Stearate‐to‐palmitate ratio modulates endoplasmic reticulum stress and cell apoptosis in non‐B non‐C hepatoma cells

The increased prevalence of hepatocellular carcinoma (HCC) without viral infection, namely, NHCC, is a major public health issue worldwide. NHCC is frequently derived from non‐alcoholic fatty liver (NAFL) and non‐alcoholic steatohepatitis, which exhibit dysregulated fatty acid (FA) metabolism. This raises the possibility that NHCC evolves intracellular machineries to adapt to dysregulated FA metabolism. We herein aim to identify NHCC‐specifically altered FA and key molecules to achieve the adaptation. To analyze FA, imaging mass spectrometry (IMS) was performed on 15 HCC specimens. The composition of saturated FA (SFA) in NHCC was altered from that in typical HCC. The stearate‐to‐palmitate ratio (SPR) was significantly increased in NHCC. Associated with the SPR increase, the ELOVL6 protein level was upregulated in NHCC. The knockdown of ELOVL6 reduced SPR, and enhanced endoplasmic reticulum stress, inducing apoptosis of Huh7 and HepG2 cells. In conclusion, NHCC appears to adapt to an FA‐rich environment by modulating SPR through ELOVL6.     

Use of non‐steroidal anti‐inflammatory drugs and risk of non‐Hodgkin lymphoma: a systematic review and meta‐analysis

Epidemiological study findings regarding the association between use of non‐steroidal anti‐inflammatory drugs (NSAIDs) and risk of non‐Hodgkin lymphoma (NHL) have been inconsistent. We aimed to systematically review epidemiological studies of the association and calculate pooled relative risks using meta‐analytic methods. We searched eight electronic literature databases and three clinical trial registers to identify all studies (including observational studies and randomized clinical trials) of the association published prior to October 2013. Identified studies were independently reviewed by two researchers. We used a random effects model to calculate pooled odds ratio (PORs). Heterogeneity amongst studies was examined using Cochran's Q and I‐squared (I²) tests; and sources of heterogeneity were explored using subgroup and meta‐regression analyses. A total of 17 studies (12 case‐control studies and five cohort studies), all adult studies, were included. Use of NSAIDs was not associated with overall risk of NHL [POR = 1.05, and 95% confidence interval (95% CI) 0.90–1.22] or NHL subtypes including B‐cell lymphoma, T‐cell lymphoma, follicular lymphoma, diffuse large B‐cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Aspirin use was associated with reduced risk of CLL/SLL (POR = 0.70, 95% CI 0.54–0.91) but not with the risk of all NHLs (POR = 1.02, 95% CI 0.89–1.17). Use of non‐aspirin NSAIDs was associated with increased risk of NHL (POR = 1.41, 95% CI 1.01–1.97) amongst females only. The epidemiologic evidence remains inconclusive. Effects of NSAIDs may differ by drug type, NHL subtype, and sex and more studies taking into consideration these differences are needed. Copyright © 2014 John Wiley & Sons, Ltd.     

Liquid biopsy in non‐Hodgkin's lymphoma

ctDNA provides an important new strategy that will aid in the treatment of non‐Hodgkin's lymphoma. Immunoglobulin sequencing provides a tumor specific marker for disease activity with a sensitivity equivalent to one tumor cell per 10‐6. Furthermore, it can provide an estimate of tumor bulk and tumor response dynamics during treatment. Interim monitoring can identify patients at high risk of treatment failure and surveillance monitoring can identify patients months before radiographic disease progression. Tumor specific mutations can also be detected in ctDNA and may reflect an averaging of mutations present within multiple tumor masses. Such analysis may aid in the molecular characterization of tumors and selection of targeted treatments for precision medicine.     

Fludarabine–Mitoxantrone–Rituximab regimen in untreated indolent non‐follicular non‐Hodgkin's lymphoma: experience on 143 patients

Indolent non‐follicular lymphomas (inFLs) are generally regarded as incurable, apart from extranodal mucosa‐associated lymphatic tissue lymphomas, which can be partially cured by surgery, local radiotherapy, or antibiotic treatment. The aim of the present study was to test the degree of effectiveness and the safety of the regimen containing fludarabine, mitoxantrone, and rituximab (FMR) in inFL patients considering all the different entities belonging to this group. An observational retrospective study was conducted on 143 inFL patients providing that their first chemoimmunotherapy performed was FMR regimen and diagnosis from September 2000 to March 2011. There were 32 small lymphocytic lymphomas and 111 marginal zone lymphomas. At the end of treatment, overall response rate was 96.5% with 88% of complete responses (CR) and 8.5% of partial responses. With a median follow‐up of 48 months, 10 out of 125 (8%) CR patients had disease relapse, yielding an estimated 9‐year disease‐free survival (DFS) of 74.9% and an estimated 10‐year overall survival of 92.8%. The estimated 9‐year progression free survival was 70.5%. The 10 relapsed patients showed lymphoma recurrence within 52 months: after this time, the DFS curve presented a plateau configuration. Only two (1.4%) patients developed a secondary hematological neoplasia. This study showed promising findings for the use of a fludarabine‐based regimen in combination with rituximab in the front‐line treatment of symptomatic inFL with a noteworthy high percentage of CR associated to an interesting long‐term DFS and favorable acute and long‐term safety profile. Copyright © 2014 John Wiley & Sons, Ltd.     

The acceleration of CAR‐T therapy in non‐Hodgkin lymphoma

Recent advances in diffuse large B‐cell lymphomas have included both identification of high‐risk subtypes characterized by multiply relapsed and/or refractory disease as well as novel treatment in the form of cellular therapy. Chimeric antigen receptor (CAR)‐T cell therapy is a recently developed approach to address the poor outcomes in this patient population. The CAR‐T cell construct has evolved although several iterations as it transitioned from the lab to the clinic. Three major studies have evaluated the efficacy of CD19‐directed CAR‐T cell therapy in aggressive B‐cell non‐Hodgkin lymphoma; each demonstrating durable complete remissions in heavily pretreated patients. The cost of this remarkable therapy, however, includes cytokine release syndrome and neurotoxicity shortly after administration as well as delayed infectious complications due to B‐cell aplasia. Future investigations are focused on the optimizing both safety and efficacy of CAR‐T cell therapy.     

Impact of KRAS mutation on response and outcome of patients with stage III non‐squamous non‐small cell lung cancer

The frequency and clinical profile of patients with stage III non‐small cell lung cancer harboring KRAS mutations have not yet been well documented. Here, we analyzed hotspot KRAS mutations using high‐resolution melting analyses in tumor specimens from patients who received chemoradiotherapy between January 2001 and December 2010 at the National Cancer Center Hospital. The associations between the presence of KRAS mutations and the response rate, relapse‐free survival, first relapse sites, survival post‐progression and overall survival were investigated. A total of 274 non‐squamous non‐small cell lung cancer patients received chemoradiotherapy at our hospital. After excluding 121 patients for whom tumor specimens were not available and 34 patients with EGFR mutations, the remaining 119 patients were included in the analysis. KRAS mutations were found at a frequency of 13%. Patients with KRAS mutations had a shorter median relapse‐free survival (6.1 vs 10.9 months) and a lower response rate (63% vs 81%). As for the first relapse site, patients with KRAS mutations had fewer local relapses (8% vs 23%) and more brain metastases (46% vs 12%). After disease progression, patients with KRAS mutations had a significantly shorter median survival post‐progression (2.5 vs 7.3 months, P = 0.028) and median overall survival (15.1 vs 29.1 months, P = 0.022). Our results suggested that KRAS mutation could be associated with a reduced efficacy of chemoradiotherapy and a shortened survival time.     

Fluconazole plus flucytosine is a good alternative therapy for non‐HIV and non‐transplant‐associated cryptococcal meningitis: A retrospective cohort study

Cryptococcal meningitis (CM) carries a high risk of mortality with increasing incidences in immune competent hosts. Current treatments are not well tolerated, and evaluation of other treatments is needed. Fluconazole and 5‐flucytosine in treating immune competent hosts have not been characterised. To evaluate the efficacy of fluconazole and 5‐flucytosine in treating non‐HIV‐ and non‐transplant‐associated CM. We performed a retrospective cohort study of the outcomes in immune competent patients with CM treated with fluconazole and 5‐flucytosine or deoxycholate‐amphotericin B and 5‐flucytosine. The primary outcome was treatment response evaluated at the 12th week after initiation of antifungal therapy. A total of 43 and 47 patients received amphotericin B deoxycholate and 5‐flucytosine or fluconazole and 5‐flucytosine, respectively. A total of 38 (88.4%) patients cannot tolerate recommended doses of amphotericin B deoxycholate and 5‐flucytosine (patients needed dose reduction during the treatment). Patients given fluconazole and 5‐flucytosine had higher baseline cryptococcal burdens (median 3632 versus 900 cryptococci/mL, P = 0.008). No significant differences were seen in cryptococcus clearance (74.4% vs 70.2%, P = 0.814), treatment time (39 days, 20‐69 days vs 21 days, 7‐63 days, P = 0.107) and successful response (including complete and partial responses) rates (69.7% vs 72.3%, P = 0.820). Fluconazole and 5‐flucytosine treatment had lower total adverse events (19.1% vs 90.7%, P < 0.001). Fluconazole and 5‐flucytosine had relatively high efficacy with few adverse events in treating CM. Fluconazole and 5‐flucytosine therapy is promising in patients that do not tolerate or are not suited for amphotericin B deoxycholate treatment.     

Role of interleukin‐17 in lymphangiogenesis in non‐small‐cell lung cancer: Enhanced production of vascular endothelial growth factor C in non‐small‐cell lung carcinoma cells

Interleukin‐17 (IL‐17), a potent pro‐inflammatory cytokine, plays an active role in inflammation and cancer. Recently, we found that increased IL‐17‐producing cells correlate with poor survival and increased lymphangiogenesis in non‐small‐cell lung cancer (NSCLC), but the mechanism is unknown. Here, we show that IL‐17 promotes lymphangiogenesis via inducing vascular endothelial growth factor‐C (VEGF‐C) production by lung cancer cells. We found that IL‐17 receptor (IL‐17R) is expressed on the surface of Lewis lung carcinoma (LLC) cells but not on lymphatic endothelial cells (LEC). Moreover, LEC chemotaxis and tube formation (measures of net lymphangiogenic potential) were increased by conditioned medium from recombinant mouse IL‐17 (rmIL‐17)‐stimulated LLC but not by rmIL‐17. Interleukin‐17 increased production of VEGF‐C in lung cancer cell lines. The enhanced chemotaxis and endothelial cord formation in the presence of LLC/rmIL‐17 was inhibited by addition of recombinant mouse VEGF R3/Fc chimera. Treatment of the A549 cells with rIL‐17 significantly increased VEGF‐C expression, which was extracellular signal‐regulated protein kinase 1/2 (ERK 1/2) dependent. Importantly, we found significant correlations between IL‐17 expression, VEGF‐C expression and lymphatic vascular density (LVD) in NSCLC. We conclude that IL‐17 is involved in lymphangiogenesis in NSCLC by enhancing production of VEGF‐C, and IL‐17 may be an important target for the treatment of NSCLC. (Cancer Sci 2010; 101: 2384–2390)