A phase I study to determine the maximum tolerated dose of trifluridine/tipiracil and oxaliplatin in patients with refractory metastatic colorectal cancer: LUPIN study.

Background The effectiveness of reintroducing oxaliplatin for metastatic colorectal cancer (mCRC) refractory to both oxaliplatin and irinotecan was previously reported in a phase II study (RE-OPEN). We conducted a phase I study to determine the maximum tolerated dose of oxaliplatin plus trifluridine/tipiracil (FTD/TPI) in patients with refractory mCRC. Patients and Methods Three dosages of intravenous oxaliplatin (50, 65 and 85 mg/m2) on days 1 and 15 and a fixed dose of FTD/TPI 35 mg/m2 twice daily (bid) on days 1-5 and 15-19 every 4 weeks were investigated in patients with refractory mCRC using a 3 + 3 design. Eligible patients had received prior oxaliplatin-based treatment that achieved a response or stable disease followed by confirmed disease progression at least 6 months before entering the study. Results Twelve patients were enrolled in the study. Three of six patients in the oxaliplatin 85 mg/m2 cohort had dose-limiting toxicities (DLTs) with treatment delays during the second cycle at ≥8 days due to grade ≥ 2 neutropenia or grade 2 AST/ALT increased. No DLTs were observed in the other cohorts. Grade ≥ 3 AEs were neutropenia (n = 3), thrombocytopenia (n = 1), anorexia (n = 1), and nausea (n = 1). There was no evidence of allergic reaction to oxaliplatin or severe peripheral sensory neuropathy. Conclusions A combination of FTD/TPI 35 mg/m2 bid on days 1-5 and 15-19 and oxaliplatin 85 mg/m2 on days 1 and 15 every 4 weeks could be a suitable regimen for the recommended dose of FTD/TPI plus oxaliplatin in patients with refractory mCRC.

Clinical utility of polyethylene glycol conjugated granulocyte colony-stimulating factor (PEG-G-CSF) for preventing severe neutropenia in metastatic colorectal cancer patients treated with FOLFOXIRI plus bevacizumab: a single-center retrospective study.

BACKGROUND: This study aimed to evaluate the efficacy and the safety of polyethylene glycol conjugated granulocyte colony-stimulating factor (PEG-G-CSF) for preventing neutropenia in metastatic colorectal cancer (mCRC) patients that received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab (Bev) in clinical practice. METHODS: We retrospectively analyzed mCRC patients who received FOLFOXIRI plus Bev between December 2015 and December 2017. We evaluated the efficacy of PEG-G-CSF as preventing or treating grade 3 or 4 neutropenia, the overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival (PFS), overall survival (OS), and adverse events of FOLFOXIRI plus Bev based on the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: A total of 26 patients (median age 53.5 years) were included. The ORR rate was 65.3%, the median PFS was 9.6 months (7.2-16.9), and the median OS was 24.2 months (13.6-NA). Grade 3 or 4 neutropenia occurred in 53.8% of the patients, and febrile neutropenia occurred in 7.7%. PEG-G-CSF was given to 77.0% of the patients, including prophylactically (n = 9) and after the development of grade 3 or 4 neutropenia (n = 11). No patients experienced grade 3 or 4 neutropenia after the administration of PEG-G-CSF. In seven of the nine patients who received PEG-G-CSF prophylactically (77.8%), no dose adjustment was required. CONCLUSIONS: PEG-G-CSF is useful in preventing severe neutropenia in mCRC patients treated with FOLFOXIRI plus Bev.

Non-V600E BRAF mutations and EGFR signaling pathway in colorectal cancer.

The Raf murine sarcoma viral oncogene homolog B (BRAFV600E ) mutation (MT) in metastatic colorectal cancer (CRC) is a well-known prognostic indicator and a negative predictive biomarker for antiepidermal growth factor receptor (EGFR) treatment. However, the clinical characteristics and significance of BRAFnon-V600E MTs remain unclear. Here, we evaluated the clinical characteristics of BRAFnon-V600E MTs vs. those of other MTs in the EGFR signaling pathway, including BRAFV600E . Consecutive CRC patients in our institute from June 2012 to November 2013 were enrolled in our study. Multiplex genotyping of the EGFR pathway was performed with archival samples using a Luminex Assay for BRAFV600E /BRAFnon-V600E , KRAS/NRAS exons 2-4, and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA). We analyzed correlations among the MT profiles, clinical data and primary tumor locations in CRC. All statistical analyses were performed using R software. CRC samples (824) from 374 (45.4%) male and 450 (54.6%) female patients were analyzed, of which 154 (18.7%), 202 (24.5%), 270 (32.8%) or 198 (24.0%) had Stages I, II, III or IV or recurrent CRC, respectively. The frequencies of BRAFV600E /BRAFnon-V600E , KRAS (including exons 2-4), NRAS and PIK3CA MTs were 5.3/1.7, 41.4, 3.3 and 9.6%, respectively. The characteristics of patients with the BRAFV600E MT were an age of ≥65 years old, a right-sided primary tumor location, poorly differentiated histology and an advanced disease stage. In contrast, the characteristics of patients with BRAFnon-V600E MTs were a left-sided primary tumor location and well-differentiated histology. BRAFnon-V600E MTs were relatively rare and showed different characteristics compared to the BRAFV600E MT. These results may contribute to future precision medicine.

Phase II trial of biweekly cetuximab and irinotecan as third-line therapy for pretreated KRAS exon 2 wild-type colorectal cancer.

Efficacy and safety of biweekly cetuximab plus irinotecan were evaluated to provide guidance for its use in Japan as third-line treatment for pretreated metastatic colorectal cancer (mCRC) patients harboring wild-type KRAS exon 2. Objective response rate (ORR) was used as primary endpoint based on an expected proportion of 0.23 with confidence width of 0.298 (95% CI, 0.105-0.403), which showed 35 to be the minimal participant number. Forty patients, refractory to first- and second-line chemotherapy containing irinotecan, oxaliplatin, and fluoropyrimidine, were enrolled. ORR and disease control rate were 25.0% (95% CI: 11.5-38.4) and 72.5% (95% CI: 56.8-86.4), respectively. Median progression-free survival (PFS), overall survival (OS), and number of courses were 5.70 months (95% CI: 2.7-7.9), 15.1 months (95% CI: 11.8-19.0), and 10.5 (range: 3.0-31.0), respectively. Grade 3 adverse events were skin toxicity (12.5%), diarrhea (10.0%), neutropenia (5.0%), febrile neutropenia (5.0%), nausea (5.0%), anorexia (5.0%), and fatigue (2.5%). Cmax mean was 723.2 µg/mL after first dose. High area under the curve (AUC)last variance was associated with t1/2 range of 131.2-1209.6 hours (median, 174.4 hours). Early tumor shrinkage (ETS) and median depth of response were 25.0% and 13.0%, respectively. Mutation frequencies in KRAS exon 3 or 4, NRAS, BRAF, and PIK3CA were 5.5%, 2.7%, 8.3%, and 5.5%, respectively. Multivariate Cox regression analysis assessed whether any gene mutations and ETS are predictors for PFS, and whether performance status, synchronous metastasis, and ETS are predictors for OS. Importantly, the data provide guidance for a biweekly cetuximab plus irinotecan regimen in mCRC patients.

Diagnostic capability of colon capsule endoscopy for advanced colorectal cancer: A pilot study.

BACKGROUND AND AIM: Colon capsule endoscopy (CCE) is a safe and effective method for detecting lesions in the colon. However, the sensitivity of CCE in detecting advanced colorectal cancer (CRC) has not been sufficiently evaluated. Therefore, the aim of the present study was to assess the sensitivity of CCE in detecting advanced CRC. METHODS: Patients previously diagnosed with advanced CRC by conventional colonoscopy underwent CCE. Primary outcome measure was the sensitivity of CCE in detecting advanced CRC per patient and per lesion. Secondary parameters measured were the sensitivity of CCE in detecting polyps ≥6 mm and ≥10 mm in size in a per-lesion analysis and the safety of CCE. RESULTS: Of the 21 advanced CRC lesions in 20 patients, 17 were detected by CCE. The per-patient and per-lesion sensitivities of CCE for detecting advanced CRC lesions were 85% (95% confidence interval [CI]: 62-97%) and 81% (95% CI: 58-95%), respectively. All advanced CRC lesions were diagnosed in the accessible region by CCE while the capsule was still functional. A significant association was found between incomplete CCE and failure to diagnose advanced CRC. No severe adverse events occurred. CONCLUSION: The diagnostic capability of CCE in detecting advanced CRC was limited in cases of procedure incompletion. Refining procedures to increase CCE procedure completion rates are required to enhance CRC detection.

Child development in developing countries: introduction and methods.

The Multiple Indicator Cluster Survey (MICS) is a nationally representative, internationally comparable household survey implemented to examine protective and risk factors of child development in developing countries around the world. This introduction describes the conceptual framework, nature of the MICS3, and general analytic plan of articles in this Special Section. The articles that follow describe the situations of children with successive foci on nutrition, parenting, discipline and violence, and the home environment. They address 2 common questions: How do developing and underresearched countries in the world vary with respect to these central indicators of children's development? How do key indicators of national development relate to child development in each of these substantive areas? The Special Section concludes with policy implications from the international findings.

Changes in the neutrophil-to-lymphocyte ratio during nivolumab monotherapy are associated with gastric cancer survival.

PURPOSE: In the ATTRACTION-2 trial, nivolumab significantly improved the survival of advanced gastric cancer patients. The pretreatment neutrophil-to-lymphocyte ratio (NLR) is prognostic in patients receiving immune checkpoint inhibitors (ICIs) to treat various cancers. However, a few reports have explored the relationships between NLR changes during ICI treatment and patient survival. Here, we evaluated factors (including NLR changes in patients on nivolumab monotherapy) prognostic for gastric cancer patients. METHODS: We retrospectively analyzed 98 gastric cancer patients who received nivolumab (3 mg/kg or 240 mg/body bi-weekly) at our institution between December 2014 and September 2018. We evaluated pretreatment data, and those obtained 30 and 60 days after treatment commenced. We explored the prognostic utility of relative NLR changes in terms of the overall survival (OS) of patients on nivolumab monotherapy. RESULTS: Over a median of 4.9 months of follow-up, 98 gastric cancer patients received a median of four treatment courses. The overall response and disease-control rates were 25% and 52%, respectively. The median OS was 6.4 months (95% confidence interval [CI] 4.6-9.1). On multivariate analysis, factors poorly prognostic in terms of OS were an ECOG performance status of 0-1, a pretreatment NLR > 3, and an NLR difference ≧ 2 over the 60 days before and after nivolumab administration (∆NLR60). Patients with ∆NLR60 values < 2 survived significantly longer than did those with ∆NLR60 values ≧ 2 (median OS 9.2 months [95% CI 6.4-11.6] vs. 4.0 months [2.1-4.9]; P = 0.0002). CONCLUSIONS: Nivolumab monotherapy was efficacious in gastric cancer patients. NLR changes during such therapy may be predictive of outcomes.

Development of Disseminated Tuberculosis with Intestinal Involvement due to Adalimumab Administration Despite Latent Tuberculosis Treatment.

Treatment of latent tuberculosis infection (LTBI) reduces the probability of reactivation of tuberculosis associated with anti-tumor necrosis factor (TNF) α inhibitors, but no chemoprophylaxis is completely protective. We herein report a woman with rheumatoid arthritis who developed disseminated tuberculosis with intestinal involvement during adalimumab administration despite LTBI treatment. Tuberculosis reactivation was not detected in sputum or urine but was detected from the terminal ileal mucosa. Detection of intestinal tuberculosis is rare in patients being treated with anti-TNFα therapy after LTBI treatment. As anti-TNFα inhibitors have become more common, the rate of reactivation of tuberculosis, including intestinal tuberculosis, has increased in patients being treated for LTBI.

Safety and efficacy of amrubicin monotherapy in patients with platinum-refractory metastatic neuroendocrine carcinoma of the gastrointestinal tract: a single cancer center retrospective study.

PURPOSE: Patients with gastrointestinal neuroendocrine carcinoma (GI-NEC) have poor prognoses. Although platinum-based combination chemotherapy is commonly used as first-line treatment, the benefit of amrubicin (AMR) and salvage chemotherapy in those who develop platinum-refractory GI-NEC remains unknown. This study aimed to evaluate the efficacy and safety of AMR monotherapy in patients with platinum-refractory GI-NEC. PATIENTS AND METHODS: Platinum-refractory GI-NEC patients who received AMR monotherapy between April 2012 and September 2017 were retrospectively analyzed. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events were evaluated. PFS and OS were estimated using Kaplan-Meier methods and compared using log-rank tests. RESULTS: In total, 16 patients were enrolled. Of them, 13 (81.3%), 1 (6.2%), and 2 (12.5%) received cisplatin plus irinotecan, cisplatin plus etoposide, and fluoropyrimidine plus platinum, respectively, before AMR monotherapy. The primary sites of NEC included the esophagus (N=3, 18.8%), stomach (N=10, 62.5%), duodenum (N=1, 6.2%) and colorectum (N=2, 12.5%). Patients were administered a median of 3 (range, 1-15) cycles of AMR. The ORR was 6.3%, and the median PFS and OS were 2.9 months (95% CI: 1.7-7.4) and 13.8 months (95% CI: 7.9-23.5), respectively. Neutropenia was the most serious adverse event. Grade 3 or higher neutropenia and febrile neutropenia occurred in 50.0% and 6.2% of patients, respectively. Other nonhematological toxicities were not severe, and no treatment-related deaths occurred. The 10 patients who received subsequent chemotherapy after AMR had significantly longer OS than those who did not (17.3 months vs 8.9 months; p=0.018). The median PFS of those who received organ-specific subsequent chemotherapy after AMR was 3.8 months, which was longer than that of those who received prior AMR. CONCLUSION: AMR is feasible with minimal side effects for platinum-refractory GI-NEC. Organ-specific subsequent chemotherapy after AMR may improve patient survival.

Second-line FOLFIRI plus ramucirumab with or without prior bevacizumab for patients with metastatic colorectal cancer.

PURPOSE: Few data of folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus ramucirumab (RAM) obtained in bevacizumab-naïve patients in clinical trials or routine clinical practice are available. The purpose of this retrospective study was to report the results of FOLFIRI plus RAM treatment as second-line chemotherapy for metastatic colorectal cancer (mCRC). METHODS: Seventy-four patients with mCRC who received second-line FOLFIRI + RAM mCRC therapy were stratified by previous first-line therapy to groups that had (PB) or had not (NPB) been given bevacizumab. The overall survival (OS), progression-free survival (PFS), and objective response were evaluated. RESULTS: The overall median PFS was 6.2 months (95% CI 4.6-9.3) and median OS was 17.0 months (95% CI 11.6-NA). Median PFS was 8.0 months (95% CI 4.9-11.2) in NPB patients and 5.0 months (95% CI 3.1-7.3) in PB patients (hazard ratio = 0.72, 95% CI 0.40-1.30, p = 0.28). The response rates were 23% and 3% in NPB and PB patients, respectively. The disease control rates were 85% and 69% in NPB and PB patients, respectively. CONCLUSIONS: The effectiveness of FOLFIRI + RAM as a second-line chemotherapy in patients with mCRC was in line with that reported in the previous RAISE phase III trial. The response was better in bevacizumab-naïve patients than those with first-line treatment that had included bevacizumab.

Analysis of predictive factors for R0 resection and immediate bleeding of cold snare polypectomy in colonoscopy.

BACKGROUND: Factors associated with efficacy and safety of cold snare polypectomy (CSP) are not well established. The aim is to elucidate the predictors of R0 resection and immediate bleeding of CSP. METHODS: We retrospectively reviewed a database of patients who underwent CSP for subcentimetric polyps at the University of Tokyo Hospital in Japan. Using the data regarding the characteristics of patients and polyps, such as location, size, and macroscopic appearance; use of narrow band imaging with magnification (NBI-M); and endoscopists' experience, we revealed the predictive factors associated with R0 resection and immediate post-CSP bleeding by univariate and multivariate analyses. RESULTS: In total, 399 polyps, in 200 patients without antithrombotics, were removed. Failure of tissue retrieval was noted in 4% of resected lesions. There was no intramucosal carcinoma observed. The overall rate of R0 resection was 46%. Multivariate analysis elucidated that the observation of the polyp with NBI-M was an independent predictor associated with R0 resection (odds ratio [OR] 1.90; p = 0.024). Although immediate post-CSP bleeding occurred in 19 polyps (4.8%), no delayed bleeding or perforation was observed. Multivariate analysis revealed protruded lesion as an independent risk factor for immediate bleeding (OR 3.54; p = 0.018). CONCLUSIONS: A higher rate of R0 resection with CSP can be achieved by performing colonoscopy with NBI-M, than with white-light imaging. Macroscopic protruding appearance of a polyp is a risk factor for immediate bleeding.

Treatment features of systemic chemotherapy in young adults with unresectable advanced or recurrent gastric cancer.

PURPOSE: Gastric cancer in young adults (GCYA) is known to have distinct clinicopathological features, including a female predominance and diffuse-type histology. Previous reports have focused on patients who had undergone gastrectomy with curative intent. Information concerning the treatment of unresectable advanced- or recurrent-stage GCYA is lacking. Therefore, we aimed to investigate whether the distinct clinicopathological features of GCYA affect the outcome of systemic chemotherapy. PATIENTS AND METHODS: We conducted a retrospective cohort study at a single institution in Japan. GCYA was classified as a disease in individuals who were <40 years of age at diagnosis. Initial systemic chemotherapy regimens for GCYA were investigated with a focus on patients who received S-1 plus cisplatin (SP) as a representative standard regimen. The efficacy, safety, and feasibility of systemic chemotherapy were evaluated. RESULTS: Eighty-nine (7.5%) of 1,184 consecutive patients who received systemic chemotherapy at our institute between December 2005 and June 2016 were enrolled. As reported previously, the female sex (57.3%) and diffuse-type histology (91.0%) were the dominant features of GCYA. Thirty-two patients (36.0%) received SP as first-line treatment. The median overall survival and progression-free survival times were 13.2 (95.0% CI: 9.5-18.7) and 5.6 (95.0% CI: 4.7-7.9) months, respectively. The median number of treatment cycles, relative dose intensity, and cumulative dose of cisplatin were 4.5 (range: 1-10), 92.0% (IQR: 83.5-98.3), and 286.5 mg/m2 (IQR: 172.5-367.5), respectively. The most common adverse event of Grade 3 or higher was neutropenia (n=5 patients; 15.6%). No patient had febrile neutropenia. Non-hematological adverse events of Grade 3 or higher were only observed in 2 (6.3%) of 32 patients. CONCLUSION: Standard chemotherapy used for general-aged GC patients has similar efficacy, reduced toxicity, and higher intensity in GCYA patients.

Modified FOLFOX6 as a first-line treatment for patients with advanced gastric cancer with massive ascites or inadequate oral intake.

BACKGROUND: Oral fluoropyrimidine plus platinum is a standard first-line treatment for advanced gastric cancer (AGC). However, this treatment is problematic for AGC patients with massive ascites or inadequate oral intake. This study aimed at evaluating the efficacy and safety of modified oxaliplatin (L-OHP) with l-leucovorin (l-LV) and bolus/continuous infusion of 5-fluorouracil (5-FU) (mFOLFOX6) regimen for patients with massive ascites or inadequate oral intake. METHODS: This retrospective study was conducted at a single Japanese institute from November 2015 to May 2018. The mFOLFOX6 regimen consisted of 85 mg/m2 L-OHP, 400 mg/m2 bolus of 5-FU, and 400 mg/m2 1-LV on the first day, followed by 2,400 mg/m2 of 5-FU as a continuous infusion in 46 hours for first-line treatment. The definition of inadequate oral intake was the need for total parenteral nutrition (TPN). Massive ascites was defined as continuous ascites from the pelvic cavity to the upper abdomen. Improvement in oral intake was defined as no TPN for more than 7 days, and improvement in ascites was defined as a decrease in ascites of more than one grade defined by the Japan Clinical Oncology Study Group trial (JCOG0106). RESULTS: Among the 364 patients with AGC who received first-line chemotherapy, 17 patients (13 [76.5%] had inadequate oral intake, and four [23.5%] had massive ascites) were enrolled in this study. Median time to treatment failure and overall survival were 4.8 (95% CI=1.5-7.5) and 8.8 months (95% CI=2.3-not available), respectively. Objective improvements in oral intake and ascites were seen in 11 of 13 patients (84.6%) and 6 of 12 patients (50%), respectively. The major grade 3 or 4 adverse events were neutropenia (35.3%), febrile neutropenia (5.9%), fatigue (5.9%), anorexia (5.9%), and infection (5.9%). No treatment-related deaths occurred. CONCLUSION: We found that mFOLFOX6 can be a novel treatment option as the first-line treatment for AGC patients with massive ascites or inadequate oral intake.

Prevalence of pks-positive Escherichia coli in Japanese patients with or without colorectal cancer.

BACKGROUND: Recent studies show that some Escherichia coli strains possessing a gene cluster named the pks island might have a causative role in the development of human colorectal cancer (CRC). In several reports from Europe, they are found more prevalently in colon tissue specimens derived from CRC patients compared to those from controls. In this study we sought to clarify the difference in pks prevalence between CRC patients and non-CRC controls in the Japanese population, by using non-invasive sample collection technique during colonoscopy. METHODS: Colonic lavage samples were collected during diagnostic colonoscopy, and bacterial DNA within each sample was extracted. Fecal DNA samples were then examined for pks island genes using conventional qualitative PCR and real-time quantitative PCR. In some patients biopsy samples were also collected in the same session of colonoscopy, and the correlation between the pks status of the colonic lavage sample and the biopsy sample of the same patients was evaluated. RESULTS: Twelve out of thirteen patients (92%) showed the same pks status by colonic lavage sample and biopsy sample, suggesting the usefulness of colonic lavage samples as a surrogate for biopsy samples. A total of 98 colonic lavage samples were collected, which included 35 from CRC patients, 37 from adenoma patients, and 26 from controls. The pks-positive bacterial DNA was detected in 43, 51, and 46% of colonic lavage samples from CRC, adenoma, and control patients, respectively, and there was no significant difference among diseases. Real-time quantitative PCR showed no significant difference in the relative concentrations of pks-positive bacterial DNA among diseases. Age, gender, location of CRC, CRC staging, or k-ras gene status was not associated with pks prevalence. CONCLUSIONS: Although the method of collecting fecal DNA from colonic lavage samples was safe and technically feasible, factors other than pks-positive bacteria appear to play more important roles in CRC development in this cohort.