SERPINE1 and SERPINB7 as potential biomarkers for intravenous vitamin C treatment in non-small-cell lung cancer.

High dose intravenous vitamin C (IVC) has been proposed as a pro-oxidant anticancer agent. However, there is a lack of biomarkers that are specific for this treatment. Here, we explored profiles of gene expression responding to IVC treatment in non-small cell lung cancer (NSCLC) cells as an effort for potential biomarker discovery. Genome-wide RNA-seq was performed in human NSCLC cell lines treated with pharmacological concentrations of vitamin C(VitC) for differential expression of genes. The identified genes were analyzed for correlations with patient prognosis using data from the Kaplan-Meier Plotter and the Human Protein Atlas databases. Further, tumor samples from a retrospective study of 153 NSCLC patients were analyzed with immunohistochemistry for expression of targeted genes, and patient prognosis was correlated to these genes. Two genes, namely SERPINE1 and SERPINB7 were found to be downregulated in NSCLC cells following VitC treatment. Combined patient data from the cohort analysis and online databases revealed that these 2 genes presented an unfavorable prognostic prediction of overall survival (OS) in NSCLC patients receiving standard of care. However, high expression level of these 2 genes were associated with prolonged OS in NSCLC patients receiving IVC in addition to standard of care. These data revealed that SERPINE1 and SERPINB7 have the potential to serve as predictive factors indicating favorable responses to IVC treatment in patients with NSCLC. Further validations are warranted.

Tissue resident memory T cells are enriched and dysfunctional in effusion of patients with malignant tumor.

Purpose Most malignant effusion is secondary to metastases to the pleura or peritoneum and portend poor oncological outcomes. Malignant effusion has different tumor microenvironment from primary tumor, containing a variety of cytokines and immune cells and directly contacting with tumor cells. However, the characteristic of CD4+ T cells and CD8+ T cells in malignant effusion remains unclear. Methods Malignant effusion including peritoneal ascites and pleural fluid from thirty-five patients with malignant tumor were collected and compared with matched blood. A detailed characterization of CD4+ T cells and CD8+ T cells in malignant effusion were conducted using flow cytometry and multiple cytokines assay. Results The concentration of IL-6 in malignant effusion was significantly higher than in blood. A substantial portion of T cells in malignant effusion were CD69+ and/ or CD103+ Trm cells. Most CD4+T and CD8+T cells in malignant effusion were exhausted T cells which expressed lower levels of cytokines, cytotoxic molecules and markedly higher levels of inhibitory receptor PD-1 compared with in blood. Conclusion Our study is the first to identify the presence of Trm cells in malignant effusion and will lay the foundation for future research on anti-tumor immunity of Trm cells in malignant effusion.

Very large hidden genetic diversity in one single tumor: evidence for tumors-in-tumor.

Despite the concern of within-tumor genetic diversity, this diversity is in fact limited by the kinship among cells in the tumor. Indeed, genomic studies have amply supported the 'Nowell dogma' whereby cells of the same tumor descend from a single progenitor cell. In parallel, genomic data also suggest that the diversity could be >10-fold larger if tumor cells are of multiple origins. We develop an evolutionary hypothesis that a single tumor may often harbor multiple cell clones of independent origins, but only one would be large enough to be detected. To test the hypothesis, we search for independent tumors within a larger one (or tumors-in-tumor). Very high density sampling was done on two cases of colon tumors. Case 1 indeed has 13 independent clones of disparate sizes, many having heavy mutation burdens and potentially highly tumorigenic. In Case 2, despite a very intensive search, only two small independent clones could be found. The two cases show very similar movements and metastasis of the dominant clone. Cells initially move actively in the expanding tumor but become nearly immobile in late stages. In conclusion, tumors-in-tumor are plausible but could be very demanding to find. Despite their small sizes, they can enhance the within-tumor diversity by orders of magnitude. Such increases may contribute to the missing genetic diversity associated with the resistance to cancer therapy.

Stent placement combined with intraluminal radiofrequency ablation and hepatic arterial infusion chemotherapy for advanced biliary tract cancers with biliary obstruction: a multicentre, retrospective, controlled study.

OBJECTIVE: To evaluate the efficacy and safety of stent placement combined with intraluminal radiofrequency ablation (intra-RFA) and hepatic arterial infusion chemotherapy (HAIC) for patients with advanced biliary tract cancers (Ad-BTCs) and biliary obstruction (BO). METHODS: We retrospectively reviewed data for patients with Ad-BTCs and BO who underwent stent placement with or without intra-RFA and HAIC in three centres between November 2013 and November 2018. The stent patency time (SPT), overall survival (OS), and adverse events (AEs) were analysed. RESULTS: Of the 135 enrolled patients, 64 underwent stent placement combined with intra-RFA and HAIC, while 71 underwent only stent placement. The median SPT was significantly longer in the combination group (8.2 months, 95% confidence interval [CI]: 7.1-9.3) than in the control group (4.3 months, 95% CI: 3.6-5.0; p < 0.001). A similar result was observed for OS (combination: 13.2 months, 95% CI: 11.1-16.5; control: 8.5 months, 95% CI: 7.6-9.6; p < 0.001). The incidence of AEs related to biliary tract operation was not significantly different between the two groups (p > 0.05). The most common AE and serious AE related to HAIC were alanine aminotransferase elevation (24/64; 37.5%) and thrombocytopenia (8/64; 12.5%), respectively. All AEs were tolerable, and there was no death from AEs. CONCLUSIONS: Stent placement combined with intra-RFA and HAIC may be a safe, potential treatment strategy for patients with Ad-BTCs and BO. KEY POINTS: • Advanced biliary cancers (Ad-BTCs) with biliary obstruction (BO) can rapidly result in liver failure and cachexia with an extremely poor prognosis. • Stent placement combined with intraluminal radiofrequency ablation and hepatic arterial infusion chemotherapy may be safe and effective for patients with Ad-BTCs and BO. • The long-term efficacy and safety of the combined treatment is promising.

High IL-6 expression in the tumor microenvironment is associated with poor prognosis of patients with extranodal natural / killer T-cell lymphoma (ENKTL).

Objectives: Extranodal natural/killer T-cell lymphoma (ENKTL) is a rare subtype of T cell non-Hodgkin's lymphoma. Current clinical prognostic models for ENKTL still have their limitations. Validated prognostic models for ENKTL have not yet been established. Methods: Tumor microenvironment IL-6 was measured by immunohistochemistry in 78 ENKTL patients. Results: Patients with negative IL-6 expression in the tumor microenvironment have a longer PFS (56.0 months vs. 25.6 months, p < 0.001) and OS (96.0 months vs. 43.3 months, p < 0.001). In the multivariate analysis, tumor microenvironment IL-6 [p = 0.048, HR = 1.76(1.00-3.08)] and extranodal involvement [p = 0.001, HR = 2.69(1.50-4.82)] were independent prognostic factors for PFS. Tumor microenvironment IL-6 [p = 0.033, HR = 2.69 (1.08-6.67)], Ann Arbor stage [p = 0.002, HR = 2.77 (1.47-5.23)] and B symptom [p = 0.027, HR = 2.02 (1.08-3.78)] were independent prognostic factors for OS. Expert opinion: A high IL-6 expression was related to poor survival, which may be a valuable biomarker for prognostic evaluation at baseline in ENKTL. These results showed that anti-IL-6R may be a potential targeted therapy for the treatment of advanced or relapsed ENKTL.

Prior anti-PD-1 therapy as a risk factor for life-threatening peri-engraftment respiratory distress syndrome in patients undergoing autologous stem cell transplantation.

Peri-engraftment respiratory distress syndrome (PERDS) is a kind of potentially life-threatening complication of autologous stem cell transplantation (ASCT). PERDS is characterized by fever, dyspnea, and hypoxemia during neutrophil engraftment. In order to identify the high-risk factors for PERDS, we retrospectively analyzed 260 patients with lymphoma undergoing ASCT in recent five years. The conditioning regimen was BuCyE (busulfan, cyclophosphamide, and etoposide). There were 16 patients (6.1%) diagnosed as PERDS. In multivariate analysis, prior anti-programmed death-1 (PD-1) therapy (hazard ratio [HR] = 8.852, 95% confidence interval [CI]: 2.954-26.527, P < 0.001) and history of pulmonary disease (HR = 3.718, 95% CI: 1.197-11.545, P = 0.023) were independent risk factors for PERDS. Patients with prior anti-PD-1 therapy (n = 31) had higher incidence of engraftment syndrome (77.4% vs. 33.4%, P < 0.001), PERDS (25.8% vs. 3.5%, P < 0.001), and transplant-related mortality (9.7% vs. 0.4%, P < 0.001), compared with those without prior anti-PD-1 therapy (n = 229). Subgroup analysis showed that sintilimab seemed to be associated with higher incidence of PERDS (42.9% vs. 11.8%, P = 0.06) compared with non-sintilimab group (pembrolizumab or toripalimab). C-reactive protein might be a feasible early predictor for PERDS. In conclusion, our study suggests that prior anti-PD-1 therapy may be a strong risk factor for life-threatening PERDS in patients with lymphoma undergoing ASCT.

Identifying high-risk patients with natural killer/T-cell lymphoma undergoing autologous stem cell transplantation.

At present, autologous stem cell transplantation (ASCT) is considered as an optional consolidation therapy for natural killer/T-cell lymphoma (NKTCL). However, the high-risk patients undergoing ASCT are not clear enough. In this study, 56 patients with advanced staged or relapsed/refractory (R/R) NKTCL undergoing ASCT were reviewed. All patients achieved clinical complete response (CR) before ASCT. The median follow-up time was 36 months (range, 3-192 months). The three-year overall survival (OS) and three-year progression-free survival (PFS) were 70.2% and 56.5%, respectively. The independent prognostic factors for OS included prior testis involvement and pre-ASCT EBV-DNA. Patients without prior testis involvement and negative pre-ASCT EBV-DNA (group A) had better three-year OS (86.3% vs. 47.6%, p < .001) than the rest patients (group B). In conclusion, our study suggests that testis involvement and elevated EBV-DNA might be strong adverse prognostic factors for NKTCL. Patients without the above risk factors are more likely to benefit from ASCT.

Recurrent ECSIT mutation encoding V140A triggers hyperinflammation and promotes hemophagocytic syndrome in extranodal NK/T cell lymphoma.

Hemophagocytic syndrome (HPS) is a fatal hyperinflammatory disease with a poorly understood mechanism that occurs most frequently in extranodal natural killer/T cell lymphoma (ENKTL). Through exome sequencing of ENKTL tumor-normal samples, we have identified a hotspot mutation (c.419T>C) in the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene, encoding a V140A variant of ECSIT. ECSIT-V140A activated NF-κB more potently than the wild-type protein owing to its increased affinity for the S100A8 and S100A9 heterodimer, which promotes NADPH oxidase activity. ECSIT-T419C knock-in mice showed higher peritoneal NADPH oxidase activity than mice with wild-type ECSIT in response to LPS. ECSIT-T419C-transfected ENKTL cell lines produced tumor necrosis factor (TNF)-α and interferon (IFN)-γ, which induced macrophage activation and massive cytokine secretion in cell culture and mouse xenografts. In individuals with ENKTL, ECSIT-V140A was associated with activation of NF-κB, higher HPS incidence, and poor prognosis. The immunosuppressive drug thalidomide prevented NF-κB from binding to the promoters of its target genes (including TNF and IFNG), and combination treatment with thalidomide and dexamethasone extended survival of mice engrafted with ECSIT-T419C-transfected ENKTL cells. We added thalidomide to the conventional dexamethasone-containing therapy regimen for two patients with HPS who expressed ECSIT-V140A, and we observed reversal of their HPS and disease-free survival for longer than 3 years. These findings provide mechanistic insights and a potential therapeutic strategy for ENKTL-associated HPS.

Safety and efficacy of non-initial rapid infusion of rituximab plus chemotherapy in Chinese patients with CD20+ non-Hodgkin's lymphoma.

OBJECTIVE: To evaluate the safety and efficacy of rapid rituximab infusion (RRI) plus chemotherapy in patients with CD20(+) non-Hodgkin's lymphoma (NHL). RESEARCH DESIGN AND METHODS: A total of 177 patients received 4 - 6 cycles of rituximab-based chemotherapy. The first cycle was given with standard schedule. In the second and subsequent cycles, RRI was initiated. Rituximab was administered as 20% of the dose infused in the first 30 min and the remaining 80% was given over 60 min. Benadryl and dexamethasone were given before infusions. Vital signs were measured at baseline and during infusion. RESULTS: In the first cycle, 48 patients experienced grade I - II infusion reactions and two patients showed grade III - IV infusion reactions. Six patients experienced infusion reactions during RRI. Two patients showed grade III infusion reactions to RRI and dropped out of the study. With a median follow up of 37.5 months, the 3-year overall survival and progression-free survival rates of the whole cohort were 93.1 and 81.1%, respectively. CONCLUSIONS: Our preliminary observations suggested that RRI may be safe and feasible for patients with CD20(+) NHL.

Clinical outcomes of patients with newly diagnosed primary central nervous system lymphoma are comparable on treatment with high-dose methotrexate plus temozolomide and with high-dose methotrexate plus cytarabine: a single-institution experience.

The role of temozolomide in untreated PCNSL patients has not yet been clearly defined. The purpose of this study was to compare the efficacy and toxicity of MT and MC chemotherapy in this population. A total of 41 consecutive patients were enrolled from March 2001 to July 2011. The ORR and CRR for MT vs. MC were 70% vs. 61.9% and 45% vs. 38.1% on ITT basis, (p = NS); 73.7% vs. 68.4% and 47.4% vs. 42.1% on PP basis, respectively (p = NS). Grade 3-4 hematological toxicities were more common in MC than in MT group (85.7% vs. 15%, p = 0.0001). One treatment-related death was observed in each group. The 5-year PFS and OS of MT (36% and 62.2%) were comparable to MC (32.6% and 46.7%), (p = NS). In summary, our preliminary results suggest that MT combination may be a simplified and effective regimen comparable to MC for newly diagnosed PCNSL.

Treatment outcome of docetaxel, capecitabine and cisplatin regimen for patients with refractory and relapsed nasopharyngeal carcinoma who failed previous platinum-based chemotherapy.

OBJECTIVE: Although cisplatin combined with 5-fluorouracil is a common first-line regimen for advanced nasopharyngeal carcinoma (NPC), there are no standard regimens for refractory or relapsed patients. A study of DXD regimen [cisplatin (D), capecitabine (X) and docetaxel (D)] was conducted to evaluate the efficacy and toxicity for patients with refractory or relapsed NPC. METHODS: The regimen was administered as follows: 50 mg/m(2) docetaxel and 50 mg/m(2) cisplatin on day 1 and 800 mg/m² capecitabine on days 1 - 14, repeated every 3 - 4 weeks. RESULTS: Thirty patients were enrolled. The overall response and complete remission rate was 46.4 and 21.4%. Median follow-up was 24 months; median overall survival (OS) and progression-free survival (PFS) were 14.0 and 8.0 months. Five-year OS and PFS rates were 14.8 and 13.3%, respectively. Four patients achieved long-term tumor-free survival (range, 53.8 - 125.3 months). Multivariate analysis demonstrated that Epstein-Barr virus DNA status (p = 0.003) and therapeutic effect (p < 0.001) were significant independent factors for OS and PFS. The main grade 3/4 toxicities included neutropenia (26.6%), anemia (13.3%) and thrombocytopenia (10.0%). There were no chemotherapy-related deaths. CONCLUSION: The DXD regimen appeared to be effective and well tolerated by patients with refractory or relapsed NPC. Further investigation is warranted.

Combination of low-dose gemcitabine in 6-hour infusion and carboplatin is a favorable option for patients in poor performance status with advanced non-small cell lung cancer.

This study sought to investigate the efficacy and tolerability of the regimen of low-dose gemcitabine combined with carboplatin in chemo-naïve patients with non-small cell lung cancer (NSCLC). The study involved 37 chemo-naive patients with unresectable stage IIIB or stage IV NSCLC. The predominant histological type was squamous carcinoma (22/37), and the performance status (PS) was 2 in 23 patients (62%). All received gemcitabine, 250 mg/m(2) in 6-hour infusion on days 1 and 8 plus carboplatin area under the curve (AUC)  =  5 on day 1, every 28 days. The overall response rate (ORR) was 62·2% and disease stabilization was achieved in 21·6% of the patients. After a median follow-up duration of 13 months, the median overall survival (OS) time was 14·0 months (95% CI 13·3-16·6 months), and the median progression-free survival (PFS) time was 7·0 months (95% CI 6·1-8·9 months). Hematological toxicities were well-tolerated with the development of grade 3/4 neutropenia and thrombocytopenia in 10·3 and 10·3% of patients respectively, and the gastrointestinal toxicities were mild.

High density of IL-17-producing cells is associated with improved prognosis for advanced epithelial ovarian cancer.

Interleukin (IL)-17 is the signature cytokine of T helper 17 cells. The role of IL-17 in the tumor microenvironment is still controversial. Few studies describing IL-17 expression in ovarian cancer have been reported. We have therefore analyzed the in situ tumor expression of IL-17 in advanced ovarian cancer and the possible correlation of IL-17 expression with tumor-associated macrophages (TAMs) and with survival in advanced ovarian cancer. Clinical data of 104 patients with stage III-IV epithelial ovarian cancer at the Sun Yat-sen University Cancer Center between 2000 and 2008 were retrospectively reviewed. Immunohistochemical staining of IL-17 and CD163 (marker for TAMs) was performed. Our data showed that levels of IL-17 were significantly increased in ovarian cancer compared with normal ovarian tissues (P<0.001). The high IL-17 expression group included more patients with grade 1 tumors than the low IL-17 expression group (P=0.042). High IL-17 expression correlated with improved progression-free survival (PFS) in advanced ovarian cancer (P<0.001). However, no significant difference was observed in overall survival between the high and low IL-17 expression groups. Multivariate analysis revealed that the density of IL-17-producing cells was a positive prognostic factor for PFS (P=0.001). Moreover, a positive correlation between the density of IL-17-producing cells and TAMs was identified (r=0.354, P<0.001). Our results indicate that the infiltration of IL-17-producing cells might contribute to improved PFS in advanced ovarian cancer. Our findings provide a new insight into the complex role of IL-17 in the tumor microenvironment of ovarian cancer.

Predictive value of pretreatment positron emission tomography/computed tomography in patients with newly diagnosed extranodal natural killer/T-cell lymphoma.

The role of (18)Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in extranodal natural killer/T-cell lymphoma (ENKL) is not well established. This study aimed to investigate the prognostic role of the pretreatment maximum standardized uptake value (SUV(max)) on PET/CT in patients with newly diagnosed ENKL. Among 364 consecutive patients with newly diagnosed ENKL, 81 patients were included and reviewed. The impact of SUV(max) on survival and the relationship between SUV(max) and other clinicopathological parameters were analyzed. The median SUV(max) was 14.6 (range 2.0-45.4). The optimal cutoff value of SUV(max) to predict overall survival (OS) was 15. Patients with high SUV(max) (SUVmax >15) were associated with bulky disease (P < 0.001), local invasion (P = 0.030), high score of Korean Prognostic Index (KPI, P = 0.046), resistance to primary treatment (P = 0.014), poor OS (P < 0.001), and unfavorable progression-free survival (P < 0.001). With a median follow-up of 25.0 months, the median OS was 63.0 months (range 2.0-99.0 months). Multivariate analyses revealed the following independent prognostic factors for OS: age >60 years (P = 0.001), stage III-IV (P = 0.023), SUV(max) >15 (P = 0.020), and bulky disease (>5 cm) (P = 0.002). By using the SUV(max), patients in most subgroups stratified by the KPI or the International Prognostic Index (IPI) were further discriminated in OS with significant statistical difference. Our results suggest the pretreatment SUV(max) is predictive of prognosis in patients with newly diagnosed ENKL. The SUV(max) may provide additional prognostic information for IPI and KPI.

Promising long-term outcome of gemcitabine, vinorelbine, liposomal doxorubicin (GVD) in 14-day schedule as salvage regimen for patients with previously heavily treated Hodgkin's lymphoma and aggressive non-Hodgkin's lymphoma.

The combination of gemcitabine (G), vinorelbine (V), and pegylated liposomal doxorubicin (D) has proved to be effective in relapsed Hodgkin's lymphoma (HL). Its efficacy in non-Hodgkin's lymphoma (NHL) remains to be discussed. We retrospectively evaluated the efficacy and toxicity of the dose-adjusted gemcitabine, vinorelbine, liposomal doxorubicin (GVD) in 14-day schedule in 35 heavily pretreated patients with relapsed and refractory aggressive NHL or HL. Treatment consisted of G: 800 mg/m(2) intravenous (i.v.) on day 1, V: 15 mg/m(2) i.v. on day 1; D: 20 mg/m(2) i.v. on day 1, repeated for 14 days. Patients responded to GVD proceeded to subsequent autologous stem cell transplantation. The objective response rate (ORR) was 48.6 %, with 31.4 % complete remission. A higher ORR was observed in patients with HL than in patients with NHL (80.0 vs. 36.0 %, P = 0.023). With a median follow-up of 26 months, the estimated median progression-free survival and overall survival were 5 (range 1-73 months) and 36 months (range 2-73 months), respectively. The estimated 5-year survival rate was 44.6 % (95 % confidence interval 28.1-61.1 %). Toxicities were mild (grade 3/4 neutropenia 34.3 %, thrombocytopenia 5.7 %). Our results suggest that the dose-adjusted GVD in 14-day schedule is effective and well tolerated in patients with refractory and relapsed HL and aggressive NHL. The potential long-term survival in NHL is promising.