Distinct roles of IL-18 and IL-1ß in murine model of macrophage activation syndrome.

BACKGROUND: IL-18 and IL-1ß play a central role in the pathogenesis of systemic juvenile idiopathic arthritis and its life-threatening complication, macrophage activation syndrome (MAS). OBJECTIVES: This study aimed to clarify the role of IL-18 and IL-1ß in the pathogenesis of MAS. METHODS: We developed a mouse model to evaluate the role of each cytokine with Toll-like receptor 9 stimulation after continuous infusion with IL-18, IL-1ß, and a combination of both for 7 days. The symptoms and laboratory findings were compared among the IL-18, IL-1ß, and combination (IL-18+IL-1ß) groups. RESULTS: Body weight was significantly decreased in the IL-1ß and combination groups. Splenomegaly was observed in all groups, whereas hepatomegaly was noted in the IL-18 group only. Decreased T-cell numbers, anemia, and thrombocytopenia were observed in the combination group. IFN-γ, CXCL9, and IL-12A mRNA levels were upregulated and IL-10 mRNA levels in the spleen were downregulated in the IL-18 group. Hepatomegaly and splenomegaly in the IL-18 group were observed in a dose-dependent manner. TNF-α, CXCL9, and IL-12A mRNA levels were upregulated only in those mice with extremely elevated plasma IL-18 levels. CONCLUSION: IL-18 and IL-1ß have distinct roles in the pathogenesis of MAS. Dual blockade of IL-18 and IL-1ß might be necessary to treat MAS.

Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial.

BACKGROUND: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC). METHODS: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33. RESULTS: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; Pnoninferiority = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%). CONCLUSIONS: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC. CLINICAL TRIAL REGISTRATION: JapicCTI-173618, jRCTs031180122.

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer.

BACKGROUND: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer. METHODS: In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety. RESULTS: Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group. CONCLUSIONS: Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).

Pattern of disease progression during third-line or later chemotherapy with nivolumab associated with poor prognosis in advanced gastric cancer: a multicenter retrospective study in Japan.

BACKGROUND: Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). METHODS: This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. RESULTS: Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6-1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2-2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8-3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). CONCLUSIONS: New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.

Phase IIb study of pembrolizumab combined with S-1 + oxaliplatin or S-1 + cisplatin as first-line chemotherapy for gastric cancer.

The KEYNOTE-659 study evaluated the efficacy and safety of first-line pembrolizumab plus S-1 and oxaliplatin (SOX) (cohort 1) or S-1 and cisplatin (SP) (cohort 2) for advanced gastric/gastroesophageal junction (G/GEJ) cancer in Japan. Herein, we update the results of cohort 1 and describe the results of cohort 2. This open-label phase IIb study enrolled patients with advanced programmed death-ligand 1 (PD-L1)-positive (combined positive score ≥ 1) human epidermal growth factor receptor 2 (HER2)-negative G/GEJ adenocarcinoma. The primary end-point was the objective response rate (ORR). Other end-points were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. One hundred patients were enrolled. In cohorts 1 and 2, median follow-up time was 16.9 and 17.1 months; ORR (central review), 72.2% and 80.4%; DOR, 10.6 and 9.5 months; DCR (central review), 96.3% and 97.8%; median PFS (central review), 9.4 and 8.3 months; and median OS, 16.9 and 17.1 months, respectively. Treatment-related adverse events (TRAEs) occurred in all patients, including peripheral sensory neuropathy (94.4%, cohort 1), decreased neutrophil count (82.6%, cohort 2), nausea (59.3% and 60.9% in cohorts 1 and 2), and decreased appetite (61.1% and 60.9% in cohorts 1 and 2). Grade 3 or higher TRAEs were reported by 59.3% (cohort 1) and 78.3% (cohort 2), including decreased platelet count (14.8%, cohort 1) and decreased neutrophil count (52.2%, cohort 2). Pembrolizumab in combination with SOX or SP showed favorable efficacy and safety in patients with PD-L1-positive, HER2-negative G/GEJ adenocarcinoma.

Dacomitinib overcomes afatinib-refractory carcinomatous meningitis in a lung cancer patient harbouring EGFR Ex.19 deletion and G724S mutation; a case report.

It has been reported that the efficacy of EGFR-TKI is predicted, not by which exon of the EGFR gene is mutated, but by the structural change in the EGFR protein due to the mutation. Here, we present an EGFR-mutated lung cancer patient with a 13-year history of anticancer treatment, in which EGFR ex.19 deletion (E746_S752 > V) and G724S mutations were detected by liquid biopsy during 12th line afatinib treatment, and switching to dacomitinib showed improvement of cancerous meningitis. We choose dacomitinib as 14th line chemotherapy based on ex.19 deletion and G724S mutant EGFR structure and its penetration rate to cerebral fluid, which successfully prolonged her life by 6 months. The optimal EGFR-TKI may be selected by understanding the EGFR compound mutation profile by next generation sequencing and predicting the effect based on the structure. Dacomitinib may be effective choice in afatinib-refractory carcinomatous meningitis harboring G724S mutation. This is the first case report showing that a change to dacomitinib responded to afatinib refractory cancerous meningitis.

Effects of long-term treatment with dietary theobromine on rat skeletal muscles.

BACKGROUND: Plastic changes of skeletal muscles, such as hypertrophy and atrophy, are dependent on physiological activities and regulated by a variety of signaling pathways, including cyclic adenosine monophosphate (cAMP) pathway. The cAMP inducing agents, such as the ß2-adrenergic agonist clenbuterol, are known to induce muscle hypertrophy, and has been reported to induce slow-to-fast transitions in rat soleus muscle. Theobromine, one of the active components of cacao, functions as an inhibitor of phosphodiesterase and increases cAMP. This study hypothesized that theobromine, like clenbuterol, can induce muscle hypertrophy and influence contractile properties. METHODS AND RESULTS: Male Wistar rats were fed a normal diet or a diet containing 0.05% theobromine for 20 weeks. Using biochemical, anatomical, and physiological techniques, effects of dietary theobromine on skeletal muscles (soleus, extensor digitorum longus, plantaris, and gastrocnemius) were examined. There were no significant differences in body weight, serum levels of proteins and lipids, muscle weights, dry/wet ratio of muscle weights, mitochondrial oxidation enzyme activity of muscles, isometric contractile properties of muscles, and muscle fatigue between control and theobromine-fed rats. Quantitative analysis of mRNA, however, revealed upregulation of myosin heavy chain 2x and myogenic differentiation 1, as previously reported in clenbuterol-treated muscles. CONCLUSION: The long-term theobromine (0.05%) diet in rats had no effect in inducing muscle hypertrophy and in changing contractile properties, although it had some similar effects of clenbuterol on muscle gene expression.

Primary tumor location as a predictor of survival in patients with RAS wild-type colorectal cancer who receive molecularly targeted drugs as first-line therapy: a multicenter real-world observational study by the Japanese Society for Cancer of the Colon and Rectum.

BACKGROUND: Primary tumor location is considered a predictor of overall survival (OS) in RAS wild-type (WT) metastatic colorectal cancer (mCRC) treated with bevacizumab (BEV) or an anti-epidermal growth factor antibody (cetuximab or panitumumab [CET/PAN]) as first-line molecularly targeted therapy. BEV is recommended for right-sided mCRC and CET/PAN for left-sided mCRC based on post-hoc analyses of clinical trial data, but real-world evidence is lacking. METHODS: We retrospectively collected data of patients who started BEV or CET/PAN plus 5-fluorouracil-based doublet chemotherapy between January 2013 and December 2016 as first-line treatment for RAS WT mCRC at any of 24 Japanese institutions. OS was compared between the BEV and CET/PAN groups according to primary tumor location by Cox multivariate regression analysis in the full cohort and in a propensity score-matched cohort. RESULTS: In total, 935 patients were enrolled. Median OS was 24.6 months with BEV and 20.9 months with CET/PAN in right-sided mCRC (n = 213; adjusted hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50-1.06) and 35.7 months and 30.0 months, respectively, in left-sided mCRC (n = 722; adjusted HR 0.92, 95% CI 0.74-1.13). In the propensity score-matched cohort, OS was significantly better in the BEV group than in the CET/PAN group in right-sided mCRC (HR 0.52, 95% CI 0.28-0.96) but was not significantly different in left-sided mCRC (HR 0.78, 95% CI 0.53-1.07). CONCLUSION: Real-world data showed that OS was better with BEV than with CET/PAN in right-sided mCRC. However, there was no significant difference in OS in left-sided mCRC.

Randomized phase II study of CPT-11 versus PTX versus each combination chemotherapy with S-1 for advanced gastric cancer that is refractory to S-1 or S-1 plus CDDP: OGSG0701.

BACKGROUND: To compare irinotecan-alone, paclitaxel-alone, and each combination chemotherapy with S-1 in patients with advanced gastric cancer (AGC) that is refractory to S-1 or S-1 plus cisplatin (SP). METHODS: Patients with AGC after first-line chemotherapy with S-1 or SP, or patients during adjuvant chemotherapy or within 26 weeks after adjuvant chemotherapy completion with S-1 with confirmed disease progression were eligible. Patients were randomly divided into four groups based on treatment: irinotecan-alone (irinotecan; 150 mg/m2, day 1, q14 days), paclitaxel-alone (paclitaxel; 80 mg/m2, days 1, 8, 15, q28 days), S-1 plus irinotecan (irinotecan; 80 mg/m2, days 1, 15, S-1; 80 mg/m2, days 1-21, q35 days), and S-1 plus paclitaxel (paclitaxel; 50 mg/m2, day1, 8, S-1; 80 mg/m2, days 1-14, q21 days). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS), response rate, and safety. RESULTS: From July 2008 to March 2012, 127 patients were enrolled. No difference in median OS was observed in the irinotecan vs. paclitaxel groups or in the monotherapy groups vs. the S-1 combination therapy groups. Median PFS was longer in the paclitaxel group compared with the irinotecan group (4.1 vs. 3.6 months, p = 0.035), although no difference was observed when comparing monotherapy vs. S-1 combination. The most common grade 3 to 4 hematological adverse events were neutropenia with no difference in incidence rate across the treatment groups. CONCLUSIONS: There was no difference in OS between irinotecan and paclitaxel no in OS prolongation of S-1 combination therapy in second-line chemotherapy.

Serum insulin-like growth factor-binding protein 2 levels as an indicator for disease severity in enterohemorrhagic Escherichia coli induced hemolytic uremic syndrome.

BACKGROUND: Insulin-like growth factor-binding protein (IGFBP) 2 plays an important role in the regulation of cell adhesion, migration, growth, and apoptosis. This study aimed to investigate the clinical significance of serum IGFBP2 as a biomarker for disease activity and severity in hemolytic uremic syndrome (HUS) induced by enterohemorrhagic Escherichia coli (EHEC). METHODS: IGFBP2 production by human renal glomerular endothelial cells (RGECs) after exposure to Shiga toxin 2 (Stx-2) was investigated in vitro. Serum IGFBP2 levels in blood samples obtained from 22 patients with HUS and 10 healthy controls (HCs) were quantified using an enzyme-linked immunosorbent assay. The results were compared to the clinical features of HUS and serum tau and cytokine levels. RESULTS: Stx-2 induced the production of IGFBP2 in RGECs in a dose-dependent manner. Serum IGFBP2 levels were significantly higher in patients with HUS than in HCs and correlated with disease severity. Additionally, serum IGFBP2 levels were significantly higher in patients with encephalopathy than in those without encephalopathy. A serum IGFBP2 level above 3585 pg/mL was associated with a high risk of encephalopathy. Furthermore, serum IGFBP2 levels significantly correlated with serum levels of tau and inflammatory cytokines associated with the development of HUS. CONCLUSIONS: Correlation of serum IGFBP2 level with disease activity in patients with HUS suggests that IGFBP2 may be considered as a possible indicator for disease activity and severity in HUS. Larger studies and additional experiments using various cells in central nervous system should elucidate the true value of IGFBP2 as a clinical diagnostic marker. ABBREVIATIONS: IGFBP: insulin-like growth factor-binding protein; HUS: hemolytic uremic syndrome; EHEC: enterohemorrhagic Escherichia coli; RGECs: renal glomerular endothelial cells; STx-2: Shiga toxin 2; HCs: healthy controls; LPS: lipopolysaccharide; ROC: receiver operating characteristic; sTNFR: soluble tumor necrosis factor receptor.

Phase II study of 5-fluorouracil-leucovorin plus bevacizumab for chemotherapy-naïve older or frail patients with metastatic colorectal cancer (OGSG 0802).

BACKGROUND: Older or frail patients are often underrepresented in clinical trials for metastatic colorectal cancer (mCRC). We here assessed the efficacy and safety of 5-fluorouracil (5-FU)-leucovorin plus bevacizumab in such patients. METHODS: The study (OGSG 0802) was designed as a single-arm, open-label, multicenter phase II trial. Eligible patients had mCRC and at least one of the following: an age of ≥ 65 years, an Eastern Cooperative Oncology Group performance status of 1 or 2, a serum albumin level of ≤ 3.5 g/dL, incompatibility with oxaliplatin or irinotecan, and a history of abdominal or pelvic radiotherapy. Patients received 5-FU (600 mg/m2) and l-leucovorin (200 mg/m2) on days 1, 8, and 15 together with bevacizumab (5 mg/kg) on days 1 and 15 every 4 weeks. The primary end point was objective response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty-one patients were enrolled and eligible. Median age was 76 years (range 56-90 years), and 51% of patients had a performance status of 0. The ORR was 36.6% [95% confidence interval (CI) 22.1-53.1%], median PFS was 9.4 months (95% CI 7.4-17.7 months), and median OS was 24.0 months (95% CI 19.9 months-not reached). The most common treatment-related adverse events of grade ≥ 3 were neutropenia (24%), anorexia (10%), leukopenia (7%), and mucositis/stomatitis (7%). There were no treatment-related deaths. CONCLUSION: Weekly 5-FU-leucovorin with biweekly bevacizumab may be a tolerable and effective treatment option for older or frail patients with mCRC.

Comparison of S-1-cisplatin every 5 weeks with capecitabine-cisplatin every 3 weeks for HER2-negative gastric cancer (recurrent after S-1 adjuvant therapy or chemotherapy-naïve advanced): pooled analysis of HERBIS-2 (OGSG 1103) and HERBIS-4A (OGSG 1105) trials.

BACKGROUND: We previously reported the HERBIS-4A phase II trial comparing S-1 plus cisplatin (SP) with capecitabine plus cisplatin (XP) in chemotherapy-naïve patients with HER2-negative advanced gastric cancer (GC). We performed a pooled analysis of HERBIS-4A and HERBIS-2, the phase II trial comparing SP with XP in HER2-negative recurrent GC patients with a recurrence-free interval after S-1 adjuvant therapy of ≥ 6 months. PATIENTS AND METHODS: Patients were randomly assigned to receive either SP [S-1 (40-60 mg twice daily for 21 days) plus cisplatin (60 mg/m2 on day 8), every 5 weeks] or XP [capecitabine (1000 mg/m2 twice daily for 14 days) plus cisplatin (80 mg/m2 on day 1), every 3 weeks]. RESULTS: In the pooled analysis, SP (n = 44-50) showed a longer progression-free survival [6.4 versus 5.1 months; hazard ratio (HR), 0.666; P = 0.062], overall survival (14.8 versus 10.6 months; HR, 0.695; P = 0.099), and time to treatment failure (4.6 versus 3.6 months; HR, 0.668; P = 0.045) as well as a higher disease control rate (86.4% versus 68.1%, P = 0.149) compared with XP (n = 47-51). A significant survival advantage for SP over XP was apparent in patients with a performance status of 0, a differentiated-type tumor histology, or a primary tumor localization to the upper portion of the stomach. CONCLUSION: Our pooled analysis supports the use of SP in the first-line setting for patients with HER2-negative advanced or recurrent GC with a recurrence-free interval of ≥ 6 months. CLINICAL TRIAL REGISTRATION: The HERBIS-2 trial was registered with UMIN-CTR as UMIN000006105.

Evaluation of FOLFOX or CAPOX reintroduction with or without bevacizumab in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy (REACT study).

BACKGROUND: Chemotherapy in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy is under debate. REACT study aimed to investigate the efficacy of reintroducing modified FOLFOX6 (mFOLFOX6) or CAPOX with or without bevacizumab in recurrent colorectal cancer patients after oxaliplatin adjuvant chemotherapy. METHODS: Patients that participated in this trial had a medical history of adjuvant chemotherapy, including oxaliplatin with a cumulative dose greater than 400 mg/m2, and recurrence that was diagnosed more six months post adjuvant chemotherapy. Primary endpoints were response rate (RR) and disease control rate (DCR), while key secondary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 31 patients were enrolled between October 2012 and October 2016. Of the 29 eligible patients, 7 received mFOLFOX6 and 22 received CAPOX. The RR was 62.1% (95% confidence interval 42.3-79.3) and the DCR was 82.8% (95% confidence interval 64.2-94.2). The RR for oxaliplatin-free interval was 100.0% in months 6-12 and 56.0% after 12 months. Median TTF, PFS, and OS were 6.3, 10.8, and 28.7 months, respectively. Grade 3 or worse peripheral sensory neuropathy developed in 6.5%. Allergic reactions occurred in 12.9% of the patients, with one (3.2%) grade 3 episode. There were no other severe treatment-related adverse events. CONCLUSION: Reintroduction of oxaliplatin was feasible and achieved high RR or DCR in patients after more than 6 months post oxaliplatin adjuvant chemotherapy.

Prognostic scores for evaluating the survival benefit of regorafenib or trifluridine/tipiracil in patients with metastatic colorectal cancer: an exploratory analysis of the REGOTAS study.

BACKGROUND: Although regorafenib or trifluridine/tipiracil (FTD/TPI) has been recognized as a later-line standard treatment in patients with metastatic colorectal cancer (mCRC), not all patients have beneficial outcomes. This study aimed to develop a prognostic scoring system for evaluating the overall survival (OS) benefit. METHODS: Patients included in the REGOTAS study, which comprised 489 patients (regorafenib group: 199; FTD/TPI group: 290 patients), were evaluated. OS was analyzed using multivariate Cox proportional model. The prognostic score was calculated using the worst four individual factors weighted by hazard ratio, and the total scores were categorized as low-, moderate-, and high-OS benefit. RESULTS: The worst four factors in the regorafenib group were AST > 40 IU/dL (point, + 3), CRP ≥ 1.0 mg/dL (+ 2), number of metastatic organ site ≥ 3 (+ 2), and duration from initiation of 1st-line chemotherapy < 18 months (+ 2), while they were AST (+ 2), CRP (+ 2), CA19-9 > 37.0 U/mL (+ 2), and ECOG PS ≥ 1 (+ 2) in the FTD/TPI group. These corresponded to a total prognostic score of > 5, 2-4, and 0 points in the regorafenib group and 8, 2-6, and 0 points in the FTD/TPI group. The median OS in the low, moderate, and high OS benefit group was 3.3 (95% CI 3.0-3.7), 8.1 (95% CI 6.4-9.7), and 12.6 months (95% CI 10.6-14.6) in the regorafenib group and 2.8 (95% CI 2.0-3.5), 7.5 (95% CI 6.6-8.3), and 15.4 months (95% CI 9.7-21.2) in the FTD/TPI group. CONCLUSION: These prognostic scores are useful for identifying patients with mCRC who will obtain survival benefits from these drugs.

Salivary Immunoglobulin A Secretion and Polymeric Ig Receptor Expression in the Submandibular Glands Are Enhanced in Heat-Acclimated Rats.

Salivary immunoglobulin A (IgA) plays a critical role in mucosal immunity. Chronic exposure to moderate heat induces heat acclimation, which modifies salivary functions. However, the changes in salivary IgA secretion in heat-acclimated rats are unclear. In this study, we investigated salivary IgA secretion and the expression of polymeric Ig receptor (pIgR), a key mediator of mucosal IgA secretion, in the submandibular glands (SMGs) of heat-acclimated rats. Following maintenance at an ambient temperature (Ta) of 24 ± 0.1 °C for 10 days, male Wistar rats were subjected to Ta of 32 ± 0.2 °C for 5 days (HE group) for heat acclimation or maintained at Ta of 24 ± 0.1°C (CN group). The rats were then anesthetized, pilocarpine (0.5 mg/kg) was intraperitoneally injected, and saliva was collected. Afterward, the SMGs and plasma were sampled. The salivary IgA concentration and IgA flow rate were significantly higher in the HE group than in the CN group. Similarly, SMG pIgR expression was significantly higher in HE rats. The levels of plasma cytokines, including interleukin (IL)-5, IL-6, and interferon-γ, were significantly greater in HE rats than in CN rats. Heat acclimation may enhance oral immunity through salivary IgA secretion and pIgR upregulation in the SMGs.

[A Phase â ¡ Study of Systemic Chemotherapy with Capecitabine and Cisplatin Followed by Surgery for Advanced Gastric Cancer with Extensive Lymph Node Metastasis(OGSG1401)].

BACKGROUND: Gastric cancer with extensive lymph node metastasis(ELM)is commonly considered unresectable and has a poor prognosis. We conducted a phase Ⅱ study to evaluate the safety and efficacy of capecitabine and cisplatin(XP)as preoperative chemotherapy for gastric cancer with ELM. METHODS: The patients received 2 21-day cycles of XP therapy(ca- pecitabine at 2,000mg/m2 twice daily for 2 weeks and cisplatin at 80 mg/m2 on day 1)followed by gastrectomy with D2 plus para-aortic nodal dissection. After R0 resection, S-1 chemotherapy was administered for 1 year. The primary end point was response rate(RR). The planned sample size was 30. RESULTS: Between April 2015 and November 2016, 4 patients were enrolled, but the enrollment was terminated because of poor patient recruitment. The clinical RR was 50%, and R0 resection was achieved in 75% of the patients. The common Grade 3 adverse events during XP therapy were leukocytopenia(25%), anemia(25%), and hyperlipidemia(25%). The common Grade 3 surgical morbidity was abdominal abscess(33%)and pancreatic fistula(33%). The pathological RR was 25%. CONCLUSIONS: Preoperative XP therapy was feasible, but its efficacy was difficult to evaluate because of the small sample size.

Exploration of potential prognostic biomarkers in aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer.

Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.

Phase II trial of aflibercept with FOLFIRI as a second-line treatment for Japanese patients with metastatic colorectal cancer.

Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 µg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.

Sex differences in the safety of S-1 plus oxaliplatin and S-1 plus cisplatin for patients with metastatic gastric cancer.

Previous studies have shown sex-related differences in the incidence of adverse events following treatment with fluoropyrimidines, however the mechanism of this difference is unknown. We examined sex-related differences in the safety of S-1 plus oxaliplatin (SOX) and S-1 plus cisplatin (CS) in 663 metastatic gastric cancer patients taking part in a phase III study. The incidences of leukopenia (odds ratio [OR] 1.9; P = .015), neutropenia (OR 2.2; P = .002), nausea (OR 2.0; P = .009), and vomiting (OR 2.8; P < .001) were increased in women versus men treated with SOX, while vomiting (OR 2.9; P < .001) and stomatitis (OR 1.8; P = .043) were increased in women versus men treated with CS. In contrast, male patients treated with CS experienced thrombocytopenia more often (OR 0.51; P = .009). The mean relative dose intensity of S-1 in SOX was 75.4% in women and 81.4% in men (P = .032). No difference in efficacy was observed between women and men undergoing either regimen. Sex-related differences in adverse reactions during SOX and CS treatment were confirmed in this phase III study. Further translational research studies are warranted to pursue the cause of this difference.

aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer.

BACKGROUND: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC. MATERIALS AND METHODS: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG). RESULTS: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS). CONCLUSION: Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC. IMPLICATIONS FOR PRACTICE: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.