Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic activity of many environmental xenobiotics. However, its role in innate immune responses during viral infection is not fully understood. Here we demonstrate that constitutive AHR signaling negatively regulates the type I interferon (IFN-I) response during infection with various types of virus. Virus-induced IFN-ß production was enhanced in AHR-deficient cells and mice and resulted in restricted viral replication. We found that AHR upregulates expression of the ADP-ribosylase TIPARP, which in turn causes downregulation of the IFN-I response. Mechanistically, TIPARP interacted with the kinase TBK1 and suppressed its activity by ADP-ribosylation. Thus, this study reveals the physiological importance of endogenous activation of AHR signaling in shaping the IFN-I-mediated innate response and, further, suggests that the AHR-TIPARP axis is a potential therapeutic target for enhancing antiviral responses.

Phase II Study of Ramucirumab Plus Irinotecan Combination Therapy as Second-Line Treatment in Patients with Advanced Gastric Cancer: HGCSG1603.

BACKGROUND: Ramucirumab is a human IgG1 monoclonal vascular endothelial growth factor receptor-2 antibody that inhibits tumor cell growth and affects the tumor cell microenvironment. We assessed the efficacy and safety of ramucirumab plus irinotecan combination therapy as second-line treatment in patients with previously treated advanced gastric cancer. MATERIALS AND METHODS: Patients with advanced gastric cancer refractory or intolerant to primary chemotherapy were included. Ramucirumab 8 mg/kg plus irinotecan 150 mg/m2 combination therapy was administered every 2 weeks. The primary endpoint was progression-free survival rate at 6 months and secondary endpoints were overall survival, progression-free survival, response rate, safety, and dose intensity for each drug. RESULTS: Thirty-five patients were enrolled between January 2018 and September 2019. The progression-free survival rate at 6 months was 26.5% [95%CI, 13.2%-41.8%, P = .1353)]. Median progression-free and overall survivals were 4.2 months (95%CI, 2.5-5.4 months) and 9.6 months (95%CI, 6.4-16.6 months), respectively. The overall response rate was 25.9% (95%CI, 11.1-36.3%) and disease control rate was 85.2% (95%CI, 66.3-95.8%). Grade ≥3 adverse events that occurred in >10% of patients included neutropenia, leucopenia, anemia, anorexia, and febrile neutropenia. No death or new safety signals with a causal relation to the study treatment were observed. CONCLUSION: Although the primary endpoint was not achieved statistically, combination therapy of ramucirumab plus irinotecan showed anticancer activity and a manageable safety profile for second-line treatment of patients with advanced gastric cancer.

Feasibility of edoxaban for asymptomatic cancer-associated thrombosis in Japanese patients with gastrointestinal cancer: ExCAVE study.

BACKGROUND: Although initial therapy with a parenteral anticoagulant is required before edoxaban, this strategy is frequently avoided in actual clinical practice because of its complexity. This study assessed the feasibility of edoxaban without initial heparin usage for asymptomatic cancer-associated thrombosis (CAT) in Japanese patients with gastrointestinal cancer (GIC) at high risk of bleeding. METHODS: In this multicenter prospective feasibility study conducted at 10 Japanese institutions, patients with active GIC who developed accidental asymptomatic CAT during chemotherapy were recruited. Edoxaban was orally administered once daily without initial parenteral anticoagulant therapy within 3 days after detecting asymptomatic CAT. The primary outcome was the incidence of major bleeding (MB) or clinically relevant non-major bleeding (CRNMB) during the first 3 months of edoxaban administration. RESULTS: Of the 54 patients enrolled from October 2017 to September 2020, one was excluded because of a misdiagnosis of CAT. In the remaining 53 patients, the primary outcome occurred in six patients (11.3%). MB occurred in four patients (7.5%), including gastrointestinal bleeding in three patients and intracranial hemorrhage in one patient. CRNMB occurred in two patients (3.8%), including bleeding from the stoma site and genital bleeding in one patient each. There were no deaths attributable to bleeding, and all patients who experienced MB or CRNMB recovered. CONCLUSIONS: The risk of bleeding after edoxaban without heparin pretreatment was acceptable, demonstrating new treatment options for asymptomatic CAT in patients with GIC.

Multicenter, prospective, observational study of chemotherapy-induced dysgeusia in gastrointestinal cancer.

PURPOSE: Dysgeusia is an adverse event caused by chemotherapy. Although retrospective studies have shown zinc administration improves dysgeusia, there have been no prospective studies. The present study examined effects of zinc therapy on dysgeusia in patients with gastrointestinal cancer. METHODS: This multicenter, prospective, observational study enrolled patients with dysgeusia during chemotherapy treatment. Patients received no intervention (control), polaprezinc p.o., or zinc acetate hydrate p.o., and serum zinc levels were measured at 0 (baseline), 6, and 12 weeks. Dysgeusia was assessed using CTCAE v5.0 and subjective total taste acuity (STTA) criteria using questionnaires at baseline and 12 weeks. RESULTS: From February 2020 to June 2021, 180 patients were enrolled from 17 institutes. There were no differences in mean baseline serum zinc levels among the groups (67.3, 66.6, and 67.5 µg/dL in the no intervention, polaprezinc, and zinc acetate hydrate groups, respectively. P = 0.846). The changes in mean serum zinc levels after 12 weeks were - 3.8, + 14.3, and + 46.6 µg/dL, and the efficacy rates of dysgeusia were 33.3%, 36.8%, and 34.6% using CTCAE and 33.3%, 52.6%, 32.7% using STTA in the no intervention, polaprezinc, and zinc acetate hydrate groups, respectively. The STTA scores improved in all groups, with significant improvement observed in the polaprezinc group compared with the no intervention group (P = 0.045). CONCLUSION: There was no significant correlation between the degree of serum zinc elevation and improvement in dysgeusia, suggesting that polaprezinc, but not zinc acetate hydrate, was effective in improving chemotherapy-induced dysgeusia. TRIAL REGISTRATION: UMIN000039653. Date of registration: March 2, 2020.

Impact of single-heterozygous UGT1A1 on the clinical outcomes of irinotecan monotherapy after fluoropyrimidine and platinum-based combination therapy for gastric cancer: a multicenter retrospective study.

BACKGROUND: It is unclear whether the UGT1A1 status, single heterozygous (SH) or wild type (WT), is associated with the efficacy and toxicity of irinotecan monotherapy in advanced gastric cancer (AGC). We investigated the association between clinical outcomes (efficacy and safety) and UGT1A1 status in patients who received irinotecan monotherapy. METHODS: We evaluated AGC patients who received irinotecan monotherapy between January 2011 and December 2017. Efficacy was assessed according to overall survival (OS) and progression-free survival (PFS). Toxicity was graded using the Common Toxicity Criteria for Adverse Events (version 4.0). RESULTS: A total of 100 patients were evaluated (62 and 38 patients with UGT1A1 WT and SH, respectively). In the WT and SH groups, the irinotecan dose was reduced in 19 (30.6%) and 18 (47.2%) patients (p = 0.135), respectively; treatment was delayed due to adverse events (AEs) in 19 (30.6%) and 13 (34.2%) patients (p = 0.826), respectively; the median PFS was 3.15 and 3.25 months (HR, 0.734; 95% CI 0.465-1.158; p = 0.184), respectively; and the median OS was 10.4 and 7.26 months (HR, 1.137; 95% CI 0.752-1.721; p = 0.543), respectively. Severe hematological AEs (Grade ≥ 3) were significantly more frequent in the SH group than in the WT group (63% vs. 36%; p = 0.008), while severe non-hematological AEs was not significantly different (16.0% vs. 6.5%; p = 0.173). CONCLUSION: There was no significant difference in the efficacy of irinotecan monotherapy between UGT1A1 WT and UGT1A1 SH, but UGT1A1 SH was associated with a high frequency of severe hematological toxicity.

Safety of Cold Polypectomy for Colorectal Polyps in Patients on Antithrombotic Medication.

BACKGROUND: The cold polypectomy (CP) technique has been increasingly used in recent years. However, there have been few studies about post-polypectomy bleeding (PPB) in patients who underwent CP and who were on antithrombotic drugs. The objective of this study was to determine the safety of CP in patients on antithrombotic medication. METHODS: The subjects were patients who underwent CP in our hospital between April 2014 and March 2016. PPB rates were examined in relation to the use of antithrombotic medication. RESULTS: CP was performed to remove 2,466 polyps in 1,003 patients. There were 549 polyps (22.3%) in186 patients in the antithrombotic group and 1,917 polyps (77.7%) in 817 patients in the non-antithrombotic group. PPB occurred in 0.55% (3/549) of patients in the antithrombotic group and in 0.10% (2/1,917) of patients in the non-antithrombotic group, showing no significant difference (p = 0.07). Patients in the antithrombotic group in whom PPB occurred included 1 aspirin user with 1 polyp and 1 aspirin plus clopidogrel user with 2 polyps. No PPB occurred in patients on other antithrombotic agents or receiving heparin bridging. There was no significant difference between PPB rates in patients with small polyps (6-9 mm) in the antithrombotic and non-antithrombotic groups, but there was a significant difference between PPB rates in the 2 groups for patients with diminutive group (1-5 mm). CONCLUSION: CP is a safe procedure even in patients on antithrombotic medication.

Study protocol of HGCSG1404 SNOW study: a phase I/II trial of combined chemotherapy of S-1, nab-paclitaxel and oxaliplatin administered biweekly to patients with advanced gastric cancer.

BACKGROUND: In Japan, S-1 plus cisplatin (SP) regimen has become a standard therapy for patients with advanced gastric cancer. Moreover, the S-1 plus oxaliplatin regimen is now a standard treatment. Nab-paclitaxel was developed for chemotherapy of gastric cancer in Japanese clinical practice. Nab-paclitaxel, created with albumin-bound paclitaxel particles, has high transferability to tumour tissues and does not cause hypersensitivity reactions because of a different chemical composition compared with docetaxel and paclitaxel. A combination of S-1, nab-paclitaxel and oxaliplatin (which we named 'SNOW regimen') can be a promising triplet therapy for advanced gastric cancer. Although we have to pay attention to chemotherapy-induced neuropathy, we aim to investigate the recommended dose of this regimen in a phase I study. Furthermore, we will investigate its efficacy and toxicity in a phase II study. METHODS: The phase I study is a dose-escalation study using a standard 3 plus 3 design, followed by expansion cohorts. The SNOW regimen involves 28-day cycles with escalated doses of nab-paclitaxel (100-175 mg/m2 on days 1 and 15) and fixed doses of oxaliplatin (65 mg/ m2 on days 1 and 15) and S-1 (80 mg/m2/day on day 1 to 14). The primary endpoints are assessment of dose limiting toxicities and determination of maximum tolerated dose to investigate the recommended dose in the subsequent phase II study. In the phase II study, the primary endpoint is objective response rate. Secondary endpoints are assessment of safety, progression-free survival, disease control rate, overall survival and time to treatment failure. Adverse events were monitored and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. DISCUSSION: Triplet therapies for advanced gastric cancer patients have been evaluated in clinical trials. The SNOW regimen can be a promising new triplet therapy. TRIAL REGISTRATION: This study is performed at institutes that participate in Hokkaido Gastrointestinal Cancer Study Group (HGCSG) and registered as UMIN000016788 . Registrated 16 March 2015.

[Clinical impact of addition of bevacizumab to the first-line chemotherapy regimen in the treatment of patients with metastatic colorectal cancer].

BACKGROUND: Combination regimens containing bevacizumab(BV)are regarded as one of the standard first-line chemotherapy (1stCTx) regimens in the treatment of metastatic colorectal cancer (mCRC). However, some patients cannot be treated with BV because of the short interval from the palliative operation or other reasons. We present a study of some patients who were treated with add-on BV in the middle of the 1stCTx before disease progression(referred to as "midway BV" regimen hereafter), and here, we report the efficacy of the midway BV regimen as observed in our patients. RESULTS: We retrospectively analyzed the data of 74 mCRC patients, who were undergoing 1stCTx treatment at our hospital from January 2010 to September 2012. We divided the patients into 3 groups, depending on when BV was introduced in their regimen: 40, 25, and 9 patients were respectively included in the "no-BV" group (patients who were treated without BV in the 1stCTx), BV group(patients treated with BV from the 1st cycle in the 1stCTx), and the midway-BV group (patients who were initially treated without BV and then received add-on BV). The response rates of patients in the no-BV, BV, and midway-BV groups were 27.5%, 44.0%, and 55.6%, respectively. The median progression-free survival (PFS) and median survival time of patients in the no-BV, BV, and midway-BV groups were, respectively, 9.7 months, 9.3 months, and 12.8 months, and 20.3 months, 22.2 months, and N. R. CONCLUSION: Although few cases were analyzed and there might be many confounding factors, our study suggests that midway BV is potentially useful for patients with metastatic colorectal cancer who are not initially treated with BV in the first cycle of the 1stCTx regimen.

Correlation of UGT1A1 Gene Polymorphisms or Prior Irinotecan Treatment and Treatment Outcomes of Nanoliposomal-Irinotecan plus 5-Fluorouracil/Leucovorin for Pancreatic Ductal Adenocarcinoma: A Multicenter, Retrospective Cohort Study (HGCSG2101).

The effects of UGT1A1 gene polymorphisms or prior irinotecan treatment on treatment outcomes of nanoliposomal-irinotecan plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with unresectable pancreatic ductal adenocarcinoma (PDAC) are not established. This multicenter, retrospective cohort study compared treatment outcomes in patients with UGT1A1*1/*1 and those with UGT1A1*1/*6 or *1/*28 genotypes. We also analyzed the impact of prior irinotecan treatment on survival outcomes in 54 patients treated with nal-IRI+5-FU/LV. Comparable effectiveness was found regardless of the UGT1A1 genotypes. While no significant differences were found, grade ≥3 neutropenia and febrile neutropenia were more frequent in patients with UGT1A1*1/*6 or *1/*28 than in those with UGT1A1*1/*1 genotypes (grade ≥3 neutropenia, 50.0% vs. 30.8%, p = 0.24; febrile neutropenia, 9.1% vs. 0.0%, p = 0.20, respectively). No significant difference in progression-free survival (PFS) and overall survival (OS) was observed between irinotecan-naïve-patients and other patients. However, irinotecan-resistant patients showed significantly shorter PFS (hazard ratio (HR) 2.83, p = 0.017) and OS (HR 2.58, p = 0.033) than other patients. Our study indicated that patients with UGT1A1*1/*6 or *1/*28 may be prone to neutropenia, though further study is needed. The survival benefit of nal-IRI+5-FU/LV could be maintained in patients without disease progression after irinotecan therapy.

Study protocol of the HGCSG1803: a phase II multicentre, non-randomised, single-arm, prospective trial of combination chemotherapy with oxaliplatin, irinotecan and S-1 (OX-IRIS) as first-line treatment for metastatic or relapsed pancreatic cancer.

INTRODUCTION: Combination chemotherapy with oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) has become one of the standard treatments for metastatic pancreatic cancer. However, the use of FOLFIRINOX requires prolonged infusion. Therefore, we planned to develop a new combination chemotherapy regimen with oxaliplatin, irinotecan and S-1 (OX-IRIS) for advanced pancreatic cancer. In the phase Ⅰ study that was conducted previously, the safety and recommended dose of OX-IRIS were assessed. In this study, we will evaluate the efficacy and safety of OX-IRIS. METHODS AND ANALYSIS: The HGCSG1803 study started as a multicentre, non-randomised, single-arm, prospective, phase II study in December 2019. Eligible subjects were patients with untreated metastatic or relapsed pancreatic cancer. OX-IRIS is administered as follows: 30 min infusion of antiemetic; 2-hour infusion of oxaliplatin (65 mg/m2); 1.5-hour infusion of irinotecan (100 mg/m2) on day 1 and 15 of each 4-week cycle; and oral S-1 (40 mg/m2) twice daily from after dinner on day one to after breakfast on day 15, followed by a 14-day rest, to be repeated every 2 weeks until disease progression, unacceptable toxicity or patient refusal. The primary endpoint is response rate. The secondary endpoints are overall and progression-free survival, safety and dose for each drug. Using a binomial test, a sample size of 40 patients was set with a threshold value of 10% and expected value of 30%. Registration of 40 cases is planned from 18 institutions in Japan. ETHICS AND DISSEMINATION: All the procedures will be conducted in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki of 1964 and its later versions. All the patients will receive written information about the trial and will provide informed consent before enrolment. This trial was approved by the Hokkaido University Certified Review Board (approval No: 018-037). TRIAL REGISTRATION NUMBER: jRCTs011190008.

Study protocol for HGCSG1801: A multicenter, prospective, phase II trial of second-line FOLFIRI plus aflibercept in patients with metastatic colorectal cancer refractory to anti-EGFR antibodies.

Background: The first-line chemotherapy for patients with RAS and BRAF wild-type metastatic colorectal cancer (mCRC) commonly involves cytotoxic regimens, such as FOLFOX and FOLFIRI, combined with epidermal growth factor receptor (EGFR) antibodies. When progression occurs following anti-EGFR antibody-combined chemotherapy, anti-angiogenic inhibitors can be used as second-line treatment. Although randomized controlled trials have shown that anti-angiogenic inhibitors [bevacizumab, ramucirumab, and aflibercept (AFL)] carry survival benefit when combined with FOLFIRI as second-line chemotherapy, such trials did not provide data on patients with mCRC refractory to anti-EGFR antibody-combined chemotherapy. Therefore, our group planned a multicenter, nonrandomized, single-arm, prospective, phase II study to investigate the safety and efficacy of FOLFIRI plus AFL as a second-line chemotherapy for patients with mCRC refractory to oxaliplatin-based chemotherapy combined with anti-EGFR antibodies. Methods: FOLFIRI (irinotecan 180 mg/m2, l-leucovorin 200 mg/m2, bolus 5-FU 400 mg/m2, and infusional 5-FU 2400 mg/m2/46 h) and AFL (4 mg/kg) will be administered every 2 weeks until progression or unacceptable toxicities occur. The primary endpoint will be the 6-month progression-free survival (PFS) rate, whereas the secondary endpoints will include overall survival, PFS, response rate, disease control rate, adverse events, and relative dose intensity for each drug. A sample size of 41 participants will be required. This study will be sponsored by the Non-Profit Organization Hokkaido Gastrointestinal Cancer Study Group and will be supported by a grant from Sanofi. Discussion: There is only an observational study reporting data on FOLFIRI plus AFL for patients with mCRC who previously received anti-EGFR antibodies; therefore, a prospective clinical trial is needed. This study will prospectively evaluate the efficacy and safety of FOLFIRI plus AFL in patients with mCRC who are resistant to anti-EGFR antibodies and have limited data. Moreover, this study will reveal predictive biomarkers for AFL-based chemotherapy. Clinical trial registration: Japan Registry of Clinical Trials, jRCTs011190006. Registered 19 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs011190006.

[Repetition of Helicobacter cinaedi infections during chemotherapy for malignant lymphoma].

A 70-year-old male, who had undergone resection of gastric malignant lymphoma in 1992, presented with cervical lymph node swelling in January 2008. Pathological examination of the lymph node biopsy demonstrated recurrence of malignant lymphoma, and he was treated with the R-CHOP regimen. Although he did not develop fever during the first through third course of R-CHOP, from the fourth course, he repeatedly demonstrated fever over 38°C for about one week after each course of chemotherapy, despite the absence of neutropenia. Helicobacter cinaedi infection was confirmed by blood culture each time. Although it is difficult to diagnose Helicobacter cinaedi infection by the standard culture method, increased numbers of recent reports especially in immunocompromised patients have emphasized the importance of diagnosing Helicobacter cinaedi infection.

POEMS syndrome complicated by follicular lymphoma.

A 59-year-old woman presented with ascites and intraperitoneal lymph node swelling. Pathological examination of the lymph node revealed follicular lymphoma. After a lymph node biopsy, she developed atypical genital bleeding, multiple endocrine disorders, polyneuropathy with a high plasma level of vascular endothelial growth factor (VEGF), and was diagnosed with POEMS syndrome. Following administration of methyl prednisolone, ascites immediately decreased and her performance status improved; however, about 18 months later, renal failure occurred, and she died despite increased steroid dosage. Lymph node swelling is often found in POEMS syndrome; however, its histological appearance is not well known, and it is very rare to be concomitant with malignant lymphoma. Therefore, it is important to perform a lymph node biopsy and investigate it in relation with VEGF.

[Imatinib mesylate plus G-CSF therapy for chronic myelogenous leukemia in the blastic crisis].

Imatinib mesylate (imatinib) has shown significant effects in patients with chronic myelogenous leukemia. However, hematological toxicity often occurs and requires dosage reduction or discontinuation of imatinib treatment. A patient with chronic myelogenous leukemia in the blastic crisis received granulocyte-colony stimulating factor (G-CSF) simultaneously with imatinib. The patient was continuously treated with imatinib and G-CSF and achieved remission without any severe infection or neutropenia. There are a few reports on the efficacy of combined therapy with G-CSF and imatinib; however, the results in our case are rare suggesting that the use of G-CSF is effective for preventing severe infection. G-CSF enables continuous treatment with high-dose imatinib.

Undiagnosed collecting duct carcinoma presenting as meningeal carcinomatosis and multiple bone metastases.

A 54-year-old woman presented with blepharoptosis, numbness in the lower lip, dysgeusia and pain in the extremities and back. MRI showed marked meningeal thickening and multiple bone lesions accompanying a prominent enhancing effect. CT scan of the chest and abdomen appeared to be unremarkable for primary cancer. She died 3 months after the admission, and postmortem autopsy showed a mass of about 2.5 cm in diameter in the renal medulla. Histological examination including immunohistochemistry confirmed the presence of a collecting duct carcinoma (CDC). This case is of particular interest because it emphasizes the possible fulminate clinical course of a small CDC.