Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade.

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

The Tumor Immune Microenvironment Is Associated With Recurrence in Early-Stage Lung Adenocarcinoma.

Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo-not reached; n = 39) and 23.7 months (95% CI: 14.5-43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29-0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.

Association of immune-related adverse events with durvalumab efficacy after chemoradiotherapy in patients with unresectable Stage III non-small cell lung cancer.

BACKGROUND: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown. METHODS: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid. RESULTS: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8+ tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration. CONCLUSIONS: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles.

Trifluridine/Tipiracil Plus Bevacizumab for Vulnerable Patients With Pretreated Metastatic Colorectal Cancer: A Retrospective Study (WJOG14520G).

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab has shown clinical benefit for metastatic colorectal cancer (mCRC) refractory to standard therapy. However, few data have been available for patients with pretreated mCRC who are intolerant of intensive therapy (vulnerable). METHODS: We performed a multicenter retrospective study (WJOG14520G; TWILIGHT) of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC. Eligibility criteria included previous chemotherapy (although patients treated with all key cytotoxic agents, a fluoropyrimidine, oxaliplatin, and irinotecan, were excluded) and intolerance of full-dose combination therapy with oxaliplatin or irinotecan at the start of FTD/TPI plus bevacizumab. RESULTS: The median age of 93 evaluable patients was 79 years (range, 21-90). Intolerance of intensive therapy was attributable to an older age in 60 (65%) patients, serious concomitant disease in 24 (26%) patients, and a poor performance status in 19 (20%) patients. FTD/TPI plus bevacizumab was administered as second-line treatment in 74 (80%) patients and as third- or fourth-line treatment in 19 (20%) patients. The objective response rate was 4.9% (95% confidence interval [CI], 1.4%-12.2%), and the disease control rate was 67.9% (95% CI, 56.6%-77.8%). With a median follow-up time of 21.6 months, median overall survival and progression-free survival were 18.6 months (95% CI, 12.1-23.2) and 6.3 months (95% CI, 5.0-8.3), respectively. Neutropenia of grade ≥3 developed in 50 (54%) patients, whereas 2 (2%) patients experienced febrile neutropenia, and no treatment-related death was observed. CONCLUSION: Our data show the potential efficacy and acceptable safety profile of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC.

The combination of soluble forms of PD-1 and PD-L1 as a predictive marker of PD-1 blockade in patients with advanced cancers: a multicenter retrospective study.

Introduction: The clinical relevance of soluble forms of programmed cell death-1 (sPD-1) and programmed cell death-ligand 1 (sPD-L1) remains unclear. We here investigated the relation between the efficacy of PD-1 blockade and pretreatment plasma levels of sPD-1 and sPD-L1 across a broad range of cancer types. Methods: We retrospectively analyzed clinical data from 171 patients with advanced solid tumors who received nivolumab or pembrolizumab monotherapy regardless of treatment line. The concentrations of sPD-1 and sPD-L1 were measured with a fully automated immunoassay (HISCL system). Results: The study subjects comprised patients with head and neck cancer (n = 50), urothelial cancer (n = 42), renal cell cancer (n = 37), gastric cancer (n = 20), esophageal cancer (n = 10), malignant pleural mesothelioma (n = 6), or microsatellite instability-high tumors (n = 6). High or low levels of sPD-1 or sPD-L1 were not significantly associated with progression-free survival (PFS) or overall survival (OS) for PD-1 blockade in the entire study population. Comparison of treatment outcomes according to combinations of high or low sPD-1 and sPD-L1 levels, however, revealed that patients with low sPD-1 and high sPD-L1 concentrations had a significantly poorer PFS (HR of 1.79 [95% CI, 1.13-2.83], p = 0.01) and a tendency toward poorer OS (HR of 1.70 [95% CI, 0.99-2.91], p = 0.05) compared with all other patients. Conclusion: Our findings suggest that the combination of low sPD-1 and high sPD-L1 levels is a potential negative biomarker for PD-1 blockade therapy.

Lack of Association of Plasma Levels of Soluble Programmed Cell Death Protein 1, Programmed Death-Ligand 1, and CTLA-4 With Survival for Stage II to IIIA NSCLC After Complete Resection and Adjuvant Chemotherapy.

Introduction: Perioperative treatment in NSCLC has gained marked attention with the introduction of immune checkpoint inhibitors. Such a paradigm shift has given us additional opportunities to evaluate potential biomarkers in patients with these curable disease stages. Methods: This study (WJOG12319LTR) was designed as a biomarker study to evaluate whether soluble immune markers were prognostic or predictive on relapse-free survival in patients with stage II to IIIA NSCLC who underwent complete resection and adjuvant chemotherapy with cisplatin plus S-1, which is an oral fluoropyrimidine formulation that consists of tegafur, gimeracil, and oteracil, or S-1 alone in the previous WJOG4107 study. Archived plasma samples were assayed for soluble (s) forms of programmed cell death protein 1 (sPD-1), programmed death-ligand 1(sPD-L1), and CTLA-4 (sCTLA-4) with the highly sensitive HISCL system. Using time-dependent receiver operating characteristic curve analysis, the area under the curves were derived and optimal cutoff values were determined. Using the cutoff values, whether the marker was prognostic or predictive was assessed by survival analysis. Results: A total of 150 patients were included in the study. The time-dependent receiver operating characteristics analysis revealed that the area under the curves for sPD-1, sPD-L1, and sCTLA-4 were 0.54, 0.51, and 0.58, respectively. The survival analysis did not reject that hazard ratios were 1 in terms of the soluble immune marker and the treatment-marker interaction for all three markers. Conclusions: There was no proof that circulating concentrations of sPD-1, sPD-L1, and sCTLA-4 were prognostic or predictive factors of the outcome for adjuvant chemotherapy after complete resection in patients with NSCLC.

Low-dose gemcitabine plus nab-paclitaxel versus standard-dose gemcitabine plus nab-paclitaxel in elderly patients with metastatic pancreatic cancer: A randomized Phase II trial.

Background and Aim: A multicenter, open-label randomized Phase II trial was conducted to determine whether low-dose gemcitabine plus nab-paclitaxel (GnP) could improve tolerability and show equivalent efficacy to the standard-dose GnP for elderly patients with metastatic pancreatic cancer. Methods: Consecutive patients aged ≥65 years with metastatic pancreatic cancer who presented at one of four Japanese referral centers between November 2016 and January 2021 were enrolled. The 60 patients were randomly assigned to low- or standard-dose groups with a 1:1 ratio. Patients in the low-dose GnP group received gemcitabine at a dose of 250 mg/m2 and nab-paclitaxel at 125 mg/m2. Results: Low-dose GnP significantly decreased the rate of cases requiring dose reduction (16.7% vs 63.3%). The response rate (36.7% vs 33.3%) and progression-free survival (7.3 vs 8 months) were comparable between the low- and standard-dose groups as determined by independent review. The difference in the median overall survival between the two groups was not significant (7.9 vs 12 months). The proportion of patients with hematologic and non-hematologic treatment-related adverse events was comparable between the two groups. Conclusion: Low-dose GnP had an equivalent efficacy to conventional therapy; however, it did not reduce adverse events.

Impact of Smad4 and p53 mutations on the prognosis of patients with pancreatic ductal adenocarcinoma undergoing chemotherapy.

BACKGROUND: This prospective cohort study evaluated the feasibility of using endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) samples for comprehensive mutational analysis of cancer-related genes using microtissues. METHODS: Fifty patients with suspected pancreatic cancer presenting consecutively at the Kindai University Hospital between January 2018 and January 2019 were enrolled. Cancerous tissues from EUS-FNB were obtained from each tumor and subjected to histological examination and mutational analysis. The primary endpoint was the collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing. Clinical history and genetic variations between the disease control and progressive disease groups of patients on chemotherapy were evaluated as secondary endpoints. RESULTS: The collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing was 93.6%. The cancer panel was sequenced for 25 patients with pancreatic cancer treated initially with systemic chemotherapy. Mutation in p53 and Smad4 were positively and negatively associated, respectively, with disease control at the initial evaluation. The median time to progression in 15 patients with p53 and without Smad4 mutations was 182.0 days; whereas, it was 92.5 days in other 10 patients; this difference was significant (p = 0.020). CONCLUSIONS: Tissue samples from EUS-FNB were suitable for mutational analysis. Pancreatic cancers with p53 and without Smad4 mutations responded better to chemotherapy and had a better prognosis than those others.

Novel single nucleotide polymorphism biomarkers to predict opioid effects for cancer pain.

There have been few studies on predictive biomarkers that may be useful to select the most suitable opioids to optimize therapeutic efficacy in individual patients with cancer pain. We recently investigated the efficacy of morphine and oxycodone using single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) rs4680 gene as a biomarker (RELIEF study). To explore additional biomarkers that may enable the selection of an appropriate opioid for individual patients with cancer pain, three SNPs were examined: C-C motif chemokine ligand 11 (CCL11; rs17809012), histamine N-methyltransferase (HNMT; rs1050891) and transient receptor potential V1 (TRPV1; rs222749), which were screened from 74 pain-related SNPs. These SNPs, which were identified as being significantly associated with the analgesic effect of morphine, were then used to genotype the 135 patients in the RELIEF study who had been randomized into a morphine group (n=69) or an oxycodone group (n=66). The present study then assessed whether the SNPs could also be used as selective biomarkers to predict which opioid(s) might be the most suitable to provide pain relief for patients with cancer. Oxycodone tended to provide superior analgesic effects over morphine in patients carrying the genotype AA for the CCL11 rs17809012 SNP (P=0.012 for interaction), suggesting that it could serve as a potential biomarker for personalized analgesic therapy for patients suffering with cancer pain.

Survival impact of microsatellite instability in stage II gastric cancer patients who received S-1 adjuvant monotherapy after curative resection.

Adjuvant S-1 monotherapy is the standard of care for stage II gastric cancer (GC) after curative resection in Japan, but its efficacy for microsatellite instability-high (MSI-H) tumors has remained unknown. Among a multi-institutional cohort of patients with stage II GC who underwent R0 resection followed by S-1 adjuvant chemotherapy between February 2008 and December 2018, we assessed MSI status with an MSI-IVD Kit (Falco). MSI status was assessable for 184 (88.5%) of the 208 enrolled patients, with MSI-H being identified in 24 (13.0%) individuals. Although neither relapse-free survival (RFS) (hazard ratio [HR] = 1.00, p = 0.997) nor overall survival (OS) (HR = 0.66, p = 0.488) differed between MSI-H versus microsatellite-stable (MSS) patients, MSI-H patients showed a nonsignificant but better RFS (HR = 0.34, p = 0.064) and OS (HR = 0.22, p = 0.057) than did MSS patients after adjustment for background characteristics by propensity score (PS) analysis. Gene expression analysis in the PS-matched cohort suggested that recurrence was associated with the immunosuppressive microenvironment in MSI-H tumors but with expression of cancer/testis antigen genes in MSS tumors. Our data reveal a better adjusted survival for MSI-H versus MSS stage II GC treated with S-1 adjuvant therapy, and they suggest that mechanisms of recurrence differ between MSI-H and MSS tumors.

Tumor Microenvironment Landscape of NSCLC Reveals Resistance Mechanisms for Programmed Death-Ligand 1 Blockade After Chemoradiotherapy: A Multicenter Prospective Biomarker Study (WJOG11518L:SUBMARINE).

INTRODUCTION: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE). METHODS: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers. RESULTS: The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocyte density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8+ tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity. CONCLUSIONS: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.

Alternating Therapy With Osimertinib and Afatinib Blockades EGFR Secondary Mutation in EGFR-Mutant Lung Cancer: A Single-Arm Phase II Trial.

BACKGROUND: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Although osimertinib or afatinib alone induced drug-resistant clones with EGFR secondary mutation in a preclinical model, its combination prevented the appearance of these mutations. We investigated alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC in a single-arm Phase II trial. METHODS: Treatment-naïve patients with stage IV NSCLC harboring an activating EGFR mutation were enrolled. Alternating cycles of osimertinib (80 mg/day) followed by afatinib (20 mg/day) were administered every 8 weeks. Genomic analysis was performed using circulating tumor DNA obtained before and after the treatment. RESULTS: Among the 46 enrolled patients, the median progression-free survival was 20.2 months. The overall response rate was 69.6%. The median overall survival was not reached. Among the 26 plasma samples obtained after the acquisition of resistance, 3 showed an increased MET gene copy number, and 1 showed BRAF mutation. Meanwhile, no EGFR secondary mutation was detected. CONCLUSION: The efficacy of our treatment was not significantly different from osimertinib alone, as reported previously in untreated advanced NSCLC patients with EGFR mutations. Although the sample size was limited, this treatment may prevent the emergence of EGFR secondary mutations that trigger drug resistance. Further studies are warranted to establish the significance of this treatment. CLINICAL TRIAL REGISTRATION: jRCTs051180009.

Multicentre, randomised, double-blind, placebo-controlled phase II study of prophylactic olanzapine for patients with metastatic breast cancer receiving T-DXd treatment: protocol for the ERICA study (WJOG14320B).

INTRODUCTION: The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has led to a change in the clinical management of breast cancer. Nausea and vomiting are the most common adverse events of T-DXd, which cannot be completely alleviated by standard prophylactic regimens. Olanzapine is particularly effective in preventing delayed nausea caused by chemotherapy. In this study, we will evaluate the efficacy of olanzapine in managing persistent nausea and vomiting during T-DXd treatment. METHODS AND ANALYSIS: The ERICA study is a multicentre, placebo-controlled, double-blind, randomised phase II study with the aim to evaluate the antiemetic effects of the prophylactic olanzapine (5 mg orally, on days 1-6) or placebo combined with a 1,5-hydroxytryptamine-3 (5-HT3)-receptor antagonist and dexamethasone in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer undergoing T-DXd treatment. For a period of 22 days from the day of T-DXd treatment, patients will document their experience in an electronic symptom diary daily during observational periods. The primary endpoint is the complete response rate, defined as no vomiting and no rescue medications during the 'delayed phase' of 24-120 hours post-T-DXd administration. In addition, we define 120-504 hour as the 'persistent phase' and 0-504 hours as the 'overall phase' for secondary endpoint analysis. We have estimated that a total sample size of at least 156 patients is needed to allow a power of 80% at a one-sided significance level of 20% in this study. The target sample size is set to 166 to account for possible case exclusions. ETHICS AND DISSEMINATION: The study protocol is approved by the West Japan Oncology Group protocol review committee and the SHOWA University Clinical Research Review Board. The study results will be presented at international conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTs031210410.

The usefulness of the endoscopic surgical skill qualification system in laparoscopic right hemicolectomy: a single-center, retrospective analysis with propensity score matching.

PURPOSE: Recently, a new certification system called the Endoscopic Surgical Skill Qualification System (ESSQS) has been launched in Japan to improve surgical safety. This study aimed to determine whether ESSQS-qualified surgeons affect the short- and long-term outcomes of laparoscopic right hemicolectomy. METHODS: A total of 187 colon cancer patients who underwent laparoscopic right hemicolectomy at Kindai University Hospital between January 2016 and December 2020 were enrolled. These patients were divided into two groups based on surgeries performed by ESSQS-qualified surgeons (QS group) and non-ESSQS-qualified surgeons (NQS group). The short- and long-term outcomes were compared between the two groups before and after propensity score matching (PSM). RESULTS: After PSM, 43 patients from each group were included in the matched cohort. In the short-term outcomes, the total operative time was significantly longer in the NQS group than in the QS group (229 vs. 174 min, p < 0.0001). However, there were no significant differences in the two groups regarding blood loss (0 vs. 0 ml, p = 0.7126), conversion (0.0% vs. 7.0%, p = 0.0779), Clavien-Dindo ≥ 2 complications (9.3% vs. 7.0%, p = 0.6933), mortality (2.3% vs. 0.0%, p = 0.3145), and postoperative hospital stay (9 vs. 9 days, p = 0.5357). In the long-term outcomes, there were no significant differences between the two groups in the 3-year overall survival (86.6% vs. 83.0%, p = 0.8361) and recurrence-free survival (61.7% vs. 72.0%, p = 0.3394). CONCLUSION: Laparoscopic right hemicolectomy performed by ESSQS-qualified surgeons contributed to shorter operative time. Under the supervision of ESSQS-qualified surgeons, almost equivalent safety and oncological outcomes are expected even in surgeries performed by non-ESSQS-qualified surgeons.

Morphine Versus Oxycodone for Cancer Pain Using a Catechol-O-methyltransferase Genotype Biomarker: A Multicenter, Randomized, Open-Label, Phase III Clinical Trial (RELIEF Study).

BACKGROUND: We hypothesized that the high-dose opioid requirement in patients carrying the rs4680-GG variant in the COMT gene encoding catechol-O-methyltransferase would be greater for patients taking morphine than for those taking oxycodone, thus providing a much-needed biomarker to inform opioid selection for cancer pain. METHODS: A randomized, multicenter, open-label trial was conducted at a Japanese hospital's palliative care service. Patients with cancer pain treated with regular doses of nonsteroidal anti-inflammatory drugs or acetaminophen were enrolled and randomized (1:1) into morphine (group M) and oxycodone (group O) groups. The minimum standard dose of immediate-release (IR) oral opioids was repeatedly administered by palliative care physicians to achieve pain-reduction goals (Pain reduction ≥ 33% from baseline and up to ≤ 3 on a numerical rating scale). The primary endpoint was the proportion of subjects requiring high-dose opioids on day 0 with the GG genotype. RESULTS: Of 140 participants who developed cancer-related pain among 378 subjects registered and pre-screened for the genotype, 139 were evaluated in the current study. Among patients carrying a COMT rs4680-GG genotype, 48.3% required high-dose opioids in group M, compared with the 20.0% in group O (95% CI, 3.7%-50.8%; P = .029). Of those with the non-GG genotype, 41.5% treated with morphine and 23.1% with oxycodone required high-dose opioids (95% CI, 3.3%-38.3%; P = 0.098). CONCLUSION: Using the COMT rs4680 genotype alone is not recommended for selecting between morphine and oxycodone for pain relief.

Implication of changes in PD-L1 expression during neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen in esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant docetaxel plus cisplatin and 5-FU (NAC-DCF) and adjuvant nivolumab monotherapy are the standard care for locally advanced resectable esophageal squamous cell carcinoma (ESCC). However, no effective biomarkers have been found in perioperative setting. We investigated how programmed death-ligand 1 (PD-L1) changes before and after NAC-DCF and how it relates to the therapeutic effect of NAC-DCF in resectable ESCC. METHODS: PD-L1 expression in paired diagnostic biopsy and surgically resected tissues from ESCC patients who underwent surgical resection after receiving two or three NAC-DCF cycles was evaluated. PD-L1 positivity was defined as a combined positive score (CPS) of 10% ≤ . Gene expression analysis was conducted using samples before NAC-DCF. RESULTS: Sixty-six paired samples from 33 patients were included in PD-L1 expression analysis, and 33 Pre-NAC samples acquired by diagnostic biopsy were included in gene expression analysis. Pretreatment, 3 (9%), 13 (39%), and 17 (52%) patients harbored tumors with CPS ranges of < 1%, 1%-10%, and 10% ≤ , respectively. After NAC-DCF, 5 (15%), 15 (45%), and 13 (39%) tumors presented CPS ranges of < 1%, 1%-10%, and 10% ≤ , respectively. The concordance rate between Pre-and Post-NAC-DCF samples was 45%. Patients with PD-L1-negative tumors both before and after NAC-DCF (n = 9) had shorter survival and different gene expression profile characterized by upregulation in WNT signaling or neutrophils. CONCLUSIONS: A substantial PD-L1 expression alteration was observed, resulting in low concordance rate before and after NAC-DCF. Tumors persistently lacking PD-L1 had distinct gene expression profile with worse clinical outcomes, raising the need for further investigation.

Feasibility and efficacy of endoscopic reintervention after covered metal stent placement for EUS-guided hepaticogastrostomy: A multicenter experience.

Background and Objectives: Although the use of a long metal stent is favored for EUS-guided hepaticogastrostomy (EUS-HGS) for the relief of malignant biliary obstruction (MBO), endoscopic reintervention (E-RI) at the time of recurrent biliary obstruction (RBO) is challenging due to a long intragastric portion. This study evaluated the feasibility and safety of E-RI after a long partially covered metal stent (L-PCMS) placement during EUS-HGS. Materials and Methods: We performed a multicenter retrospective study between January 2015 and December 2019 examining patients with MBO who underwent E-RI for RBO through the EUS-HGS route after the L-PCMS placement. Technical and clinical success rates, details of E-RI, adverse events (AEs), stent patency, and survival time were evaluated. Results: Thirty-three patients at eight referral centers in Japan who underwent E-RI through the EUS-HGS route were enrolled. The location of MBO was distal in 54.5%. The median intragastric length of the L-PCMS was 5 cm. As the first E-RI attempt, E-RI via the distal end of the existing L-PCMS was successful in 60.6%. The overall technical and clinical success rates of E-RI were 100% and 81.8%, respectively. Liver abscess was noted in one patient. A proximal biliary stricture was associated with the clinical ineffectiveness of E-RI in multivariable analysis (odds ratio, 12.5, P = 0.04). The median survival and stent patency duration after E-RI were 140 and 394 days, respectively. Conclusions: Our study findings suggest that E-RI for RBO after EUS-HGS with a L-PCMS is technically feasible and clinically effective, without any severe AEs, especially for patients with distal MBO.

Contribution of MMP14-expressing cancer-associated fibroblasts in the tumor immune microenvironment to progression of colorectal cancer.

Matrix metalloproteinase 14 (MMP14) expression is implicated in progression of colorectal cancer, but its role in the tumor microenvironment (TME) has been unclear. The relevance of MMP14 to colorectal cancer progression was explored by analysis of transcriptomic data for colorectal adenocarcinoma patients (n = 592) in The Cancer Genome Atlas. The role of MMP14 in the TME was investigated in a retrospective analysis of tumor samples from 86 individuals with stage III colorectal cancer by single cell-based spatial profiling of MMP14 expression as performed by 12-color multiplex immunohistochemistry (mIHC). Analysis of gene expression data revealed that high MMP14 expression was associated with tumor progression and implicated both cancer-associated fibroblasts (CAFs) and tumor-associated macrophages in such progression. Spatial profiling by mIHC revealed that a higher percentage of MMP14+ cells among intratumoral CAFs (MMP14+ CAF/CAF ratio) was associated with poorer relapse-free survival. Multivariable analysis including key clinical factors identified the MMP14+ CAF/CAF ratio as an independent poor prognostic factor. Moreover, the patient subset with both a high MMP14+ CAF/CAF ratio and a low tumor-infiltrating lymphocyte density showed the worst prognosis. Our results suggest that MMP14+ CAFs play an important role in progression of stage III colorectal cancer and may therefore be a promising therapeutic target.

The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC.

Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056.