemotherapy for stage II colorectal cancer (CRC) is considered appropriate for patients with risk factors for recurrence, rather than for all patients uniformly. However, the risk factors for recurrence remain controversial, and there is limited information, especially for elderly patients. The Geriatric Nutritional Risk Index (GNRI) is widely used as a simple nutritional screening tool in the elderly and is associated with cancer prognosis and recurrence. This study aimed to investigate the risk factors for recurrence in the elderly with stage II CRC, focusing on the GNRI. Methods We enrolled 348 elderly patients (≥ 75 years) with stage II CRC who underwent curative resection at the Department of Surgery, Tottori University and our 10 affiliated institutions. The patients were divided into GNRIhigh (≥ 93.465) and GNRIlow (

Abstract Background Thoracoscopic esophagectomy has been extensively used worldwide as a curative surgery for patients with esophageal cancer; however, complications such as anastomotic leakage and stenosis remain a major concern. Therefore, the objective of this study was to evaluate the efficacy of circular stapling anastomosis with indocyanine green (ICG) fluorescence imaging, which was standardized for cervical esophagogastric anastomosis after thoracoscopic esophagectomy. Methods Altogether, 121 patients with esophageal cancer who underwent thoracoscopic esophagectomy with radical lymph node dissection and cervical esophagogastric anastomosis from November 2009 to December 2020 at Tottori University Hospital were enrolled in this study. Patients who underwent surgery before the anastomotic method was standardized were included in the classical group (n = 82) and patients who underwent surgery after the anastomotic method was standardized were included in the ICG circular group (n = 39). The short-term postoperative outcomes, including anastomotic complications, were compared between the two groups using propensity-matched analysis and the risk factors for anastomotic leakage were evaluated using logistic regression analyses. Results Of the 121 patients, 33 were included in each group after propensity score matching. The clinicopathological characteristics of patients did not differ between the two groups after propensity score matching. In terms of perioperative outcomes, a significantly higher proportion of patients who underwent surgery using the laparoscopic approach (P

Abstract L-type amino acid transporter 1 (LAT1), also referred to as SLC7A5, is believed to regulate tumor metabolism and be associated with tumor proliferation. In invasive breast cancer, we clinicopathologically investigated the utility of LAT1 expression. LAT1 expression was evaluated via immunohistochemistry analyses in 250 breast cancer patients undergoing long-term follow-up. We assessed the relationships between LAT1 expression and patient outcomes and clinicopathological factors. Breast cancer-specific survival stratified by LAT1 expression was assessed. Human epidermal growth factor receptor 2 (HER2)-positive patients with metastasis received trastuzumab therapy. The density of tumor-infiltrating lymphocytes (TILs) was evaluated according to the International Working Group guidelines. In the current study, high LAT1 expression was significantly correlated with estrogen receptor (ER) negativity, progesterone receptor negativity, high histological grade, increased TILs, and programmed death ligand 1 positivity. Among the ER-positive and HER2-negative patients, high LAT1 was an independent indicator of poor outcomes (hazard ratio (HR) = 2.97; 95% confidence interval (CI), 1.16–7.62; p = 0.023). Moreover, high LAT1 expression was an independent poor prognostic factor in luminal B-like breast cancer with aggressive features (HR = 3.39; 95% CI 1.35–8.52; p = 0.0094). In conclusion, high LAT1 expression could be used to identify a subgroup of invasive breast cancer characterized by aggressive behavior and high tumor immunoreaction. Our findings suggest that LAT1 might be a candidate therapeutic target for breast cancer patients, particularly those with luminal B-like type breast cancer.

BackgroundThere are no established predictive biomarkers for the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with small-cell lung cancer (SCLC). Therefore, the current study aimed to investigate whether the Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) can predict the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with extensive-disease SCLC.MethodsWe reviewed data from 84 patients who received first-line atezolizumab plus carboplatin and etoposide therapy for SCLC at nine Japanese institutions between August 2019 and May 2021. Further, we evaluated the prognostic value of the GPS, NLR, and BMI. The Kaplan–Meier and Cox proportional hazard models were used to examine differences in progression-free survival (PFS) and overall survival (OS). Moreover, the GPS, NLR, and BMI consisted of C-reactive protein and albumin concentrations, neutrophil and lymphocyte counts, and body weight and height, respectively.ResultsThe response rate was 72.6% (95% confidence interval: 63.0–82.1%). The median PFS and OS from the initiation of treatment were 5.4 (95% CI: 4.9–5.9) months and 15.4 (95% CI: 11.4–16.8) months, respectively. The GPS independently predicted the effectiveness of first-line atezolizumab plus carboplatin and etoposide treatment, as a favorable GPS (GPS 0–1) was correlated with significantly better PFS and OS rates compared to a poor GPS (GPS 2) (PFS: 5.8 vs. 3.8 months, p = 0.0005; OS: 16.5 vs. 8.4 months, p

It has been reported that 5.1–7.0% of acute pericarditis are carcinomatous pericarditis. Malignant pericardial effusion (MPE) can progress to cardiac tamponade, which is a life-threatening condition. The effectiveness and feasibility of intrapericardial instillation of carboplatin (CBDCA; 150 mg/body) have never been evaluated in patients with lung cancer, which is the most common cause of MPE. Therefore, we evaluated the effectiveness and feasibility of intrapericardial administration of CBDCA following catheter drainage in patients with lung cancer-associated MPE. In this retrospective study, 21 patients with symptomatic lung cancer-associated MPE, who were administered intrapericardial CBDCA (150 mg/body) at Gunma Prefectural Cancer Center between January 2005 and March 2018, were included. The patients’ characteristics, response to treatment, and toxicity incidence were evaluated. Thirty days after the intrapericardial administration of CBDCA, MPE was controlled in 66.7% of the cases. The median survival period from the day of administration until death or last follow-up was 71 days (range: 10–2435 days). Grade 1–2 pain, nausea, fever, and neutropenia were noted after intrapericardial CBDCA administration. No treatment-related deaths were noted in the current study. Intrapericardial administration of CBDCA (150 mg/body) did not cause serious toxicity, and patients exhibited promising responses to lung cancer-associated MPE. Prospective studies using larger sample sizes are needed to explore the efficacy and safety of this treatment for managing lung cancer-associated MPE.

Abstract Background The mortality rate of patients with unresectable gastric cancer (UGC) has decreased with the development of chemotherapies and surgical techniques. However, the survival rate remains low. We retrospectively examined the prognostic significance of the pretreatment skeletal muscle mass index (SMI) and nutritional and inflammatory factors in patients with UGC. Methods This study included 83 patients diagnosed with UGC at Tottori University Hospital who received palliative chemotherapy based on 5-fluorouracil. Pretreatment computed tomography (CT) measured overall skeletal muscle mass (SMM) and cross-sectional SMM at the third lumbar vertebra (L3). We focused on the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein-to-albumin ratio (CAR), prognostic nutritional index (PNI), and platelet-to-lymphocyte ratio (PLR) as nutritional and inflammatory factors. Results Receiver operating characteristic curve analysis was performed for median survival time (MST) after palliative chemotherapy. SMIs for males and females (43.9 cm2/m2 and 34.7 cm2/m2, respectively) were the cutoff values, and patients were divided into high (SMIHigh; n = 41) and low SMI groups (SMILow; n = 42). Body mass index (BMI) was significantly higher in patients in the SMIHigh group than in the SMILow group (p

Background: The standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC study. Although multiple Japanese phase II studies have shown high efficacy and tolerability of CRT with cisplatin plus S-1 (SP), no prospective study using durvalumab after SP-based CRT has been reported. Objectives: We conducted a multicenter phase II study of this approach, the interim analysis of which showed a high transition rate to durvalumab consolidation therapy. Here, we report the primary analysis results. Design: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m 2 , day 1) and S-1 (80–120 mg/body, days 1–14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab (10 mg/kg) every 2 weeks for up to 1 year. Methods: The primary endpoint was 1-year progression-free survival (PFS). The expected 1-year PFS and its lower limit of the 80% confidence interval (CI) were set as 63% and 47%, respectively, based on the results of TORG1018 study. Results: In all, 59 patients were enrolled, with 51 (86.4%) proceeding to durvalumab. The objective response rate throughout the study was 72.9% (95% CI: 59.7–83.6%). After median follow-up of 21.9 months, neither median PFS nor OS was reached. The 1-year PFS was 72.5% (80% CI: 64.2–79.2%, 95% CI: 59.1–82.2%), while the 1-year overall survival was 91.5% (95% CI: 80.8–96.4%). No grade 5 adverse events were observed throughout the study. The most common adverse event during the consolidation phase was pneumonitis (any grade, 78.4%; grade ⩾3, 2.0%). Eventually, 52.5% of patients completed 1-year durvalumab consolidation therapy from CRT initiation. Conclusion: This study of durvalumab after SP-based CRT met its primary endpoint and found a 1-year PFS of 73% from CRT initiation. This study provides the first prospective data on the prognosis and tolerability of durvalumab consolidation from the initiation of CRT. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127

Abstract Objectives Various drug‐sensitivity markers have been reported to be associated with tumor progression and chemotherapy resistance. Detailed expression profiles of sensitivity markers for cytotoxic chemotherapy in pulmonary large cell neuroendocrine carcinoma (LCNEC) remain unclear. Herein, we aimed to clarify the correlation between the expression of drug‐sensitivity markers and clinicopathological features, prognostic impact, and status of tumor immunity in patients with LCNEC. Methods We retrospectively analyzed the correlation between clinicopathological features and the expression of drug‐sensitivity‐related markers, including vascular endothelial growth factor 2 (VEGFR2), thymidylate synthase (TS), tubulin beta 3 class III (TUBB3), topoisomerase I (Topo‐I), and Topo‐II in 92 surgically resected LCNEC samples. Furthermore, we examined the prognostic significance of expression of these and their correlation with the immune cell status. Results Overall, high expression of TS, TUBB3, VEGFR2, Topo‐I, and Topo‐II was detected in 50 (54%), 31 (34%), 23 (25%), 65 (71%), and 36 (39%) samples, respectively. Univariate and multivariate analyses revealed that advanced pathological T and N factors, positive lymphatic permeation, and Topo‐II expression were independent unfavorable prognosticators for recurrence‐free survival, and advanced pathological T and N factors, Topo‐II positive expression, and TS positive expression were independent unfavorable prognosticators for overall survival. In terms of correlation with immune cell status, higher expression of VEGFR2 was closely linked to negative PD‐L1 expression. Conclusions These findings suggest that elevated Topo‐II and TS expression may contribute to poor outcomes through protumoral biology in patients with LCNEC, and elevated VEGFR2 expression might negatively impact tumor immune reactions in LCNEC.

Abstract Background For early‐stage non‐small cell lung cancer (NSCLC), surgical resection is considered the most effective treatment strategy and curative treatment. Unfortunately, even after complete resection, almost half of all patients with stage I–IIIA NSCLC relapse and die. Although the possibility of a cure for postoperative recurrence of NSCLC is significantly low, the course of subsequent treatment can possibly affect overall survival (OS). Here, we examined the association of relapse‐free survival (RFS) and post‐progression survival (PPS) with OS in patients with postoperative recurrence of NSCLC. Methods We evaluated 128 patients with NSCLC who underwent complete resection between January 2007 and December 2018. The association between RFS and PPS on OS was examined at the patient level. Results Spearman's rank correlation and linear regression analyses revealed that PPS was strongly correlated with OS (r = 0.83, p

Abstract Background There are no established biomarkers for predicting the efficacy of first‐line pembrolizumab monotherapy in patients with high programmed death‐ligand 1 (PD‐L1) expression. In this study, we investigated whether the Glasgow prognostic score (GPS), neutrophil‐to‐lymphocyte ratio (NLR), and body mass index (BMI) can be used to evaluate the effect of first‐line pembrolizumab monotherapy in patients with advanced non‐small cell lung cancer (NSCLC) who express high levels of PD‐L1. Methods We reviewed data from 142 patients with high PD‐L1 expression who underwent first‐line pembrolizumab monotherapy for NSCLC at six Japanese institutions between February 2017 and June 2019 and assessed the prognostic value of the GPS, NLR, and BMI. The Kaplan–Meier method and Cox proportional hazard models were used to examine differences in progression‐free survival (PFS) and overall survival (OS). The GPS, NLR, and BMI were calculated using C‐reactive protein and albumin concentrations, neutrophil and lymphocyte counts, and body weight and height, respectively. Results The GPS independently predicted the first‐line pembrolizumab monotherapy efficacy, as a good GPS (GPS 0–1) was associated with a significantly better PFS and OS compared to a poor GPS (GPS 2) (PFS: 11.8 vs. 2.9 months, p

Abstract Background 2‐deoxy‐2‐[fluorine‐18] fluoro‐d‐glucose (18F‐FDG) positron emission tomography (18F‐FDG‐PET) is a convenient modality to assess the metabolic activity within tumor cells. However, there is no consensus regarding the relationship between 18F‐FDG uptake and the immune environment in thymic epithelial tumors (TETs). We conducted a clinicopathological study to elucidate the relationship between 18F‐FDG uptake and programmed death ligands 1 and 2 (PD‐L1/PD‐L2) expression in patients with TETs. Methods: A total of 108 patients with histologically confirmed TETs classified as thymomas or thymic carcinomas who underwent surgical resection or biopsy or needle biopsy and 18F‐FDG PET before any treatment between August 2007 and March 2020 were enrolled in this study. Tumor specimens underwent immunohistochemical staining for PD‐L1, PD‐L2, GLUT1, HIF‐1α, VEGFR2, VEGF‐C, and β2 adrenergic receptor. Results: High uptakes of SUVmax, SUVmean, MTV, and TLG were identified in 28 (25.9%), 61 (56.5%), 55 (50.9%), and 55 (50.9%) of 108 patients, respectively. High uptake of SUVmax significantly correlated with PS (performance status) of 1–2, thymic carcinoma, and advanced stage, and SUVmax on 18F‐FDG uptake displayed a close association with PD‐L1 and PD‐L2 expressions, but not with MTV and TLG. Our analysis revealed that SUVmax was identified as being significant relationship for positive PD‐L1/PD‐L2 expression. GLUT1, HIF‐1α, and VEGFR2 were significantly associated with the expression of PD‐L1/PD‐L2 from the biological viewpoint. Conclusion 18F‐FDG accumulation was closely associated with the expression of PD‐L1/PD‐L2, which, in turn, was correlated with glucose metabolism and hypoxia. PD‐L1/PD‐L2 could affect the glucose metabolism and hypoxia in thymic tumor cells.

Abstract Background Colorectal cancer and peripheral artery disease are common conditions in older adults and may coexist in this population. Lymph node dissection along the inferior mesenteric artery is a vital procedure in cases of left-sided colorectal cancer. However, the inferior mesenteric artery may show a collateral blood pathway in rare cases of peripheral artery disease. We report a case of advanced sigmoid colon cancer in which the lower limbs received inferior mesenteric artery flow owing to asymptomatic peripheral artery disease. The possibility of catastrophic lower-limb ischemia because of complete mesenteric excision with ligation of the inferior mesenteric artery was a matter of concern in this case. Case presentation A 73-year-old man with asymptomatic peripheral artery disease was diagnosed with stage IIIB advanced sigmoid colon cancer. Angiography using a balloon-occlusion catheter revealed that his lower limbs received prominent inferior mesenteric artery blood flow through a collateral pathway. Therefore, interventional radiologists and cardiovascular surgeons evaluated the indications for endovascular stents or bypass grafts. The patient also had dilated cardiomyopathy, so the cardiovascular physicians evaluated his tolerance in the worst-case scenario of a colorectal anastomotic leak. The patient underwent axillofemoral artery bypass and two-stage laparoscopic sigmoid colectomy without anastomosis. The postoperative course was uneventful, and he resumed his job within a month after the resection. Conclusions Although collateral flow from the inferior mesenteric artery is rare in patients with peripheral artery disease, a few case reports have described fatal lower-limb ischemia following anterior resection. The perioperative multidisciplinary evaluation enabled us to understand the patient’s condition and risks, and allowed successful cancer treatment without ischemia of the lower limbs.

Abstract Background Mucosa associated lymphoid tissue (MALT) lymphoma of the orbit is rare, often indolent, but can recur, and spread to extra‐nodal sites. Pleural and retroperitoneum recurrences of MALT lymphoma are rare. Case A 65‐year‐old man was referred to our hospital due to right pleural effusion and difficulty in breathing. He had a medical history of having undergone surgery for MALT lymphoma of the left orbit. A chest computed tomography (CT) scan showed right pleural thickness, pleural effusion, and a retroperitoneal mass, spreading from the muscular layer to the subcutaneous layer. The thickened pleural lesion was surgically biopsied and diagnosed as a recurrence of MALT lymphoma. Conclusion Pleural effusion should be carefully examined and monitored for the possibility of recurrence in MALT lymphoma patients.

Objectives: Fusobacterium nucleatum, which is the predominant subgingival microbial species found in chronic periodontitis, has been recently proposed as a risk factor for both the initiation and progression of colorectal cancer. We evaluated whether the number of teeth, which represents oral health, is a marker for the prognosis of patients with colorectal cancer. Methods: This retrospective single-center study recruited 179 patients who underwent primary colorectal cancer resection with curative intent between 2015 and 2017. The baseline characteristics and survival were analyzed according to the number of teeth observed in dental panoramic radiographs taken before surgical resection as a part of the perioperative surveillance for oral function and hygiene. Results: The median number of teeth was 20 (interquartile range: 6-25), including 28 patients with no teeth. Patients with 20 or more teeth had better overall survival (p = 0.002) and colorectal cancer-specific survival (p = 0.032) than those with less than 20 teeth. Multivariate analyses confirmed that the number of teeth was a significant prognostic factor for overall survival (p = 0.045) but not for colorectal cancer-specific survival (p = 0.258). We also took a propensity score-weighting approach using inverse probability weighting, and the p-values of the number of teeth were 0.032 for overall survival and 0.180 for colorectal cancer-specific survival. Conclusions: A low number of teeth, which can be easily and noninvasively assessed, has been a poor prognostic factor for overall survival in colorectal cancer patients who underwent surgery with curative intent.

Abstract Frequent loss of heterozygosity (LOH) on the short arm of human chromosome 3 (3p) region has been found in pancreatic cancer (PC), which suggests the likely presence of tumor suppressor genes in this region. However, the functional significance of LOH in this region in the development of PC has not been clearly defined. The human telomerase reverse transcriptase gene (hTERT) contributes to unlimited proliferative and tumorigenicity of malignant tumors. We previously demonstrated that hTERT expression was suppressed by the introduction of human chromosome 3 in several cancer cell lines. To examine the functional role of putative TERT suppressor genes on chromosome 3 in PC, we introduced an intact human chromosome 3 into the human PK9 and murine LTPA PC cell lines using microcell-mediated chromosome transfer. PK9 microcell hybrids with an introduced human chromosome 3 showed significant morphological changes and rapid growth arrest. Intriguingly, microcell hybrid clones of LTPA cells with an introduced human chromosome 3 (LTPA#3) showed suppression of mTert transcription, cell proliferation, and invasion compared with LTPA#4 cells containing human chromosome 4 and parental LTPA cells. Additionally, the promoter activity of mTert was downregulated in LTPA#3. Furthermore, we confirmed that TERT regulatory gene(s) are present in the 3p21.3 region by transfer of truncated chromosomes at arbitrary regions. These results provide important information on the functional significance of the LOH at 3p for development and progression of PC.

Abstract Background We retrospectively examined the relationship among skeletal muscle mass index (SMI), prognosis, and chemotherapy side effects in patients with recurrent gastric cancer (RGC). Methods Sixty-seven patients who developed recurrence after undergoing curative gastrectomy for gastric cancer at Tottori University Hospital and received palliative chemotherapy were included in this study. Pretreatment computed tomography was performed to measure the skeletal muscle mass (SMM) and cross-sectional SMM at the third lumbar vertebra. We focused on haematologic toxicity (neutropenia, thrombocytopenia, and anaemia), febrile neutropenia, and gastrointestinal toxicity (diarrhoea, vomiting, and stomatitis) as the side effects of chemotherapy. Results Median SMIs for males and females (43.9 and 34.7 cm2/m2, respectively) were used as cutoff values. The patients were classified into high (SMIHigh; n = 34) and low SMI groups (SMILow; n = 33). The SMILow group included more patients treated with monotherapy (P = 0.016) compared with the SMIHigh group, had a significantly lower number of chemotherapy lines (P = 0.049), and had a significantly higher incidence of grade 3 or 4 side effects (P = 0.010). The median survival rate was significantly higher in the SMIHigh group (17.8 vs 15.8 months; P = 0.034). In the univariate analysis, body mass index, SMI, histological type, and prognostic nutritional index were identified as prognostic indicators. The multivariate analysis identified SMI (P = 0.037) and histological type (P = 0.028) as independent prognostic factors. Conclusion The incidence of grade 3 or 4 side effects was significantly higher in patients with SMILow RGC. SMI was a useful prognostic marker of RGC.

Background: The standard of care for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC trial. Disease progression and pneumonitis were reported as the main reasons to preclude the initiation of durvalumab in multiple retrospective studies. However, the transition rate and the reasons for failure to proceed to consolidation therapy with durvalumab after CRT were not evaluated prospectively. Although phase II studies in Japan have shown high efficacy and tolerability of CRT with cisplatin + S-1 (SP), no prospective study using durvalumab after SP-based CRT has yet been reported. We therefore conducted a phase II study to verify the efficacy and safety of durvalumab following SP-based CRT. In this interim analysis, we report the transition rate and the reasons for its failure. Methods: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m 2 , day 1) and S-1 (80–120 mg/body, days 1–14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab every 2 weeks for up to 12 months. The primary endpoint was 12 month progression-free survival rate. Results: Fifty-nine patients were enrolled, of whom 86.4% (51/59) proceeded to durvalumab. All of them initiated durvalumab within 42 days after CRT [median 18 days (range: 3–38)], including 27.5% (14/51) in

Abstract Background The effect of second‐line treatment on overall survival (OS) may be affected by subsequent treatment in patients with non‐small cell lung cancer (NSCLC); however, in such patients, the correlation between post‐progression survival (PPS) and OS is unclear. Our study assessed the correlation of progression‐free survival (PFS) and PPS with OS, using individual patient data, in advanced NSCLC patients who were treated with second‐line nivolumab monotherapy, Methods Between January 2016 and March 2019, we evaluated 92 NSCLC patients who received second‐line nivolumab treatment after first‐line platinum‐based combination chemotherapy. Using individual patient data, the correlations of PFS and PPS with OS were examined. Results Linear regression and Spearman rank correlation analysis demonstrated that PPS was strongly correlated with OS (r = 0.85, p

Abstract Background There is currently insufficient information available on effective therapies that can be administered to patients with non‐small cell cancer (NSCLC) who develop resistance to epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs). However, sequential treatment via programmed death‐1 (PD‐1) blockade followed by EGFR‐TKI rechallenge is suggested to improve the therapeutic efficacy in such patients. Methods A total of 75 patients with advanced NSCLC harboring sensitive EGFR mutations treated with afatinib, erlotinib, or gefitinib after EGFR‐TKI treatment failure were retrospectively analyzed. Among them, 13 patients were treated with EGFR‐TKI rechallenge immediately after the failure of PD‐1 blockade therapy (experimental group) and the remaining 62 patients did not receive PD‐1 inhibitor therapy before EGFR‐TKI rechallenge (control group). Blood samples were collected at two time points; before the initiation of anti‐PD‐1 therapy and at EGFR‐TKI rechallenge. Results The objective response rates of EGFR‐TKI rechallenge in the experimental and control groups were 46.1% and 16.1%, respectively, with a significant difference (p = 0.026). In the experimental group, the median progression‐free survival (PFS) and overall survival (OS) after EGFR‐TKI rechallenge were 5.0 and 25.0 months, respectively, and no statistically significant difference in the percentage of lymphocytes before immune checkpoint inhibitor (ICI) therapy and EGFR‐TKIs was observed in patients with partial response (PR) and without PR after EGFR‐TKI rechallenge. In particular, the sequential treatment of PD‐1 blockade therapy followed by EGFR‐TKI rechallenge was consecutively repeated three times in two out of 13 patients in the experimental group, and EGFR‐TKI rechallenge consecutively for the third time yielded a PR without increased toxicities. Conclusions EGFR‐TKI rechallenge immediately after PD‐1 blockade treatment was identified as an effective therapy for NSCLC patients with resistance to EGFR‐TKIs.

Abstract Background The geriatric nutritional risk index (GNRI), originally developed as a nutritional assessment tool to evaluate mortality and morbidity in older hospitalized patients (i.e., those aged ≥65 years), is regarded as a prognostic factor in several cancers. Body composition is also an important consideration when predicting the prognosis of patients with cancer. This study aimed to investigate the relationship between the GNRI and psoas muscle volume (PMV) for survival outcomes in patients with pancreatic cancer. Methods This retrospective study evaluated the prognostic significance of the GNRI and PMV in 105 consecutive patients aged ≥65 years who underwent pancreatectomy for histologically confirmed pancreatic cancer. The patients were divided into high (GNRI > 98) and low GNRI groups (GNRI ≤98), and into high (PMV > 61.5 mm3/m3 for men and 44.1 mm3/m3 for women) and low PMV (PMV ≤ 61.5 mm3/m3 for men and 44.1 mm3/m3 for women) groups. Results Both the 5-year overall survival (OS) and recurrence-free survival (RFS) rates were significantly greater among patients in the high GNRI group than among patients in the low GNRI group. Similarly, both the 5-year OS and RFS rates were significantly greater among patients in the high PMV group than among patients in the low PMV group. Patients were stratified into three groups: those with both high GNRI and high PMV; those with either high GNRI or high PMV (but not both); and those with both low GNRI and low PMV. Patients with both low GNRI and low PMV had a worse 5-year OS rate, compared with patients in other groups (P

Abstract Background The safety of pembrolizumab monotherapy in treatment‐naïve non‐small cell lung cancer (NSCLC) patients with high programed death‐ligand 1 (PD‐L1) expression and pre‐existing interstitial lung disease (ILD) has not yet been determined. Here, we aimed to evaluate the prognosis, efficacy and safety associated with pembrolizumab in such settings. Methods In this single‐institution retrospective study conducted from May 2017 to October 2019, pembrolizumab was administered to 72 Japanese patients with treatment‐naïve advanced NSCLC with PD‐L1 tumor proportion score (TPS) ≥50%. Patients with ILD were assigned to the ILD group, and those without to the non‐ILD group. Between‐group comparisons were then performed. Results Of the 72 patients, 61 (84.7%) were male. The median age was 70 years. A total of 64 patients (88.9%) had a smoking history, median PD‐L1 TPS status was 77.5%, and 10 of the 72 patients (13.9%) had ILD on pretreatment computed tomography. The objective response rate (ORR) was 45.8% and disease control rate (DCR) was 75.0%. The ORR was 70.0% and DCR was 90.0% in the ILD group, while the ORR was 41.9% and DCR was 72.6% in the non‐ILD group. The median overall survival was 568 days; the value in the non‐ILD group was 521 days, while in the ILD group was not reached. There was no significant difference between the two groups (log‐lank, P = 0.73). Conclusions Pembrolizumab was administered to patients with pre‐existing ILD with no difference in prognosis compared to patients without ILD. In patients with ILD, physicians should consider the expected long‐term prognosis and risk of adverse events.

Background and Objectives: Opioid analgesics, which are used for cancer-related pain management, cause opioid-induced constipation (OIC). Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in hepatobiliary pancreatic cancers. We performed a multi-institutional study on the efficacy and safety of naldemedine in patients with hepatobiliary pancreatic cancer using opioids in clinical practice. Materials and Methods: We retrospectively evaluated patients with hepatobiliary pancreatic cancer (including liver, biliary tract, and pancreatic cancers) treated with opioids and naldemedine during hospitalization at ten institutions in Japan from June 2017 to August 2019. We assessed the frequency of bowel movements before and after the initiation of naldemedine therapy. Responders were defined as patients who defecated ≥3 times/week, with an increase from a baseline of ≥1 defecations/week over seven days after the initiation of naldemedine administration. Results: Thirty-four patients were observed for one week before and one week after starting naldemedine. The frequency of bowel movements increased by one over the baseline frequency or to at least thrice per week in 21 patients. The response rate was 61.7% (95% confidence interval: 45.4–78.0%). The median number of weekly bowel movements before and after naldemedine treatment was 2 (range: 0–9) and 6 (range: 1–17), respectively, in the overall population (n = 34); the increase in the number of bowel movements following naldemedine administration was statistically significant (Wilcoxon signed-rank test, p < 0.0001). Diarrhea was the predominant gastrointestinal symptom, and 10 (29.4%) patients experienced grade 1, grade 2, or grade 3 adverse events. The only other adverse event included fatigue in one patient; grade 2–4 adverse events were absent. Conclusions: Naldemedine is effective, and its use may be safe in clinical practice for patients with hepatobiliary pancreatic cancer receiving opioid analgesics.

Abstract Anti-programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) antibodies are administered in varied human cancer types. The expression of PD-L1 within tumor cells has been identified as a predictive marker, although assessing its expression has benefitted only patients with non-small cell lung cancer (NSCLC) or head and neck cancer. Whereas, more than 75% of the patients with NSCLC showing partial response to PD-1 blockade therapy experienced long-term survival for more than 5-years Thus, identifying the responders to PD-1 blockade at early phase after its initiation is of clinical importance. The 2-deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG) on positron emission tomography (PET) can evaluate any tumor shrinkage by assessing the metabolic tumor volume at an earlier phase than conventional modalities such as computed tomography (CT). While several reports describe the correlation of PD-L1 expression with 18F-FDG uptake rate in the tumor cells, it remains to be delineated whether this rate determined by the glucose metabolism and hypoxia is associated with the status of immune microenvironment, including the expression of PD-L1. Moreover, details of the relationship between expression of PD-L1 and 18F-FDG uptake is still unclear. Therefore, we reviewed the clinical significance of 18F-FDG uptake on PET as a predictor of the efficacy of PD-1 blockade therapy, by correlating with the expression of PD-L1, in patients with several neoplasms.

Abstract Background Durvalumab is a standard drug used during maintenance therapy after chemoradiotherapy in patients with locally advanced non-small cell lung cancer (LA-NSCLC). However, little is known about the clinical benefits of durvalumab after chemoradiotherapy in patients with LA-NSCLC with a performance status (PS) of 2 and/or aged > 75 years. As daily carboplatin plus concurrent thoracic radiotherapy is recommended for elderly patients according to guideline, the current phase II study aims to investigate the effect of daily carboplatin plus radiotherapy followed by durvalumab for patients with stage III NSCLC who have a PS of 2 and/or are older. Methods Daily carboplatin plus radiotherapy followed by durvalumab is performed for the patients with stage III NSCLC who have a PS of 2 and/or are older. This is a trial in progress manuscript. Study treatment Daily, intravenous, low-dose carboplatin (30 mg/m2 in a 30-min infusion) is administered to patients 1 h before radiotherapy for the first 20 fractions. Radiotherapy for all patients consisted of 60 Gy administered as 30 fractions over 6 weeks. Durvalumab at a dose of 10 mg/kg/body is intravenously administered every 2 weeks for up to 12 months after chemoradiotherapy. Exploratory assessment In the future, an exploratory investigation will be performed to determine whether the combined assessment of T-cell markers, PD-L1 expression, and tumor mutation burden could predict the outcomes of the regimen. Discussion The results of our study will exhibit the efficacy and tolerability of durvalumab as maintenance therapy after daily carboplatin plus radiotherapy. Trial registration During the first registration (before induction chemoradiotherapy), 70 patients will be included; then, we include 58 patients during the second registration (before durvalumab treatment after chemoradiotherapy). https://jcrb.niph.go.jp/ . Primary endpoint The primary endpoint of the current study is the 12-month progression-free survival (PFS) rate after the initiation of durvalumab. Secondary endpoints The secondary endpoints are the feasibility, objective response, PFS, overall survival, and adverse events.