粒细胞-巨噬细胞集落刺激因子基因修饰的树突状细胞疫苗增强体外抗肿瘤免疫效应

Objective To investigate if granulocyte-macrophage colony stimulating factor (GM-CSF) gene-modified dendritic cells ( DC) enhance antitumor immunity in vitro. Methods Mice were injected with chemokine ligand 3 (CCL3) via the tail vein. Fresh B220-CD11c+ cells were sorted from the peripheral blood mononuclear cells (PBMCs) and cultured into DCs by cytokines. DCs were transfected with AdGM-CSF gene at different ratios of multiplicity of infection ( MOI) to determine the optimal gene transfection conditions, and the expression of GM-CSF was detected after transfection. The variation of GM-CSF gene-modifiedDCs were analyzed by morphological examination, phenotype analysis, and mixed lymphocyte reaction (MLR). DCs were loaded with gastric cancer antigen obtained by freezing and thawing method. The killing effect of DCs vaccine-stimulated T lymphocytes on gastric cancer cells was assessed by MTT assay. INF-γ production was determined with the INF-γ ELISA kit. Results B220- CD11c+ cells increased obviously after CCL3 injection. The ELISA results showed that after GM-CSF gene modification, DCs could produce high level of GM-CSF. When DCs were transfected with AdGM-CSF gene at MOI equal to 100, the GM-CSF level in culture supematants reached saturation [(130.00±12.61) pg/ml]. After GM-CSF gene-modification, DCs tend to be more maturated as detected by morphological observation and phenotype analysis. At the same time, the capacity of activating the proliferation of allogeneic T lymphocytes was enhanced greatly. T lymphocytes stimulated by DCs transfected with GM-CSF gene showed a specific killing effect on gastric carcinoma cells and produced high level of INF-γ[ ( 1245. 00±13. 75) pg/ml].Conclusion After GM-CSF gene modification, DCs can produce high level of GM-CSF, which tend to be more maturated, and the capacity of activating the proliferation of allogeneic T lymphocytes is enhanced greatly. GM-CSF gene modified DCs can induce specific CTL to target tumor cells in vitro.     

粒细胞-巨噬细胞集落刺激因子基因修饰的树突状细胞疫苗增强体外抗肿瘤免疫效应

Objective To investigate if granulocyte-macrophage colony stimulating factor (GM-CSF) gene-modified dendritic cells ( DC) enhance antitumor immunity in vitro. Methods Mice were injected with chemokine ligand 3 (CCL3) via the tail vein. Fresh B220-CD11c+ cells were sorted from the peripheral blood mononuclear cells (PBMCs) and cultured into DCs by cytokines. DCs were transfected with AdGM-CSF gene at different ratios of multiplicity of infection ( MOI) to determine the optimal gene transfection conditions, and the expression of GM-CSF was detected after transfection. The variation of GM-CSF gene-modifiedDCs were analyzed by morphological examination, phenotype analysis, and mixed lymphocyte reaction (MLR). DCs were loaded with gastric cancer antigen obtained by freezing and thawing method. The killing effect of DCs vaccine-stimulated T lymphocytes on gastric cancer cells was assessed by MTT assay. INF-γ production was determined with the INF-γ ELISA kit. Results B220- CD11c+ cells increased obviously after CCL3 injection. The ELISA results showed that after GM-CSF gene modification, DCs could produce high level of GM-CSF. When DCs were transfected with AdGM-CSF gene at MOI equal to 100, the GM-CSF level in culture supematants reached saturation [(130.00±12.61) pg/ml]. After GM-CSF gene-modification, DCs tend to be more maturated as detected by morphological observation and phenotype analysis. At the same time, the capacity of activating the proliferation of allogeneic T lymphocytes was enhanced greatly. T lymphocytes stimulated by DCs transfected with GM-CSF gene showed a specific killing effect on gastric carcinoma cells and produced high level of INF-γ[ ( 1245. 00±13. 75) pg/ml].Conclusion After GM-CSF gene modification, DCs can produce high level of GM-CSF, which tend to be more maturated, and the capacity of activating the proliferation of allogeneic T lymphocytes is enhanced greatly. GM-CSF gene modified DCs can induce specific CTL to target tumor cells in vitro.     

A POTENTIAL TUMOR SUPPRESSOR GENE： Doc-1R

Objective: To detect the expression and the genomie sequence of Doe-1R gene in mice. Methods: The gene specific primers were designed and synthesized according to the cDNA sequence of Doe-1R gene. The sequence of Doc-1R gene was cloned by nested PCR. The expression of Doe-1R gene was examined by RT-PCR in thirteen kinds of tissues of mice. Results: The mouse Doe-1R gene has been obtained by two times genomie walking, which spans 2787bp and contains four exons and three introns. All of the splice donor/aeeeptor site sequences are in accordance with the consensus “GT-AG” rule. There was expression of Doe-1R gene in the thirteen tissues. Conclusion: Themouse Doe-1R gene was cloned successfully. The expression pattern suggests that Doe-1R gene is a housekeeping gene,which is important to keep the function of tissues and organs.     

Preliminary research on dendritic cells loaded with resistant breast cancer antigens in breast cancer-bearing nude mice

Objective The aim of the study was to investigate the inhibitory effects of dendritic cells(DCs) loaded with resistant breast cancer antigens on breast cancer in nude mice. Methods A single-cell suspension was prepared from a primary breast cancer and chemotherapeutic drugs were screened using the ATP-PCA susceptibility testing system. Cancer cells were treated with 1/10 × IC50, 1/5 × IC50, 1/2 × IC50, 1 × IC50, and 2 × IC50 medium until their growth became steady in the 2 × IC50 medium. Peripheral blood mononuclear cells(PBMCs) were obtained from the peripheral blood of patients with leukapheresis. The obtained adherent cells were induced by granulocyte-macrophage colony-stimulating factor(GM-CSF) and interleukin-4(IL-4) to generate DCs, which carried resistant strain cell lysis compounds or non-treated cancer cell lysis compounds. The former mature DCs carried resistant breast tumor antigens. A breast tumor-bearing nude mouse model was established with these resistant strains and the mice were randomly divided in three groups. The mice in the treatment group were injected with DCs loaded with resistant breast cancer antigens. The control group consisted of mice injected with DCs loaded with primary tumor cell antigens and the blank group consisted of mice injected with the same volume of normal saline. Changes in the cancers were observed. Results After treatment with the effector cells, the cancer volume and weight were significantly different to those before treatment in every group of mice(P < 0.05). The tumor volume in the blank group was the largest(3.362 ± 0.068 cm3) and the tumor weight was 637.50 ± 59.398 mg. Compared to the blank group, the tumor volume in the experimental group was the smallest(1.273 ± 0.071 cm3) and the tumor weight was 206.81 ± 32.711 mg. Conclusion DCs loaded with resistant breast cancer antigens demonstrated a significant inhibition effect on the cancers of breast tumor-bearing nude mice.     

同基因混合G-CSF动员的异基因骨髓移植物诱导的抗白血病效应

Objective:To explore whether the graft-versus-leukemia (GVL) effects could be enhanced and acute graft-versus-host disease (aGVHD) could be relieved by syngeneic bone marrow mixed with G-CSF-primed H-2 haploidentical marrow grafting.Methods:Female L615 (H-2k) mice were recipient mice and male (615×BALB/c) F1 (6BF1) (H-2k×H-2d) mice were donors respectively.Donor mice were injected subcutaneously with G-CSF daily at 0.01 μg/g for 6 days,and splenocytes were harvested on day 7.A total of 615 mice were loaded with L615 tumor cells and received 8.5 Gy (60Co γ-ray) irradiation three days later,followed by a mixed bone marrow transplantation (MBMT).The allo-grafts consisted of a mixture of syngenetic plus G-CSF-mobilized (control diluents) H-2 haploidetical marrow cells.GVL effects were monitored by survival time and survival rate of recipient mice.GVHD was assessed by clinical signs of weight loss,ruffled fur,diarrhea and histological changes of skin,liver and small intestines.Allogeneic chimerism was detected using cytogenetic analysis.Enzyme-linked immunosorbent assay (ELISA) method was used to detect cytokines (IL-2,IL-4 and IFN-γ).Fluorescence-activated cell sorting (FACS) analysis was used to detect T-cell phenotype.Results:(1) The mice merely received L615 leukemia cells were all died of leukemia.The L615 mice of 3∶1 and 4∶1 MBMT groups survived longer than those post syngeneic BMT (P＜0.01).(2) The survival time of mice in the G-CSF-treated MBMT groups was longer than that of non-primed MBMT groups (P＜0.05).Administration of G-CSF-treated 6BF1 mice could markedly increase the survival rate of 3:1 and 4:1 MBMT mice (P＜0.01) with little or a little GVHD.(3) As the post-transplanted time prolonged,the rates of allogeneic chimerism were decreased.The chimerism rates decreased to zero when the mice died of leukemia relapse.(4) L3T4 cells and relative ratio in both subsets were significantly reduced in G-CSF-treated donor mice.After G-CSF-treated donors,splenocytes from recipients at day 14 post-MBMT showed an increased production of IL-4 and a decreased production of IL-2 and IFN-γ.Conclusion:Syngeneic bone marrow mixed with H-2 haploidentical marrow grafts had a potential way to increase GVL effects,and this GVL effects could be enhanced with little or a little GVHD by G-CSF preetreatment of donors.Improved survival in recipients of G-CSF-mobilized donors is associated with increased IL-4 production and decreased IL-2 and IFN-γ production.     

不同化疗方案对MCF-7乳腺癌荷瘤裸鼠的抑瘤作用及对PCNA表达的影响

Objective: To investigate the antitumor activity of different combination regimens to human breast cancer xenograft (MCF-7) transplanted in nude mice and the effects on the expression of PCNA, and to evaluate the value of PCNA as predictive factor for the response of chemotherapy and individualized treatment. Methods: (1) 88 nude mice models of human breast cancer xenograft (MCF-7) were established, and then were randomly divided into control group and 10 chemotherapy groups (each group, n = 8). Among them, the mice of 5 chemotherapy groups were treated intraperitoneally/orally by 5 combination chemotherapy regimens (CMF, CAF, NP, TP, Xeloda) respectively at 1/3 LD10 dosage schedule (dose lethal to 10%of the mice), and that in another 5 chemotherapy groups were treated at 2/3 LD10 dosage schedule. Control animals were administered intraperitoneally with normal saline. (2) The body weight of nude mice and transplanted tumor growth were observed and recorded, then inhibition rate of tumor growth was calculated. (3) The pathological features of transplanted tumor were studied under microscope. The expression of proliferating cell nuclear antigen (PCNA) was comparatively studied in chemotherapy group and control group by SP immunohistochemical method and flow cytometry analysis. Results: (1) Body weight, tumor weight and inhibition rate of tumor growth of athymic mice bearing cancer: Body weights and tumor weights of nude mice in every 2/3 LD10 chemotherapy group were significantly lower than those of the control group (P ＜ 0.05), and the inhibition rates of tumor growth were 83.1%, 75.5%, 84.6%, 87.9% and 91.0%, respectively. Body weights of athymic mice in every 1/3 LD10 chemotherapy group were lower than that of the control (P ＜ 0.05). The results showed that the 2/3 LD10chemotherapy groups could reflect the effect of combination chemotherapy on the nude mice and the clinical dependability was better. So the data of 2/3 LD10 chemotherapy groups were appropriated for successive study. (2) Immunohistochemical studies: The expressions of PCNA in every chemotherapy group were significantly lower than that of the control (P ＜ 0.05).Moreover, the expression of PCNA in NP group was significantly lower than those of CMF, CAF, TP and Xeloda groups (P ＜0.05), while the expressions of TP and Xeloda groups were significantly lower than those of CMF and CAF groups (P ＜ 0.05).(3) FCM analysis: FI values of PCNA in every chemotherapy group were significantly lower than that of the control (P ＜ 0.05).FI values of PCNA in TP and Xeloda groups were significantly lower than those of CMF and CAF groups (P ＜ 0.05), while the value of NP group was significantly lower than that of CMF group (P ＜ 0.05). (4) Relationship between PCNA expression and pathologic response: The expression of PCNA was significantly correlated with pathological therapeutic response of transplanted breast carcinoma (P = 0.001). Conclusion: In vivo chemosensitivity testing with 2/3 LD10 dosage combinations in nude mice bearing cancer can reflect the effects of chemotherapeutics and affects of organism exactly. Various chemotherapy regimens all can decrease the expression of PCNA in breast cancer. The PCNA can be regarded as the factor to judge the response to chemotherapy, and it become possibly one of the prospective factors in the selection of chemotherapy regimen and play a rule in individualized therapy in the clinic.     

Experimental Study of Ultrasound on MDR in a Human Tumor in Vivo

OBJECTIVE To evaluate the potential efficacy of low-intensity ultrasound(US)in combination with anticancer drugs to reverse multidrug resistance(MDR)in nude mice. METHODS A total of 40 male and female athymic nude mice were inoculated subcutaneously with 5x106 HepG 2 /ADM and HepG 2 cells.Ultrasound with pulsed irradiation at an average intensity of 0.5 W/cm2 was given to the tumor area 10 min after administration of adriamycin(ADM).The tumor 3 dimensional diameters were measured by calipers before and after treatment, and the tumor growth indexes(TGI)calculated.RT-PCR was used to detect the gene levels of the HepG 2 /ADM cells.Immunohistochemical analyses for MDR proteins were conducted on the tumor tissues. RESULTS The ultrasonic treatment resulted in an average reduction in the tumor volume of 62%one month later.The relative mRNA levels of MDR1 and MRP were significantly different among the folowing 4 groups: untreated group as control,ADM treated;US treated;and ADM plus US treated.The mRNA levels of mdr1 and mrp were down-regulated in the US groups compared to those of the non-ultrasound groups by multiple com- parisons.The relative mRNA levels of lrp expression were not significantly changed.The results of immunohistochemistry indicated that tumor tissue from animals treated with US had remarkably low mdr1 and mrp expression. CONCLUSION The results showed that low-intensity US can effectively reduce the size of adriamycin-resistant human hepotacarcinoma in a nude mouse model,and support the efficacy of US to overcome multiple mechanisms of drug resistance.     

沉默轴突导向蛋白4D基因对卵巢癌SKOV3细胞恶性生物学行为的影响

Objective To observe the effect of DNA Sema4D gene silencing by RNA interfering on the proliferation, migration and invasion of human ovarian cancer SKOV3 cells, and to study the effect of pshRNASema4D on the growth of SKOV3 cells in transplanted tumor in nude nice. Methods Recombinant plasmid pshRNASema4D-A, B and C were respectively transfected into SKOV3 cells by lipofetamine 2000, while cells transfected by plasmid vector pcDNA3.1 and cells untreated as control groups. RT-PCR was adopted to select the recombinant plasmid which showed the most optimal inhibition effect. RT-PCR and Western blotwere used to detected the mRNA and protein expression of Sema4D in SKOV3 cells tranfected for 24, 48 and 72 hours. MTT assay was used to investigate the proliferation of the SKOV3 cells after trasnsfection. Transwell cell migration and invasion assays were used to investigate the migration and invasion abilities of the SK0V3 cells after trasnsfection. Human ovarian cancer model was established in nude mice, and the nude mice were treated with pshRNASema4D-B once every 3 days for 3 weeks. The bulk of the transplanted tumor was measured. Results Three Sema4D-targeted short hairpin RNA (shRNA) A, B and C were successfully inserted into the plasmid vector pshRNA, and the coding sequences of the obtained shRNA were consistent with the designed fragment. The results indicated that both recombinant plasmid pshRNASema4D-A and B could effectively knock down the expression of Sema4D gene in human ovarian cancer cells, of which pshRNASema4D-B was the better choice, while no effect of pshRNASema4D-C was seen. RT-PCR results showed that the relative mRNA expression of Sema4D gene in SKOV3 cells transfected with pshRNA-Sema4D for 24, 48 and 72 hours were 0. 401 ±0.051, 0. 120 ±0.035 and 0.014 ±0. 015, respectively, which were significantly lower than that in SKOV3 cells transfected by empty vector and non-transfected cells at 72 hours after transfection. (0.521 ±0.019, 0.536 ±0.040,respectively, P<0.05). The Westen blot analysis manifested that the relative expression of Sema4D protein of SKOV3 cells transfected by pshRNASema4D for 24, 48 and 72 hours were 0. 196 ± 0. 023, 0. 074 ± 0. 015 and 0. 040 ± 0.014, respectively, which were significantly lower than that in SKOV3 cells transfected by empty vector and non-transfected cells at 72 hours after transfection. (0. 275 ± 0. 009, 0. 282 ± 0. 015, respectively, P < 0. 05 ). Comparing with the empty vector-transfected and non-transfected cells, the proliferation, invasion and migration ability of SKOV3 cells transfected with pshRNA-Sema4D were obviously weakened. The pshRNASema4D-B significantly suppressed the growth of the SKOV3 cells-transplanted tumors in nude mice, and the IR( inhibitory rate ) of pshRNASema4D-B group was ( 61.0 ± 3.3 ) % ( P < 0.05). Conclusions Sema4D can be successfully silenced by RNA interfering in human ovarian cancer SKOV3 cells. Downregulation of Sema4D can inhibit the proliferation, migration and invasion of ovarian cancer cells. The pshRNASema4D can significantly suppress the growth in transplanted tumor of human ovary cancer in nude mice. Sema4D may become a candidate gene of gene therapy of human ovarian cancer.     

粒细胞集落刺激因子减轻混合骨髓移植后移植物抗宿主病的实验研究

Objective: How to reduce the incidence and severity of acute graft-versus-host disease (aGVHD) is a crucial step to improve the overall survival of allogeneic bone marrow transplantation (allo-BMT). The low incidence of severe aGVHD observed in allogeneic peripheral blood stem cell transplantation (allo-PBSCT), which may be related to modulating immune function of T lymphocytes by granulocyte colony-stimulating factor (G-CSF) primed donors. The study aimed to explore whether aGVHD could be alleviated by syngeneic bone marrow mixed with G-CSF-mobilized H-2 haploidentical marrow grafting. Methods: Female BALB/c mice and neonatal BALB/c mice were recipients and male (BALB/c × C57BL/6)F1(BCF1) mice were donor mice respectively. Donor mice were injected subcutaneously with G-CSF daily at 0.01 μg/g body weight or saline for 6 days, and splenocytes were harvested on day 6. Spleen index (SI) represented GVHD in neonatal mice after the intraperitoneal injection of mixed spleen cells. Lethally irradiated (60Co, 8.5 Gy) adult mice were transplanted with a mixture of syngeneic plus G-CSF-mobilized (control diluents) H-2 haploidentical marrow cells. Survival time and survival rate of the recipients were observed after mixed marrow transplantation (MBMT). GVHD was assessed by observing signs of weight loss, ruffled fur, diarrhea and histological change of skin, liver and small intestines. Enzyme-linked immunosorbent assay (ELISA) method was used to detect cytokines (IL-2, IL-4 and INF-γ). Fluorescence-activated cell sorting (FACS) analysis was used to detect T cells phenotype. Results: (1) The neonatal mice subject to injection of 2:1 and 1:1 mixed spleen cells and H-2 haploidentical spleen cells all suffered from aGVHD. The severity of aGVHD in recipient mice receiving G-CSF-mobilized splenocytes was dramatically reduced. (2) The aGVHD signs and histological change were observed in most mice of 2:1 and 1:1 MBMT groups. However, the survival time of G-CSF-mobilized MBMT was longer than in control groups and these mice had signs of moderate GVHD. (3) L3T4 cells and relative ratio in both subsets was significantly reduced in G-CSF-treated donor mice. The total number of Thy1.2 and lyt2 cells was increased after G-CSF pretreatment of donors, but no statistical difference. (4) The supernatants from a primary MLR were collected at 48 h for cytokine measurement. The results showed an increased production of IL-4 and a decreased production of IL-2 and INF-γ after stimulating with concanavalin A for 48 h. Conclusion: The GVHD could be reduced using syngeneic bone marrow mixed with H-2 haploidentical marrow cells. The severity of aGVHD in recipient mice receiving G-CSF-mobilized splenocytes or marrow cells could be further moderated, which is associated with increased IL-4 production and decreased IL-2 and INF-γ production.     

Circulating tumor DNA-based molecular residual disease detection for treatment monitoring in advanced melanoma patients

Background

Immune checkpoint inhibitors (ICIs) have substantially improved overall survival in patients with advanced melanoma; however, the lack of biomarkers to monitor treatment response and relapse remains an important clinical challenge. Thus, a reliable biomarker is needed that can risk-stratify patients for disease recurrence and predict response to treatment.

Methods

A retrospective analysis using a personalized, tumor-informed circulating tumor DNA (ctDNA) assay on prospectively collected plasma samples (n = 555) from 69 patients with advanced melanoma was performed. Patients were divided into three cohorts: cohort A (N = 30), stage III patients receiving adjuvant ICI/observation; cohort B (N = 29), unresectable stage III/IV patients receiving ICI therapy; and cohort C (N = 10), stage III/IV patients on surveillance after planned completion of ICI therapy for metastatic disease.

Results

In cohort A, compared to molecular residual disease (MRD)-negative patients, MRD-positivity was associated with significantly shorter distant metastasis-free survival (DMFS; hazard ratio [HR], 10.77; p = .01). Increasing ctDNA levels from the post-surgical or pre-treatment time point to after 6 weeks of ICI were predictive of shorter DMFS in cohort A (HR, 34.54; p < .0001) and shorter progression-free survival (PFS) in cohort B (HR, 22; p = .006). In cohort C, all ctDNA-negative patients remained progression-free for a median follow-up of 14.67 months, whereas ctDNA-positive patients experienced disease progression.

Conclusion

Personalized and tumor-informed longitudinal ctDNA monitoring is a valuable prognostic and predictive tool that may be used throughout the clinical course of patients with advanced melanoma.     

Combined transcatheter arterial chemoembolization and radiofrequency ablation in single‐session for solitary hepatocellular carcinoma larger than 7 cm

1 Aims

To evaluate technical feasibility and treatment results of combined transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) in single‐session for solitary hepatocellular carcinoma (HCC) larger than 7 cm in diameter.

2 Methods

Institutional review board approved this retrospective study. Written informed consent was obtained from all patients. Between June 2007 and July 2013, 87 patients (75 men, 12 women; mean age, 55.5 years ± 15.0) with solitary HCC with a mean maximum diameter of 9.5 cm ± 2.4 (range, 7.1–13.5 cm) not feasible for surgical resection underwent combined TACE and RFA in a single‐session. Immediately following TACE, RFA was performed under fluoroscopy and CB‐CT guidance. The primary endpoint was overall survival (OS). The secondary endpoints were technical safety and local tumor progression (LTP) rates. OS and time to progression (TTP) were analyzed with the Kaplan–Meier method. Univariate and multivariate analyses were performed to identify prognostic factors affecting OS and TTP.

3 Results

Technical success of combined TACE and RFA in a single‐session was achieved in all patients (100%). On 1‐month follow‐up MRI, complete response (CR) was observed in 76 of 87 patients (87.4 %), partial response (PR) in 8 and stable disease (SD) in 3 patients. The median follow‐up period was 49.5 months (interquartile range, 30.0–70.0 months). The median OS was 39 months (range, 15–86 months). The cumulative OS rates at 1, 3 and 5 years were 100%, 65.5% and 47.5%, respectively. The estimated 1, 3 and 5 year LTP rates were 0 %, 29.9% and 55.2 %, respectively. Univariate and multivariate analyses showed a tumor larger than 10.0 cm (P < 0.05) and presence of portal vein branch invasion (P < 0.05) led to the worst prognosis. No major complications were noted.

4 Conclusions

Combined use of TACE and RFA in single‐session is a safe and effective option in the treatment of patients with solitary large HCC (> 7 cm) not amenable to surgery.     

Use of electronic cigarettes among African American cancer survivors

Background

The use of electronic cigarettes (e-cigarettes) is increasing rapidly in the United States, although the negative health outcomes associated with these products are still unknown. Emerging research has examined the use of e-cigarettes in the cancer survivor population as a whole, yet none has focused on e-cigarette use in the African American (AA) cancer survivor population.

Methods

The authors used data from the Detroit Research on Cancer Survivors cohort study, comprised of AA adult cancer survivors. Logistic regression models were used to evaluate factors potentially associated with e-cigarette ever use and current use.

Results

Of 4443 cancer survivors who completed a baseline interview, 8.3% (n = 370) reported ever using e-cigarettes, and 16.5% (n = 61) of those reporting ever use also reported current use of e-cigarettes. Ever users and current users were on average younger than those who did not use e-cigarettes (57.5 vs. 61.2 years; p < .001). Current cigarette smokers were >20 times more likely (odds ratio, 20.75; 95% confidence interval, 12.84–33.55) and former smokers were almost 10 times more likely (odds ratio, 9.50; 95% confidence interval, 6.03–14.97) to have ever used e-cigarettes than never-smokers. Preliminary data suggested that ever use of e-cigarettes is associated with later stage at diagnosis for breast and colorectal cancers.

Conclusions

As the use of e-cigarettes increases in the general population, it is important to continue to monitor their use in cancer survivors and to gain more insight as it pertains to the AA cancer survivor population. Elucidation of the factors associated with e-cigarette use in this population may help inform comprehensive cancer survivorship recommendations and interventions.     

Prevalence of oral and blood oncogenic human papillomavirus biomarkers among an enriched screening population: Baseline results of the MOUTH study

Background

Human papillomavirus (HPV)-related oropharyngeal cancer screening is being explored in research studies, but strategies to identify an appropriate population are not established. The authors evaluated whether a screening population could be enriched for participants with oncogenic HPV biomarkers using risk factors for oral HPV.

Methods

Participants were enrolled at Johns Hopkins Hospitals and Mount Sinai Icahn School of Medicine. Eligible participants were either men aged 30 years or older who had two or more lifetime oral sex partners and a personal history of anogenital dysplasia/cancer or partners of patients who had HPV-related cancer. Oral rinse and serum samples were tested for oncogenic HPV DNA, RNA, and E6 or E7 antibodies, respectively. Participants with any biomarker were considered at-risk.

Results

Of 1108 individuals, 7.3% had any oncogenic oral HPV DNA, and 22.9% had serum antibodies for oncogenic HPV E6 or E7. Seventeen participants (1.5%) had both oral and blood biomarkers. HPV type 16 (HPV16) biomarkers were rarer, detected in 3.7% of participants, including 20 with oral HPV16 DNA and 22 with HPV16 E6 serum antibodies (n = 1 had both). In adjusted analysis, living with HIV (adjusted odds ratio, 2.65; 95% CI, 1.60–4.40) and older age (66–86 vs. 24–45 years; adjusted odds ratio, 1.70; 95% CI, 1.07–2.70) were significant predictors of being at risk. Compared with the general population, the prevalence of oral HPV16 (1.8% vs. 0.9%), any oncogenic oral HPV DNA (7.3% vs. 3.5%), and HPV16 E6 antibodies (2.2% vs. 0.3%) was significantly elevated.

Conclusions

Enrichment by the eligibility criteria successfully identified a population with higher biomarker prevalence, including HPV16 biomarkers, that may be considered for screening trials. Most in this group are still expected to have a low risk of oropharyngeal cancer.     

Genetic variants in <Emphasis Type="Italic">MMP9</Emphasis> and <Emphasis Type="Italic">TCF2</Emphasis> contribute to susceptibility to lung cancer

Objective|  

The Wnt signaling pathway is crucial for pulmonary development and differentiation; dysregulation of the Wnt signaling pathway may impair lung function. Indeed, single nucleotide polymorphisms (SNPs) of Wnt pathway-related genes have been suggested as risk factors for certain types of cancers. In this study, we aimed to evaluate the influence of SNPs in Wnt-related genes (TCF2, MMP9) on susceptibility to lung cancer.     

Frequency of mesenchymal‐epithelial transition factor gene (MET) and the catalytic subunit of phosphoinositide‐3‐kinase (PIK3CA) copy number elevation and correlation with outcome in patients with early stage breast cancer

BACKGROUND:

The current study was conducted to determine the frequency and association between recurrence‐free survival (RFS) and MET and catalytic subunit of phosphoinositide‐3‐kinase (PIK3CA) copy number elevations in patients with early stage breast cancer.

METHODS:

Tumor DNA was extracted from 971 formalin‐fixed, paraffin‐embedded early breast cancers for molecular inversion probes arrays. Data were segmented using the single‐nucleotide polymorphism (SNP)‐FASST2 segmentation algorithm. Copy number gains were called when the copy number of each segment was greater than 2.3 or 1.7, respectively. RFS was estimated by the Kaplan‐Meier method. Cox proportional hazards models were fit to determine independent associations between copy number and RFS.

RESULTS:

Of the 971 tumors studied, 82 (8.44%) and 134 (13.8%) had an elevation of the MET or PIK3CA copy number, respectively, and 25.6% of tumors with a MET copy number elevation had a PIK3CA copy number elevation. Patients with either a MET or PI3KCA high copy number tended to have poorer prognostic features (larger tumor size, higher tumor grade, and hormone receptor negativity). Both MET and PIK3CA high copy numbers were more likely to occur in patients with triple receptor‐negative disease (P = .019 and P < .001, respectively). At a median follow‐up of 7.4 years, there were 252 cases of disease recurrence. The 5‐year RFS rates were 63.5% and 83.1% for MET high copy number and MET normal/low copy number, respectively (P = .06) and 73.1%, and 82.3% for PIK3CA high copy number and PIK3CA normal/low copy number, respectively (P = .15). A high copy number for either gene was not found to be an independent predictor of RFS.

CONCLUSIONS:

A high copy number of MET or PIK3CA was found to be associated with poorer prognostic features and triple receptor‐negative disease. Coamplification was frequent. Patients with tumors with high MET copy numbers tended to have a worse RFS. Cancer 2013. © 2012 American Cancer Society.     

Prospective evaluation of the tolerability and efficacy of niraparib dosing based on baseline body weight and platelet count: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial

Background

The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer.

Methods

In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose.

Results

Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46–0.76] vs. ISD HR, 0.69 [95% CI, 0.48–0.98]) and the homologous recombination–deficient (FSD HR, 0.44 [95% CI, 0.30–0.64] vs. ISD HR, 0.39 [95% CI, 0.22–0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD.

Conclusions

In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.     

Prognostic factors of childhood acute lymphoblastic leukemia with TCF3::PBX1 in CCCG-ALL-2015: A multicenter study

Background

Contemporary risk-directed treatment has improved the outcome of patients with acute lymphoblastic leukemia (ALL) and TCF3::PBX1 fusion. In this study, the authors seek to identify prognostic factors that can be used to further improve outcome.

Methods

The authors studied 384 patients with this genotype treated on Chinese Children's Cancer Group ALL-2015 protocol between January 1, 2015 and December 31, 2019. All patients provisionally received intensified chemotherapy in the intermediate-risk arm without prophylactic cranial irradiation; those with high minimal residual disease (MRD) ≥1% at day 46 (end) of remission induction were candidates for hematopoietic cell transplantation.

Results

The overall 5-year event-free survival was 84.4% (95% confidence interval [CI], 80.6–88.3) and 5-year overall survival 88.9% (95% CI, 85.5–92.4). Independent factors associated with lower 5-year event-free survival were male sex (80.4%, [95% CI, 74.8–86.4] vs. 88.9%, [95% CI, 84.1–93.9] in female, p = .03) and positive day 46 MRD (≥0.01%) (62.1%, [95% CI, 44.2–87.4] vs. 87.1%, [95% CI, 83.4–90.9] in patients with negative MRD, p < .001). The presence of testicular leukemia at diagnosis (n = 10) was associated with particularly dismal 5-year event-free survival (33.3% [95% CI, 11.6–96.1] vs. 83.0% [95% CI, 77.5–88.9] in the other 192 male patients, p < .001) and was an independent risk factor (hazard ratio [HR], 5.7; [95% CI, 2.2–14.5], p < .001).

Conclusions

These data suggest that the presence of positive MRD after intensive remission induction and testicular leukemia at diagnosis are indicators for new molecular therapeutics or immunotherapy in patients with TCF3::PBX1 ALL.     

血清白细胞介素-18和NO活性在前列腺癌患者的临床价值(英文)

Objective  

The aim of the study was to estimate the clinical value of serum interleukin-18 (IL-18) and nitric oxide (NO) activities in patients with prostate cancer.