A multi-institutional observational study evaluating the incidence and the clinicopathological characteristics of NeoRAS wild-type metastatic colorectal cancer.

PURPOSE: As circulating tumor DNA (ctDNA) measurement becomes more widespread, the "NeoRAS" phenomenon, where tissue rat sarcoma viral oncogene homolog (RAS) status converts from mutant (MT) to wild-type (WT) after treatment in metastatic colorectal cancer (mCRC), is gaining attention because ineffective epidermal growth factor receptor (EGFR) inhibitors may made effective. This study investigated its incidence and clinicopathological characteristics. PATIENTS AND METHODS: In total, 107 mCRC patients (refractory or intolerant to previous chemotherapies) with tissue RAS MT were enrolled in four institutions from June 2021 to August 2022. The RAS status in ctDNA was assessed using OncoBEAM™ RAS CRC assay. Clinicopathologic features were compared between patients according to their RAS status in ctDNA, whether WT conversion was noted or not. RESULTS: The incidence rate of NeoRAS WT mCRC was 21.5% (23/107). According to tissue RAS mutation sites, NeoRAS WT frequency in patients with KRAS mutation in exon 2 was significantly lower than those in exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). Regarding clinical background, there were significant differences in NeoRAS WT frequency between male vs female patients (30.6% [19/62] vs 8.9% [4/45], P = 0.008), and absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P < 0.001). Comparing the two groups divided by the median value, NeoRAS WT was associated with smaller tumor diameter (>60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P < 0.001), lower carcinoembryonic antigen level (>38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), and lower carbohydrate antigen 19-9 level (>158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). In the logistic regression multivariate analysis, liver metastasis absence (Odds ratio [OR], 4.62; P = 0.019), smaller tumor diameter (OR, 7.92; P = 0.012), and tissue RAS MT in other than KRAS exon 2 (OR, 9.04; P = 0.026) were significantly related to the conversion to NeoRAS WT in ctDNA. CONCLUSIONS: Original RAS variants in tissue, tumor diameter, and liver metastasis are related to conversion to NeoRAS WT mCRC in ctDNA.

Multicentre single-arm phase II trial evaluating the safety and effiCacy of Panitumumab and iRinOtecan in NeoRAS Wild-type mEtaStatic colorectal cancer patientS (C-PROWESS trial): study protocol.

INTRODUCTION: A new concept of 'NeoRAS wild-type (WT)', which means conversion of RAS status from RAS mutant to RAS WT after treatment, has been reported. Previous observational and proof-of-concept studies have demonstrated the efficacy of epidermal growth factor receptor inhibitors in patients with NeoRAS WT metastatic colorectal cancer (mCRC). Moreover, posthoc biomarker analyses of these studies have suggested that not only the RAS status in the circulating tumour DNA (ctDNA) but also other gene mutational status may be useful as biomarkers of epidermal growth factor receptor inhibitors for NeoRAS WT mCRC. METHODS AND ANALYSIS: This trial is a multicentre, single-arm, phase II trial to assess the efficacy and safety of panitumumab plus irinotecan therapy for patients with NeoRAS mCRC. The key eligibility criteria include RAS mutant mCRC initially proven in tumour tissue refractory or intolerant to fluoropyrimidine, oxaliplatin and irinotecan; RAS WT in ctDNA (defined as plasma mutant allele frequencies of all RAS ≤0.1%) within 28 days before enrolment and Eastern Cooperative Oncology Group performance status ≤2. The primary endpoint is the response rate. The target sample size is 30 patients. Biomarker analyses are planned to be performed using next-generation sequencing-based ctDNA analysis. ETHICS AND DISSEMINATION: This study was approved by the certified review board of National Cancer Center Hospital. The main results of the trial will be presented in international meetings and in medical journals. TRIAL REGISTRATION NUMBER: s031210565.

Characteristics and Endoscopic Classification of Ulcerative Lesions Affecting the Ileocecal Valve.

OBJECTIVES: The aim of this study was to propose an endoscopic classification system for ulcerative lesions on the ileocecal valve and investigate its relevance to the underlying etiology. METHODS: Among the 60,325 patients who underwent colonoscopy at our hospital from January 2006 to December 2018, patients with ulcerative lesions on the ileocecal valve were included. The following data were obtained using the hospital's medical records: sex, age, clinical diagnosis, laboratory data, and endoscopic and histological findings. Patients who have ulcerative colitis and who were not evaluated by histological examination were excluded. Ulcerative lesions on the ileocecal valve were classified into 3 groups according to their endoscopic appearance: small shallow ulcerative lesions without edematous change (group A), lateral spreading shallow ulcerative lesions with edematous change (group B), and deep deformed ulcerative lesions (group C). The association between this endoscopic classification and its clinical diagnosis, clinical course, and the interobserver reliability were evaluated. RESULTS: Of 72 patients who were eligible for analysis, 18 were assigned to group A, 9 to group B, and 45 to group C. Infectious enteritis was mainly assigned to group A (group A, 12; group B, none; and group C, 6; p < 0.0001), inflammatory bowel disease was mainly assigned to group C (group A, none; group B, 5; and group C, 35; p < 0.0001), and malignant tumor was assigned to group C only. Interobserver reliability was extremely high among the 3 examining doctors (kappa value 0.7-0.8). CONCLUSION: Endoscopic classification was divided into 3 groups for ulcerative lesions on the ileocecal valve, and this system could be beneficial for presuming their clinical diagnoses.

Tumor growth rate during re-challenge chemotherapy with previously used agents as salvage treatment for metastatic colorectal cancer: A retrospective study.

BACKGROUND: In clinical practice, the same chemotherapeutic agents are occasionally reused (re-challenge) after failure of all available standard chemotherapy options for metastatic colorectal cancer (mCRC). However, the benefits of re-challenge chemotherapy (Re-Cx) are unclear. This retrospective study evaluated the efficacy of Re-Cx, focusing on the tumor growth rate (TGR). METHODS: The study included mCRC patients with measurable lesions who received Re-Cx from November 2011 to October 2018 at National Cancer Center Hospital. Re-Cx was defined as re-administration of agents which had been used in prior lines of chemotherapy and discontinued due to disease progression. We compared the TGR immediately after initiating Re-Cx regimens with that observed at the time of disease progression during prior chemotherapy (Prior-Cx) immediately before Re-Cx. RESULTS: Of the 25 patients who received Re-Cx, five patients received two Re-Cx regimens. Therefore, a total of 30 cases of Re-Cx were analyzed in this study. The regimens of Re-Cx were oxaliplatin based (19 cases), irinotecan based (8 cases), and others (3 cases). Although the objective response rate to Re-Cx was 0%, the disease control rate was 60% (18 cases), and 40% (12 cases) showed some tumor shrinkage. We compared the effects of Re-Cx and Prior-Cx by the TGR and found that the TGR of Re-Cx was slower than that recorded in Prior-Cx in 26 of 30 cases (87%). In particular, the ratio of% TGR <0, which indicates tumor shrinkage, was obtained in 13 of 30 cases (43.3%). The median progression-free survival and overall survival after Re-Cx were 3.8 and 6.57 months, respectively. CONCLUSION: We found that Re-Cx may have some anti-tumor efficacy as salvage treatment for mCRC and these results also suggested the clinical benefits of Re-Cx.

Need to Inspect the Total Gastrointestinal Tract of Patients With Malignant Lymphomas.

BACKGROUND/AIM: Malignant lymphoma (ML) cases with overlapping gastrointestinal (GI) lesions are often encountered. We aimed to elucidate the importance of examining the GI tract in patients with ML and assess the overlap rate. PATIENTS AND METHODS: We analysed 190 patients diagnosed with GI MLs. We compared the overlap rates among the different histopathological types. RESULTS: Twenty-five (13.2%) patients had overlapping GI lesions in more than two segments. The overlap rates were 100% in mantle cell lymphomas (MCL), 27.6% in follicular lymphomas (FL), and 16.3% in diffuse large B-cell lymphomas (DLBCL). MCL, FL, and DLBCL cases showed significantly higher overlap rates than mucosa-associated lymphoid tissue lymphoma cases (p<0.01). About 64.0% of cases of ML with overlapping lesions involved the small intestine. CONCLUSION: In GI ML cases, it is ideal to examine the entire GI tract by esophagogastroduodenoscopy, colonoscopy, and capsule endoscopy and/or balloon-assisted endoscopy, especially in MCL, FL, and DLBCL.

Small Neuroendocrine Tumors of the Whole Gastrointestinal Tract Performed Endoscopic or Surgical Resections Also Show Positive for Lymphovascular Invasion.

BACKGROUND AND AIMS: In gastrointestinal neuroendocrine tumors (GI-NETs), tumor size and grading based on cellular proliferative ability indicate biological malignancy but not necessarily clinically efficient prognostic stratification. We analyzed tumor size- and grading-based prevalence of lymphovascular invasion in GI-NETs to establish whether these are true biological malignancy indicators. METHODS: We included 155 cases (165 lesions), diagnosed histologically with GI-NETs, that had undergone endoscopic or surgical resection. Patient age, sex, method of treatment, tumor size, invasion depth, lymphovascular invasion positivity according to Ki-67 index-based neuroendocrine tumor grading, distant metastases, and outcome were evaluated. The primary endpoints were the prevalence of lymphovascular invasion according to tumor size and grading. RESULTS: Overall, 24.8% were positive for lymphovascular invasion. There was a high rate of lymphovascular invasion positivity even among grade 1 cases (22.8%). The rate of lymphovascular invasion was 3.4% for grade 1 cases <5 mm, with a lymphovascular invasion rate of 8.7% for those 5-10 mm. Lymphovascular invasion ≤10% required a tumor size ≤8 mm, and lymphovascular invasion ≤5% required a tumor size ≤6 mm. A cutoff of 6 mm was identified, which yielded a sensitivity of 79% and a specificity of 63%. Even small GI-NETs grade 1 of the whole GI tract also showed positive for lymphovascular invasion. CONCLUSIONS: GI-NETs ≤10 mm had a lymphovascular invasion prevalence exceeding 10%. The lymphovascular invasion impact in GI-NET development is incompletely understood, but careful follow-up, including consideration of additional surgical resection, is crucial in cases with lymphovascular invasion.

Efficacy of second-line treatment and prognostic factors in patients with advanced malignant peritoneal mesothelioma: a retrospective study.

BACKGROUND: Standard treatment for malignant peritoneal mesothelioma has not been established, and systemic chemotherapy is administered according to malignant pleural mesothelioma. We previously reported the efficacy of cisplatin plus pemetrexed as first-line chemotherapy; however, the efficacy of second-line chemotherapy remains unknown. METHODS: We retrospectively evaluated patients with malignant peritoneal mesothelioma who started first-line systemic chemotherapy with platinum plus pemetrexed between March 2007 and February 2019 at the National Cancer Center Hospital. Patients who received second-line chemotherapy after failure of platinum plus pemetrexed were identified. We evaluated the efficacy of first- and second-line chemotherapy, and explored the prognostic factors. Survival outcomes were estimated using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards models. RESULTS: A total of 54 and 26 patients received platinum plus pemetrexed as first- and second-line chemotherapy, respectively (gemcitabine in 12 patients; taxane, six; nivolumab, three; and others, five). In all patients, the median overall survival and progression-free survival after first-line chemotherapy were 16.6 and 7.3 months, respectively. Among patients who received second-line chemotherapy, the median overall survival, progression-free survival, and second-line overall survival were 16.9, 3.2, and 9.9 months, respectively. Patients who received ≥6 cycles of platinum plus pemetrexed as first-line chemotherapy had longer overall survival after second-line chemotherapy than those who did not (hazard ratio, 0.23; 95% confidence interval: 0.06-0.82; p = 0.02). CONCLUSIONS: Second-line chemotherapy may be an option for refractory malignant peritoneal mesothelioma, especially in patients who have completed 6 cycles of platinum plus pemetrexed as first-line chemotherapy.

Photoimmunotherapy targeting biliary-pancreatic cancer with humanized anti-TROP2 antibody.

Photoimmunotherapy (PIT) is a new type of tumor-specific treatment utilizing monoclonal antibody (mAb)-photosensitizer conjugates and near-infrared (NIR) light irradiation. One potential PIT target, the type I transmembrane protein TROP2, is expressed at high levels in many cancers, including pancreatic carcinoma (PC) and cholangiocarcinoma (CC), in which its expression is correlated with poor prognosis and tumor aggressiveness. In this study, we assessed the efficacy of PIT utilizing newly developed humanized anti-TROP2 mAb conjugated to the photosensitizer IR700 (TROP2-IR700) for PC and CC. Immunohistochemistry on PC and CC tissue microarrays confirmed that TROP2 is overexpressed in about half of PC and CC specimens. Using cultured PC and CC cells, TROP2-IR700 localized TROP2-specific and target-specific cell killing was observed after NIR light irradiation. In addition, TROP2-IR700 was localized to mouse xenograft tumors expressing TROP2 after intravenous injection. PC and CC xenograft tumor growth was significantly inhibited by TROP2-targeted PIT relative to controls. The efficacy of TROP2-targeted PIT in vitro and against xenografted tumors in vivo suggests promise as a therapy for human PC and CC, both of which currently have dismal prognoses and limited therapeutic options.

High blood levels of soluble OX40 (CD134), an immune costimulatory molecule, indicate reduced survival in patients with advanced colorectal cancer.

The interaction between tumor necrosis factor receptor superfamily, member 4 (OX40) on T cells and the OX40 ligand (OX40L) on antigen­presenting cells (APCs) is a pivotal step for T­cell activation and the promotion of antitumor immunity. However, it is hypothesized that soluble OX40 (sOX40) in blood suppresses T­cell activation by blocking the OX40/OX40L interaction. In the present study, the association between blood sOX40 levels and the clinical characteristics of advanced colorectal cancer (CRC) patients was investigated. Blood was collected from 22 patients with advanced CRC. Blood sOX40 levels were determined by enzyme­linked immunosorbent assay (ELISA). Messenger RNA (mRNA) expression encoding OX40 or cytokines was analyzed by quantitative RT­PCR. Blood sOX40 levels were positively correlated with the blood levels of carbohydrate antigen (CA) 19­9, carcinoembryonic antigen (CEA), C­reactive protein (CRP) and soluble programmed cell death ligand­1 (PD­L1) in patients but negatively correlated with the blood levels of albumin. Blood sOX40 levels were not correlated with the mRNA expression of interferon (IFN)­gamma, interleukin (IL)­6, IL­10 and IL­4 in the peripheral blood mononuclear cells (PBMCs) of the patients and were not correlated with the frequency of programmed cell death­1 (PD­1) expressing CD4+, CD8+ and CD56+ cells. Notably, according to both univariate and multivariate analyses, high blood sOX40 levels were significantly correlated with a reduced survival time in patients. Although activated Jurkat cells (a human T cell line) exhibited an upregulation of sOX40 production and OX40 mRNA expression, the OX40 mRNA expression of the PBMCs of patients was not correlated with blood sOX40 levels. High blood levels of sOX40 were correlated with a reduced survival time in patients with advanced CRC, possibly associated with the suppression of antitumor immunity by sOX40.

Efficacy and safety of pemetrexed plus cisplatin as first-line chemotherapy in advanced malignant peritoneal mesothelioma.

BACKGROUND: Malignant peritoneal mesothelioma (MPeM) is a rare cancer for which no standard systemic chemotherapy has been established. While cisplatin plus pemetrexed, the standard treatment for malignant pleural mesothelioma (MPlM), is usually used for MPeM, its efficacy remains unclear. METHODS: We retrospectively reviewed the medical charts of MPeM patients who had received cisplatin plus pemetrexed as first-line chemotherapy between January 2001 and July 2016 at the National Cancer Center Hospital. Patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day1, repeated every 3 weeks until progressive disease, unacceptable toxicities or patient's refusal to continue. RESULTS: A total of 29 MPeM patients received cisplatin plus pemetrexed. Median progression-free survival and overall survival were 7.1 months (95% CI: 4.8-9.3) and 15.4 months (95% CI: 9.5-21.2), respectively. Among 16 patients with measurable lesions, the response rate was 38%. Incidences of grade 3/4 leukopenia, neutropenia, anemia and thrombocytopenia were 21%, 17%, 14% and 3%, respectively. Non-hematological toxicities were mild, and there were no treatment-related deaths. CONCLUSIONS: Cisplatin plus pemetrexed, showing consistent efficacy with MPlM, can be recommended as first-line treatment for unresectable MPeM patients.

[A case of acquired immunodeficiency syndrome with ileocecal ulcer].

We report a case of a patient with acquired immunodeficiency syndrome (AIDS) and ileocecal ulcer. A 31-year-old man was admitted with chief complaints of decreased body weight and abdominal pain. Colonoscopy revealed a round punched-out ulcer on the ileocecal valve. Initially, we suspected entero-Behçet's disease and simple ulcer as the cause of the ileocecal ulcer. However, after histologic examination of tissue biopsies obtained during colonoscopy, we diagnosed the patient as having cytomegalovirus (CMV) enteritis. Based on the patient's white blood cell depletion and CMV enteritis, we performed a human immunodeficiency virus (HIV) antibody test. The test was positive, and the diagnosis of AIDS was established. The number of patients with AIDS has been increasing in Japan; thus, we should consider the possibility of CMV enteritis and AIDS in young adult patients affected by ileocecal ulcer with no notable history.

A retrospective study of docetaxel or paclitaxel in patients with advanced or recurrent esophageal squamous cell carcinoma who previously received fluoropyrimidine- and platinum-based chemotherapy.

INTRODUCTION: Fluoropyrimidine plus platinum (FP)-based chemotherapy has been widely used as a first-line regimen for advanced or recurrent esophageal cancer, and taxanes have shown efficacy after FP-based chemotherapy, but there is no standard regimen for second-line chemotherapy (SLC). We retrospectively investigated the clinical features of taxane therapy in SLC for esophageal squamous cell carcinoma (ESCC). METHODS: The selection criteria were pathologically proven ESCC; advanced or recurrent disease previously treated with FP at our hospital; performance status (PS) 0-2; and adequate organ function. Docetaxel (DTX) was administered 3-weekly at 70 mg/m(2). Paclitaxel (PTX) was administered at 100 mg/m(2) weekly for 6 weeks, with 1 week's rest. RESULTS: The analysis covered 163 patients from August 2006 to June 2012. Median age was 64 years (range 37-83: DTX group 132 patients and PTX group 31). Progression-free survival and median overall survival (OS) were 2.3 and 6.1 months, respectively, with PTX and 2.3 and 5.3 months with DTX. Response rates were 20.7 % for PTX and 5.9 % for DTX. The rate of grades 3-4 neutropenia was higher with DTX (32.6 %) than with PTX (16.1 %). Grade 3 febrile neutropenia was seen in 6.1 % of DTX recipients but in no PTX group. According to multivariate analyses of OS, PS 2, number of metastatic sites ≧2, and CRP ≧1 mg/dL were independent predictors of poor prognosis. CONCLUSIONS: PTX and DTX were both effective in SLC for ESCC, but their toxicity profiles differed. In terms of febrile neutropenia, PTX seems more appropriate.