Molecular subtypes predict the preferential site of distant metastasis in advanced breast cancer: a nationwide retrospective study.

Objective: This study aimed to explore possible associations between molecular subtypes and site of distant metastasis in advanced breast cancer (ABC). Methods: 3577 ABC patients were selected from 21 hospitals of seven geographic regions in China from 2012-2014. A questionnaire was designed to collect medical information regarding demographic characteristics, risk factors, molecular subtype, recurrence/metastasis information, and disease-free survival (DFS). The cancers were classified into Luminal A, Luminal B, HER2-enriched and Triple Negative subtypes. Chi-square test and multivariate Cox proportional hazard models were performed to explore the associations between molecular subtypes and distant metastasis sites. Results: A total of 2393 cases with molecular subtypes information were finally examined. Patients with Luminal A (51.1%) and Luminal B (44.7%) were most prone to bone metastasis, whereas liver metastasis was more frequently observed in HER2-enriched ABC patients (29.1%).The cumulative recurrence and metastasis rates of ABC patients at 36 months of DFS were the most significant within molecular types, of which Triple Negative was the highest (82.7%), while that of Luminal A was the lowest (58.4%). In the adjusted Cox regression analysis, Luminal B, HER2-enriched and Triple Negative subtypes increased the risk of visceral metastasis by 23%, 46% and 87% respectively. In addition, Triple Negative patients had a higher probability of brain metastasis (HR 3.07, 95% CI: 1.04-9.07). Conclusion: Molecular subtypes can predict the preferential sites of distant metastasis, emphasizing that these associations were of great help in choices for surveillance, developing appropriate screening and cancer management strategies for follow-up and personalized therapy in ABC patients.

A prospective, open-label, multicenter phase IV clinical trial on the safety and efficacy of lobaplatin-based chemotherapy in advanced breast cancer.

Background: Since lobaplatin (LBP) has been approved to treat metastatic breast cancer in China, this study aimed to evaluate the safety and efficacy of LBP-based chemotherapy in clinical practice. Methods: This trial was a prospective, open-label, multicenter phase IV clinical trial that enrolled patients with unresectable locally advanced or recurrent/metastatic breast cancer from 34 sites between July 2013 and March 2017. Patients were treated with LBP monotherapy or in combination for four to six cycles. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results: A total of 1179 patients were analyzed; 59 (5.0%) were treated with LBP alone, 134 (11.4%) with LBP plus paclitaxel, 263 (22.3%) with LBP plus docetaxel, 237 (20.1%) with LBP plus gemcitabine, 403 (34.2%) with LBP plus vinorelbine, and 83 (7.0%) with other LBP-based regimens. The overall incidence of adverse events (AEs) was 95.2%, and 57.9% of patients had grade >3 AEs. The most common grade >3 AEs were neutropenia (43.9%), leukopenia (39.4%), anemia (17.8%), and thrombopenia (17.7%). LBP monotherapy showed the lowest incidence of grade >3 AEs (39.0%), followed by LBP plus docetaxel (52.9%), LBP plus paclitaxel (59.0%), LBP plus vinorelbine (62.5%), and LBP plus gemcitabine (62.9%). The ORR and DCR were 36.8 and 77.0%, respectively. The median PFS was 5.5 months (95% confidence interval: 5.2-5.9). Conclusion: LBP-based chemotherapy shows favorable efficacy in patients with advanced breast cancer, with manageable safety profile. Trial registration: This trial was registered with ChiCTR.org.cn, ChiCTR-ONC-13003471.

Age at initial diagnosis and prognosis of breast cancer: a nationwide multicenter retrospective study in China.

Background: Several studies have indicated possible associations between age and the prognosis of breast cancer (BC), but limited data are available from hospital-based multicenter studies in China. This study aimed to explore the associations between age at initial diagnosis of BC and the risk of recurrence or metastasis among Chinese women with newly diagnosed advanced breast cancer (ABC) and provide treatment decision support for BC patients of different ages to medical workers. Methods: The medical records of patients newly diagnosed with ABC were obtained from 21 hospitals in seven geographic regions in China from 2012 to 2014. Patients' general information, clinicopathological features at first diagnosis, treatment information, and prognosis were retrospectively collected based on the self-designed case report form (CRF). Cox proportional hazards regression models were used to determine hazard ratios (HR) and 95% confidence intervals (CI) for the associations between age groups and the risk of recurrence and metastasis. Results: A total of 1,852 cases were included in the final analysis. Age at initial diagnosis was shown to be significantly related to hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, molecular subtypes, and the number of lymph node metastasis (all P<0.05). Patients aged <35 years were more likely to have bone metastasis (45.6%). Patients aged ≥65 years had a lower percentage of receiving surgery (87.1%), adjuvant chemotherapy (61.3%), adjuvant radiotherapy (35.5%), and adjuvant endocrine therapy (30.6%) than the other groups (all P<0.05). Compared with patients aged <35 years, the risk of recurrence or metastasis in those aged 55-64 years was significantly higher (HRage 55-64 =1.24, 95% CI: 1.04-1.47), and the risk of bone metastasis and lung metastasis in those aged 35-44 years was lower (HRbone metastasis =0.74, 95% CI: 0.59-0.93; HRlung metastasis =0.70, 95% CI: 0.53-0.93). After adjusting for stage, grade, and molecular subtype, surgery, neoadjuvant chemotherapy, adjuvant chemotherapy, adjuvant radiotherapy, adjuvant endocrine therapy, and family history of BC, patients aged 35-44 years still had a significantly reduced risk of bone metastasis and lung metastasis by 31% and 52%, respectively (HRbone metastasis =0.69, 95% CI: 0.48-0.98; HRlung metastasis =0.48, 95% CI: 0.31-0.74). Conclusions: Age at initial diagnosis is related to the clinicopathological characteristics and treatment pattern. Although the risk of site-specific metastasis varies by age, age is not an independent factor influencing the risk of total recurrence and metastasis. In accordance with current clinical practice guidelines for BC, however, precise treatment shall be chosen personally for patients whose ages at initial diagnosis are different.

Comparisons of Treatment for HER2-Positive Breast Cancer between Chinese and International Practice: A Nationwide Multicenter Epidemiological Study from China.

OBJECTIVE: To better understand the status of medical treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer and the differences between the Chinese and the international clinical practice. METHODS: This was a retrospective, nationwide, multicenter, epidemiological study of advanced breast cancer patients from China. Between January 01, 2012, and December 31, 2014, a total of 3649 patients, covering 7 geographic regions and 21 institutions, participated in this series of studies. HER2-positive breast cancer was selected among the group and adopted into this study. In comparison, we summarized the demographics and clinical characteristics of HER2-positive breast cancer from the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: A total of 918 patients diagnosed as HER2-positive breast cancer patients were included. The median age at diagnosis was 46 years (ranging, 23 to 78) with a single-peak incidence. The proportions of stages II-IV at diagnosis and distance metastasis in viscera were more than half of the participants. In comparison, the prevalence of estrogen or progesterone receptor-positive expression and luminalB subtype was relatively lower than that of the United States. The receipt of chemotherapy was fairly higher, while the usage of targeted therapy was seriously insufficient. Tumor size was in significantly positive associations with the duration of targeted therapy (Kendall's correlation coefficient = 0.3, P < 0.0001), while no prohibitive variables among clinical characteristics were detected. CONCLUSION: Our study suggested that HER2-positive breast cancer patients were characterized as a younger trend, a lower prevalence of hormonal receptor (HR)-positive expression, and less accessible to anti-HER2 targeted therapy with insufficient duration over the past few years in China. Concerted efforts should be exerted for promising survival benefits in the future. The trial registration number is https://clinicaltrials.gov/ct2/show/NCT03047889.

Profile, treatment patterns, and influencing factors of anthracycline use in breast cancer patients in China: A nation-wide multicenter study.

BACKGROUND: Anthracycline-based chemotherapy (ABC) is one of the standard therapies against breast cancer. However, few guidelines are currently available to optimize the use of ABC. Therefore, the present analysis aimed at determining the profile and treatment patterns of ABC and the association of clinicopathological characteristics with ABC selection. METHODS: We retrospectively analyzed the data of a nation-wide multicenter epidemiological study, which collected the medical records of breast cancer patients receiving chemotherapy in different settings from seven geographic regions in China (NCT03047889). RESULTS: In total, 3393 patients were included, with 2917 treated with ABC. Among them, 553 (89.8%), 2165 (81.7%), and 814 (25.7%) were subjected to ABC as neoadjuvant, adjuvant, and advanced chemotherapy, respectively. The most frequently used regimens were anthracycline-taxane-based combinations for neo- and adjuvant chemotherapy, along with taxanes and oral fluorouracils for the palliative stages. In the overall cohort, patients aged < 40 or 40-65 (p < 0.001), in premenopause (p < 0.001), without comorbidities (p = 0.016), with invasive ductal carcinoma (p= 0.001), high lymph node involvement (p < 0.001), in the pTNM stage II, III, or IV versus stage I (p < 0.001), subjected to mastectomy (p < 0.001) or subjected to sentinel lymph node biopsy combined with axillary lymph node dissection (p = 0.044), or with a decreased disease-free survival (p < 0.001) were more likely to be recommended to ABC. CONCLUSION: Taken together, ABC remained the mainstay of breast cancer treatment, especially in neo and adjuvant therapy. ABC was mainly used as a combination therapy, and the correlation between influencing factors and ABC choice varied during different settings, indicating the preference and different perspectives of medication considered by medical oncologists regarding the use ABC in China.

Increased Risk of Lymphoma in Men or the Elderly Infected with Tuberculosis.

PURPOSE: To identify factors associated with lymphoma in patients with prior Mycobacterium tuberculosis infection. METHODS: A retrospective case-control analysis was performed in a highly tuberculosis (TB)-endemic area. Patients with a history of TB before the diagnosis of lymphoma were retrospectively identified. Inpatients with lymphoma (n=1,057) and pathologically confirmed benign diseases (n=12,916) were consecutively enrolled at Xinjiang Medical University Cancer Hospital between January 2016 and December 2019. RESULTS: The proportion of TB infection in patients with lymphoma (n=148, 14.0%) was significantly higher than that in the control (benign diseases) group (n=175, 1.4%) (p<0.0001). The frequencies of TB infection in patients with Hodgkin lymphoma, B-cell non-Hodgkin lymphoma (NHL), and T/NK-cell NHL were 13.6%, 14.6%, and 11.9%, respectively. Relatively high proportions of TB infection were found in patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma (MZBL), and diffuse large B-cell lymphoma (DLBCL), at 20.6%, 18.6% and 15.3%, respectively, compared to other subtypes of B-cell NHL. For T/NK-cell NHL, the proportions of TB infection in patients with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), and anaplastic large cell lymphoma (ALCL) were 18.2% and 20%, respectively. The multivariate analysis revealed that male sex was an adverse risk factor for lymphoma after tubercular infection. In addition, male sex and older age (>60 years) were associated with B-cell NHL. CONCLUSION: A high proportion of TB infection was found in patients with lymphoma. In TB-infected patients, older age and male sex were associated with susceptibility to lymphoma, suggesting that screening programmes might be useful for the early detection of lymphoma. Keywords Lymphoma; tuberculosis; Burkitt's lymphoma; diffuse large B lymphoma; Hodgkin's disease.

Cancer risk in tuberculosis patients in a high endemic area.

BACKGROUND: Tuberculosis (TB) may facilitate carcinogenesis. We performed a case-control study of the association between TB and cancer in Xinjiang, a high TB endemic area of China. METHODS: From January 2016 to December 2018, a total of 45,455 patients hospitalized in Xinjiang Cancer Hospital were consecutively enrolled and divided into a malignant tumor group (n = 32,539) and a benign tumor group (n = 12,916). Patients with active and previous TB before the diagnosis of cancer were retrospectively identified in the two groups. RESULTS: A significantly higher proportion of TB was found in the malignant tumor group (n = 1776, 5.46%) than in the control (benign tumor) group (n = 175, 1.35%) (p < 0.0001). The highest and lowest proportions of TB in the malignant group were in patients with non-Hodgkin's lymphoma (16.74%) and thyroid cancer (0.77%), respectively. In multivariate analysis adjusting for age, sex, and ethnicity, TB remained an independent risk factor for all cancers (odds ratio (OR) 1.68; 95% confidence interval (CI) 1.43-1.97). Furthermore, TB was associated with a significantly higher risk of non-Hodgkin's lymphoma, cervical cancer, esophageal cancer, "other" cancers, ovarian cancer, and breast cancer. Moreover, females with TB were more likely to develop cancer than males (p < 0.0001), except for esophageal cancer and lymphoma. CONCLUSION: TB patients have an elevated cancer risk. A screening strategy for TB should be taken into consideration before treatment in patients with some cancer types that are associated with a high proportion of TB.

Randomized and dose-escalation trials of recombinant human serum albumin /granulocyte colony-stimulating factor in patients with breast cancer receiving anthracycline-containing chemotherapy.

BACKGROUND: To evaluate the efficacy and safety of recombinant human serum albumin /granulocyte colony-stimulating factor (rHSA/G-CSF) in breast cancer following receipt of cytotoxic agents. METHODS: The phase 1b trial assessed the pharmacokinetics, pharmacodynamics, and safety of dose-escalation, ranging from rHSA/G-CSF 1800 µg, 2100 µg, and 2400 µg. Randomized controlled phase 2b trial was further conducted to ensure the comparative efficacy and safety of rHSA/G-CSF 2400 µg and rhG-CSF 5 µg/kg. In multicenter, randomized, open-label, parallel, phase 2 study, participants treated with anthracycline-containing chemotherapy were assigned in a ratio 1:1:1 to receive double delivery of rHSA/G-CSF 1200 µg, 1500 µg, and continuous rhG-CSF 5 µg/kg. RESULTS: Between December 16, 2014, to July 23, 2018, a total of 320 patients were enrolled, including 25 individuals in phase 1b trial, 80 patients in phase 2b trial, and 215 participants in phase 2 study. The mean duration of agranulocytosis during the first chemotherapeutic intermission was observed as 1.14 ± 1.35 days in rHSA/G-CSF 1500 µg, which was comparable with that of 1.07 ± 0.97 days obtained in rhG-CSF control (P = 0.71). Safety profiles were assessed to be acceptable ranging from rHSA/G-CSF 1800 µg to 2400 µg, while the double delivery of HSA/G-CSF 2400 µg failed to meet the noninferiority in comparison with rhG-CSF. CONCLUSION: The prospective randomized controlled trials demonstrated that rHSA/G-CSF was efficacious and well-tolerated with an approachable frequency and expense of application for prophylactic management of agranulocytosis. The double delivery of rHSA/G-CSF 1500 µg in comparisons with paralleling G-CSF preparations is warranted in the phase 3 trial. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02465801 (11/17/2014), NCT03246009 (08/08/2017), NCT03251768 (08/07/2017).

Efficacy and Safety of the Biosimilar IBI301 Plus Standard CHOP (I-CHOP) in Comparison With Rituximab Plus CHOP (R-CHOP) in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A Randomized, Double-Blind, Parallel-Group, Phase 3 Trial.

INTRODUCTION: Patients with diffuse large B-cell lymphoma (DLBCL) have limited access to rituximab. IBI301 is a recombinant chimeric murine/human anti-CD20 monoclonal antibody and is a candidate biosimilar to rituximab. This study aimed to assess the therapeutic equivalence of IBI301 and rituximab in previously untreated patients with diffuse large B-cell lymphoma (DLBCL). METHODS: This multicenter, randomized, double-blind, parallel-group, phase 3 trial compared IBI301 and rituximab, both plus the chemotherapy of doxorubicin, cyclophosphamide, vindesine, and prednisone (CHOP), was conducted in 68 centers across China. Eligible patients with untreated CD20 positive (CD20+) DLBCL randomly received IBI301 (375 mg/m2) plus the standard CHOP or rituximab (375 mg/m2) plus the standard CHOP for six cycles of a 21-day cycle. The primary end point was the overall remission rate (ORR). Efficacy equivalence was defined if 95% CIs for the ORR difference between the two groups were within a ± 12.0% margin. RESULTS: Between August 22, 2016, and September 5, 2018, 419 patients were randomly allocated into the IBI301 group (N = 209) and rituximab group (N = 210). In the full analysis set, the ORR was 89.9% and 93.8% in the IBI301 and rituximab groups, respectively, and the ORR difference was -3.9% (95% CI - 9.1%-1.3%), falling within a ± 12.0% margin. The occurrences of treatment-emergent adverse events (TEAEs) (100% vs. 99.0%) and AEs of grade ≥ 3 (87.1% vs. 83.3%) were similar in the two groups (P > 0.05). CONCLUSIONS: IBI301 had a non-inferiority efficacy and a comparable safety compared with rituximab. IBI301 plus CHOP could be suggested as a candidate treatment regimen for untreated patients with CD20+ DLBCL. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov (NCT02867566).

Profile and outcome of receptor conversion in breast cancer metastases: a nation-wide multicenter epidemiological study.

Although receptor status including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) of the primary breast tumors was related to the prognosis of breast cancer patients, little information is yet available on whether patient management and survival are impacted by receptor conversion in breast cancer metastases. Using data from the nation-wide multicenter clinical epidemiology study of advanced breast cancer in China (NCT03047889), we report the situation of retesting ER, PR and HER2 status for breast cancer metastases and evaluate the patient management and prognostic value of receptor conversion. In total, 3295 patients were analyzed and 1583 (48.0%) patients retesting receptor status for metastasis. Discordance in one or more receptors between the primary and the metastatic biopsy was found in 37.7% of women. Patients who remained hormone receptor (HR) positive in their metastases had similar progression-free survival of first-line and second-line treatment compared to patients with HR conversion (P > .05). In multivariate analysis, patients who showed ER conversion from negative to positive had longer disease-free survival (DFS) than patients who remained negative in their metastases (hazard ratio, 2.05; 95% confidence interval [CI], 1.45-2.90; P < .001). Patients with PR remained positive and had longer DFS than patients with PR conversion from negative to positive (hazard ratio, 0.56; 95% CI, 0.38-0.83; P = .004). Patients with PR conversion have shorter overall survival than patients with PR remained positive or negative (P = .016 and P = .041, respectively). Our findings showed that the receptors' conversions were common in metastatic breast cancer, and the conversion impacted the survival.

MicroRNA-103a-3p potentiates chemoresistance to cisplatin in non-small cell lung carcinoma by targeting neurofibromatosis 1.

Lung cancer remains the leading cause of cancer-associated mortality worldwide, and non-small-cell lung cancer (NSCLC) contributes to ~80% of these deaths. However, both primary and acquired cisplatin resistance frequently occurs within the disease and represents a huge clinical treatment problem. The underlying molecular mechanisms are not yet completely understood, but in recent years, microRNAs (miR) have been reported to play vital roles in the development of lung cancer and chemoresistance. In the present study, it was revealed that there were increased expression levels of miR-103a-3p in both NSCLC cell lines and human NSCLC samples that exhibited resistance to cisplatin. The results also revealed that the inhibition of miR-103a-3p in A549/cisplatin cells significantly sensitized these cells to cisplatin, while inhibition of miR-103a-3p expression inhibited tumor growth and enhanced the function of cisplatin in a xenograft animal model. Furthermore, the present study demonstrated that miR-103a-3p regulates cisplatin resistance by targeting neurofibromatosis 1 (NF1) via activating ERK signaling in vitro and in vivo. In conclusion, NF1 was identified as a special miR-103a-3p target in the present study, and it was revealed that targeting NF1 via miR-103a-3p may help reverse chemoresistance and provide a biomarker to cisplatin responsiveness in NSCLC.

Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer: A Nation-Wide Multicenter Epidemiological Study in China.

BACKGROUND: Clinical guidelines generally recommend endocrine therapy (ET) as first-line treatment of hormone receptor-positive advanced breast cancer (HR+ ABC) whereas chemotherapy (CT) should be considered in the presence of life-threatening disease or limited clinical benefit after three sequential ET regimens. However, it is unclear if real-world clinical practice is in accordance with the current guidelines. This study was to present the real-world treatment patterns and ET regimens among HR+ ABC patients in China. METHODS: Using data from the Nation-wide Multicenter Retrospective Clinical Epidemiology Study of Female Advanced Breast Cancer in China (ClinicalTrials.gov identifier: NCT03047889), we investigated the clinicopathological characteristics, clinical profiles, and treatment patterns of HR+ ABC patients from January 2012 to December 2014. RESULTS: A total of 2,342 patients with HR+ ABC were included in this study. Our findings revealed that, in comparisons with those receiving initial CT (n = 1445), patients initiated ET (n =402) were significantly older, later recurrent after adjuvant treatment, with a lower rate of visceral involvement and a decreasing quantity of metastatic sites. A total of 1,308 patients received palliative ET while only 18.9% patients (n = 247) reached three lines of ET. Among patients completing more than one line of ET, the median treatment duration was 8 months for the first line, 6 months for the second line, and 3 months for the third line for patients receiving ET. In the advanced setting, the choices of palliative ET regimens were diverse, yet aromatase inhibitor (AI) monotherapy was still the overall mainstay of ET; in contrast, patients were less accessible to everolimus plus AI regimen in this population. CONCLUSIONS: Less than one quarter of patients initiated palliative ET for HR+ ABC in routine clinical practice. Patients who received multi-lines of ET experienced successive shorter durations following each line of therapy. This real-life data provides a solid overview of ET for HR+ ABC from China, indicating unmet need for treatment options that improve the effectiveness of endocrine therapy.

Downregulation of MANCR inhibits cancer cell proliferation in mantle cell lymphoma possibly by interacting with RUNX2.

The mitotically associated lncRNA (MANCR) participates in breast cancer cell proliferation, while its involvement in other cancers is still unknown. In this study, we therefore studied the role of MANCR in mantle cell lymphoma (MCL). We found that serum MANCR and Runt-related transcription factor 2 (RUNX2) were upregulated in MCL patients when compared with those in healthy controls. A positive correlation between serum MANCR and RUNX2 was found in MCL patients but not in controls. Upregulation of serum MANCR distinguished MCL patients from controls. MANCR overexpression promoted RUNX2 expression in MCL cells, while RUNX2 overexpression failed to significantly change the expression levels of MANCR. MANCR overexpression promoted the proliferation of MCL cells, while MANCR silencing inhibited the proliferation of MCL cells. In addition, RUNX2 overexpression attenuated the inhibitory effects of MANCR silencing on cell proliferation. However, MANCR overexpression and silencing had no significant effects on cell migration and invasion. Further bioinformatics analysis showed that MANCR may sponge miR-218 to upregulate RUNX2. Therefore, we conclude that downregulation of MANCR may inhibit cancer cell proliferation in MCL possibly by interacting with RUNX2.

An oral second-generation proteasome inhibitor oprozomib significantly inhibits lung cancer in a p53 independent manner in vitro.

The destruction of proteins via the ubiquitin-proteasome system is a multi-step, complex process involving polyubiquitination of substrate proteins, followed by proteolytic degradation by the macromolecular 26S proteasome complex. Inhibitors of the proteasome promote the accumulation of proteins that are deleterious to cell survival and are promising anticancer agents. Oprozomib (OPZ), an oral second-generation proteasome inhibitor, has been shown to inhibit the growth of several cancers in preclinical and clinical trials, including multiple myeloma and head and neck cancers, but its effects on lung cancer has not yet been determined. In this study, we evaluated the inhibitory effects of OPZ on lung cancer cell lines in vitro. The results showed that OPZ significantly suppressed cell proliferation and strongly induced apoptosis in both tested lung cancer cells independent of p53 expression. OPZ was able to cause obvious caspase 3 and PARP cleavages and stabilize p53 and its transcriptional targets p21, PUMA, and Noxa. Moreover, OPZ was capable of sensitizing lung cancer cells to the conventional chemotherapeutic drug cisplatin. Our study provides preclinical data and sheds light on the potential applications of proteasome inhibitor OPZ in lung cancer treatment.

Primary breast diffuse large B-cell lymphoma in the rituximab era: Therapeutic strategies and patterns of failure.

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of DLBCL with limited data on patterns of failure. This multicenter study aimed to define the optimum treatment strategy and patterns of failure for PB-DLBCL patients. We retrospectively reviewed data on 108 PB-DLBCL patients from 21 Chinese medical centers. Only patients with localized disease (involvement of breast and localized lymph nodes) were included. After a median follow-up of 3.2 years, 32% of patients developed progression or relapse. A continuous pattern of relapse was observed, characterized by frequent late relapses in the contralateral breast and central nervous system (CNS). Although rituximab significantly reduced the overall cumulative risk of progression or relapse (5-year cumulative risk 57% vs 24%, P = .029), it had limited effect on the reduction of breast relapse (P = .46). Consolidative radiotherapy significantly decreased the risk of breast relapse, even in the subgroup of patients treated with rituximab (5-year cumulative risk 21.2% vs 0%, P = .012). A continuous risk of CNS progression or relapse up to 8.2 years from diagnosis was observed (10-year cumulative risk 28.3%), with a median time to CNS relapse of 3.1 years. Neither rituximab nor prophylactic intrathecal chemotherapy significantly decreased the risk of CNS relapse. In summary, our study indicates that PB-DLBCL has a continuous pattern of relapse, especially with frequent late relapses in the CNS and contralateral breast. Rituximab and RT confer complementary benefit in the reduction of relapse. However, neither the addition of rituximab nor prophylactic intrathecal chemotherapy could effectively prevent CNS relapse for PB-DLBCL patients.

MGCD0103 induces apoptosis and simultaneously increases the expression of NF-κB and PD-L1 in classical Hodgkin's lymphoma.

At present there is no consensus on the treatment of classical Hodgkin's lymphoma (CHL) following relapse. The aim of the present study was to access the class I-selective histone deacetylase (HDAC) inhibitor (HDACI) MGCD0103 on the expression levels of Bcl-2, nuclear factor (NF)-κB and programmed death-ligand 1 (PD-L1) in CHL, to explore the possible therapeutic value of MGCD0103 in combined relative target drugs for patients with CHL. In L1236 and L428 cell lines, apoptosis and cell cycle stage were identified using flow cytometry, and the effects of HDACI on CHL were assessed in terms of Bcl-2, NF-κB and PD-L1 expression levels, which were detected by western blotting and co-focusing experiments. The results demonstrated that MGCD0103 could induce cell apoptosis and cell cycle arrest, down-regulate Bcl-2 and increase NF-κB and PD-L1 expression levels in L1236 and L428 cell lines. MGCD0103 decreases Bcl-2 levels and upregulates PD-L1, which indicates that the combined use of HDACIs and a PD-L1 inhibitor in theory may improve treatment outcomes in patients with CHL. MGCD0103 may also up-regulate NF-κB, which seems to induce resistance towards anti-apoptotic drugs. Clinical trials combining HDACIs with NF-κB and/or PD-L1 inhibitors should be designed to further improve treatment outcomes for patients with CHL.

Expression profiles of long noncoding RNAs in lung adenocarcinoma.

PURPOSE: This study aimed to analyze expression profiles of long noncoding RNAs (lncRNAs) in lung adenocarcinoma. METHODS: lncRNA microarray technology was employed to detect lncRNA profiles of 3 pairs of lung adenocarcinoma tissues and adjacent tissues. RESULTS: We found 134 upregulated lncRNAs and 460 downregulated lncRNAs in lung adenocarcinoma tissues compared to adjacent tissues. Among them, LINC00152, LINC00691, and LINC00578 showed the most significant changes of upregulation, while LINC00668, LINC00710, and LINC00607 showed the most significant changes of downregulation. Fluorescent quantitative polymerase chain reaction (PCR) analysis of tissue samples from an additional 90 patients with lung adenocarcinoma showed significantly increased levels of LINC00152, LINC00691, and LINC00578 and decreased levels of LINC00668, LINC00710, and LINC00607 in lung adenocarcinoma tissues. In addition, LINC00578 was closely associated with the existence of metastasis of lung adenocarcinoma, but the other 5 lncRNAs showed no significant correlation with clinicopathologic characteristics such as age, gender, tumor stage, and the existence of metastasis. Further follow-up study showed that LINC00578 expression was closely associated with the survival of patients with lung adenocarcinoma. CONCLUSION: We revealed the expression profiles of lncRNAs in lung adenocarcinoma and identified LINC00578 as a promising biomarker and therapeutic target for lung adenocarcinoma.

Association between ERα gene Pvu II polymorphism and breast cancer susceptibility: A meta-analysis.

BACKGROUND: Estrogen has played an important role in the development of breast cancer. ER-α PvuII gene polymorphism is in close association with the occurrence risk of breast cancer, but no consensus has been achieved currently. METHODS: PubMed, Embase, China National Knowledge Infrastructure (CNKI) database, Wanfang database, and VIP database were retrieved to collect the case-control studies on association between ERα gene Pvu II polymorphism and breast cancer risk published before September 1, 2017. Newcastle-Ottawa Scale (NOS) was used to assess the quality of the literatures, Stata 14.0 software was applied for meta-analysis, and the pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated. The subgroup analysis was performed to assess the confounding factors, followed by assessment of publication bias and sensitivity analysis. RESULTS: A total of 26 studies were enrolled in the analysis based on inclusion criteria, which included 15,360 patients and 26,423 controls. The results demonstrated that ERα gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in 3 genetic models (C vs T, OR = 0.962, 95% CI = 0.933-0.992, P = .012; CC vs TT, OR = 0.911, 95% CI = 0.856-0.969, P = .003; CC vs TT/CT, OR = 0.923, 95% CI = 0.874-0.975, P = .004). Subgroup analysis was conducted on the basis of ethnicity and source of controls, whose results illustrated that ERα gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in Asians rather than in Caucasians (CC vs TT, OR = 0.862, 95% CI = 0.750-0.922, P = .038; CC vs TT/CT, OR = 0.851, 95% CI = 0.755-0.959, P = .008). In population-based subgroup rather than in hospital-based subgroup, ERα gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in the allele model, homozygous model, dominant model, and recessive model (C vs T, OR = 0.943, 95% CI = 0.911-0.977, P = .001; CC vs TT, OR = 0.878, 95% CI = 0.817-0.944, P = .000; CC/CT vs TT, OR = 0.936, 95% CI = 0.881-0.994, P = .031; CC vs TT/CT, OR = 0.902, 95% CI = 0.847-0.960, P = .001). CONCLUSION: ERα gene Pvu II polymorphism exerts an important function in the progression of breast cancer.

MicroRNA-10b regulates epithelial-mesenchymal transition by modulating KLF4/KLF11/Smads in hepatocellular carcinoma.

BACKGROUND: Our previous work showed that miR-10b was overexpressed in hepatocellular carcinoma (HCC) and promoted HCC cell migration and invasion. Epithelial-mesenchymal transition (EMT) is involved in HCC metastasis. So, we suspected that miR-10b might participate in the HCC EMT. METHODS: We performed morphological analysis and immunofluorescence to observe the roles of miR-10b in HCC EMT. The expression of KLF11 and EMT markers were detected by real-time RT-PCR and western blot. The regulation roles of miR-10b on KLF11 and KLF4 were determined by luciferase reporter assay. The chromatin immunoprecipitation revealed the binding relationship between KLF4 and KLF11. RESULTS: We found that overexpression of miR-10b could promote HCC EMT. miR-10b could upregulated KLF11 expression. The upregulation of KLF11 reduced the downstream molecular Smad7 expression, which upregulated the Smad3 expression to promote EMT development. Furthermore, the induction role of miR-10b in HCC EMT could be blocked by KLF11 siRNA. But our results showed that there was no direct regulation of miR-10b in KLF11 expression. Specifically, miR-10b could bind to the 3'UTR of KLF4 and inhibit KLF4 expression. KLF4 could directly bind to KLF11 promoter and downregulate KLF11 transcription. CONCLUSION: Our results reveal that miR-10b downregulates KLF4, the inhibitory transcriptional factor of KLF11, which induces Smads signaling activity to promote HCC EMT. Our study presents the regulation mechanism of miR-10b in EMT through the KLF4/KLF11/Smads pathway for the first time and implicates miR-10b as a potential target for HCC therapies.

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.