Targeting the Na+/K+ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a potent chemotherapeutic drug for various cancers. Yet, the cardiotoxic side effects limit its application in clinical uses, in which ferroptosis serves as a crucial pathological mechanism in DOX-induced cardiotoxicity (DIC). A reduction of Na+/K + ATPase (NKA) activity is closely associated with DIC progression. However, whether abnormal NKA function was involved in DOX-induced cardiotoxicity and ferroptosis remains unknown. Here, we aim to decipher the cellular and molecular mechanisms of dysfunctional NKA in DOX-induced ferroptosis and investigate NKA as a potential therapeutic target for DIC. A decrease activity of NKA further aggravated DOX-triggered cardiac dysfunction and ferroptosis in NKAα1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAα-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAα1 interacted with SLC7A11 to form a novel protein complex, which was directly implicated in the disease progression of DIC. Furthermore, the therapeutic effect of DR-Ab on DIC was mediated by reducing ferroptosis by promoting the association of NKAα1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DR-region of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity.

Oxidation of organoarsenicals and antimonite by a novel flavin monooxygenase widely present in soil bacteria.

Arsenic can be biomethylated to form a variety of organic arsenicals differing in toxicity and environmental mobility. Trivalent methylarsenite (MAs(III)) produced in the methylation process is more toxic than inorganic arsenite (As(III)). MAs(III) also serves as a primitive antibiotic and, consequently, some environmental microorganisms have evolved mechanisms to detoxify MAs(III). However, the mechanisms of MAs(III) detoxification are not well understood. In this study, we identified an arsenic resistance (ars) operon consisting of three genes, arsRVK, that contribute to MAs(III) resistance in Ensifer adhaerens ST2. ArsV is annotated as an NADPH-dependent flavin monooxygenase with unknown function. Expression of arsV in the arsenic hypersensitive Escherichia coli strain AW3110Δars conferred resistance to MAs(III) and the ability to oxidize MAs(III) to MAs(V). In the presence of NADPH and either FAD or FMN, purified ArsV protein was able to oxidize both MAs(III) to MAs(V) and Sb(III) to Sb(V). Genes with arsV-like sequences are widely present in soils and environmental bacteria. Metagenomic analysis of five paddy soils showed the abundance of arsV-like sequences of 0.12-0.25 ppm. These results demonstrate that ArsV is a novel enzyme for the detoxification of MAs(III) and Sb(III) and the genes encoding ArsV are widely present in soil bacteria.

Giant osteochondroma of ilium: a case report and literature review.

Osteochondroma is one of the most common benign bone tumors. It usually grows on the metaphysis of long bones and rarely develops in bones of scapula, feet, hands, and pelvis. The management of this disease is en-bloc excision of the tumor. We present a 45-year-old female subject, who complained of having found a mass on the right hip for more than 20 years which was diagnosed to be osteochondroma on X-ray, computed tomography (CT) and 3-dimensional (3-D) reconstruction. We performed en-bloc excision for the patient. Pathologic examination of surgical specimen confirmed the diagnosis of osteochondroma. The patient made a complete recovery and there has been no recurrence after one year of follow-up. Osteochondroma usually represents an osteo-cartilaginous aberrant overgrowth of normal epiphyseal growth plates. The disease has a slow onset and a long history. X-rays and CT scans are sufficient for diagnosis before surgery and the final diagnosis should based on pathology. Differential diagnosis includes chondrosarcoma or other neoplasms. When osteochondroma causes pain, compression of peripheral nerves, or continuous growth and other clinical symptoms, en-bloc excision of the tumor is needed. Better recognition and more comprehensive evaluation of these rare cases should be highlighted to avoid misdiagnosis during our clinical practice.

Survival of patients with advanced lung adenocarcinoma before and after approved use of gefitinib in China.

BACKGROUND: To compare the overall survival (OS) of patients with advanced lung adenocarcinoma in China before and after the approved use of gefitinib, and analyze clinical factors that may affect OS. METHODS: Clinical data of 558 patients with advanced lung adenocarcinoma who received chemotherapy from January 2002 to December 2010 were retrospectively analyzed. According to the matched-pair case-control study design, 255 patients who only received chemotherapy and 255 patients who received gefitinib treatment after its approval were stringently matched by age, gender, and smoking history and enrolled in the study. Clinical factors including age, gender, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status (PS), tumor stage, organ metastasis, and the number of prior chemotherapies were analyzed to determine their correlations with OS. RESULTS: The median survival time (MST) of the 510 enrolled patients with advanced lung adenocarcinoma was 22.8 months. The MST of the patients who received gefitinib treatment was significantly longer than that of patients who did not receive gefitinib treatment (33.5 vs. 14.1 months, P < 0.001). The OS in patients who received gefitinib treatment was significantly longer than in patients who did not receive gefitinib treatment in almost all clinical factor-based subgroups, including age, gender, smoking history, ECOG PS 0-1, tumor stage, the presence or absence of lung, pleural, bone, brain, adrenal gland and liver metastasis, and the number of prior chemotherapies (all P < 0.001), except in the ECOG PS ≥2 subgroup. CONCLUSIONS: Gefitinib treatment significantly improved the survival of patients with advanced lung adenocarcinoma in China.

[Association between different EGFR mutation status and survival in pemetrexed-based chemotherapy for advanced non-small cell lung cancer].

OBJECTIVE: To explore the association between different epidermal growth factor receptor (EGFR) mutation status and survival in pemetrexed-based chemotherapy for advanced non-small-cell lung cancer (NSCLC). METHODS: A retrospective cohort study was performed to assess 146 patients with advanced NSCLC at Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. The first-line regimens included pemetrexed based chemotherapy (pemetrexed first-line therapy group, n = 79), pemetrexed based chemotherapy plus pemetrexed maintenance chemotherapy (pemetrexed maintenance therapy group, n = 38) and pemetrexed based chemotherapy plus tyrosine kinase inhibitors (TKI) maintenance therapy (TKI maintenance therapy group, n = 29). Median progression-free survival (PFS) was determined.For comparison, median PFS was evaluated for EGFR-positive,EGFR-negative versus EGFR mutation unknown NSCLC patients in first-line pemetrexed therapy and pemetrexed maintenance therapy groups. RESULTS: The median PFS was 4.6 (95%CI: 2.8-6.4), 9.8 (95%CI: 6.1-13.5) and 14.5 (95%CI: 11.8-17.2) months in pemetrexed first-line therapy, pemetrexed maintenance therapy and TKI maintenance therapy groups respectively (P = 0.000). No difference existed in PFS for pemetrexed first-line therapy group with a median PFS of 5.2 (95%CI: 2.8-7.7), 4.0 (95%CI: 0-10.8) and 4.6 (95%CI: 3.4-5.8) months respectively (P = 0.661). Among EGFR-positive,EGFR-negative and EGFR mutation status unknown patients in pemetrexed maintenance therapy group, the median PFS was 8.5 (95%CI: 4.0-13.1), 12.6 (95%CI: 11.6-13.7) and 8.0 (95%CI: 5.8-10.3) months with no significant statistical difference (P = 0.468). CONCLUSIONS: No significant difference exists in survival between different EGFR mutation status for pemetrexed based first-line chemotherapy. And TKI maintenance therapy is associated with better survival than pemetrexed maintenance therapy regardless of EGFR status.

[Efficacy analysis of third-generation plus platinum doublets in the first-line chemotherapy of advanced non-small cell lung cancer].

OBJECTIVE: To compare the chemotherapeutic efficacies of third-generation plus platinum doublets in advanced non-small cell lung cancer (NSCLC) patients. METHODS: A total of 1112 patients were diagnosed as advanced NSCLC at Chinese Academy of Medical Science and Cancer Hospital from January 2005 to August 2009. Their clinical efficacies and regimen compositions were retrospectively analyzed. All calculations were performed by SPSS 17.0. RESULTS: Differences in objective response rate (ORR) existed among four third-generation agents (paclitaxel, gemcitabine, vinorelbine and docetaxel) plus platinum doublets. Their ORRs were 35.6%, 35.4%, 25.9% and 37.4% respectively (χ(2) = 16.331, P = 0.001). And vinorelbine doublets had the lowest ORR (all P < 0.01). The ORRs of cisplatin and carboplatin doublets were 35.2% and 33.5% respectively. There was no difference in ORR among them (χ(2) = 0.352, P = 0.569). Subgroup analysis showed that the ORRs of four third generation plus platinum doublets were 34.8%, 35.3%, 23.2% and 37.1% in non-agers. And the vinorelbine doublets performed the worst. In the patients with squamous-cell lung cancer, the ORRs of paclitaxel and gemcitabine doublets were 45.5% and 28.4% respectively. And the paclitaxel doublets had the better performance (χ(2) = 5.250, P = 0.026). When combined with carboplatin, the ORRs of four doublets were 36.2%, 16.7%, 15.4% and 32.0% respectively. And the paclitaxel regimen was more effective than the gemcitabine and vinorelbine regimens (P = 0.018 and P = 0.034). The influences of subsequent therapy were nullified when the progression-free survival (PFS) was analyzed. The PFSs of these doublets were (3.67 ± 0.19), (2.95 ± 0.18), (3.05 ± 0.36) and (3.40 ± 0.37) months respectively. There was no difference among them. Pairwise comparisons showed that the mean PFS of patients on paclitaxel doublets was longer than those on gemcitabine doublets. And their PFSs were (3.67 ± 0.19) and (2.95 ± 0.18) months respectively (χ(2) = 7.037, P = 0.008). The PFSs of cisplatin and carboplatin doublets were (3.05 ± 0.14) and (3.65 ± 0.20) months respectively. The patients on carboplatin doublets had a longer PFS than that of those on cisplatin doublets (χ(2) = 6.012, P = 0.014). CONCLUSIONS: No difference exist in ORRs among different third-generation plus platinum doublets. But as the first-line treatment of advanced NSCLC, carboplatin doublets is superior to cisplatin doublets in terms of PFS.

[Clinical study on curing the cervical spondylotic radiculopathy with the methods of Blade needle closed loosing and reduction with traction at the same time].

OBJECTIVE: To observe the effects of curing the cervical spondylotic radiculopathy with the methods of Blade needle closed loosing and reduction with traction at the same time. METHODS: From May 2006 to May 2009, 65 patients with cervical spondylotic radiculopathy were divided into treatment group and control group according the random number table produced by SAS Software. There were 18 males and 17 females in the treatment group,age in range from 42 to 73 years old with an average of (61.3 +/- 6.4) years, course of disease was from 8 to 42 months with an average of (23.8 +/- 13.8) months, preoperatively cervical functional score was from 4 to 17 scores with the mean of (11.45 +/- 3.31) scores. And in the control group, including 14 males and 16 females, aged from 44 to 76 years old with an average of (62.4 +/- 8.8) years, course of disease was from 7 to 43 months with an average of (24.4 +/- 16.8) months, preoperatively cervical functional score was from 4 to 18 scores with the mean of (11.40 +/- 3.24) scores. The patients of treatment group were treated with Blade needle closed loosing the specific pain point on the neck and shoulder, then immediately underwent traction and reduction after operation. And the patients of control group were treated with traditional traction. The cervical functional score were compared between the two groups at 10, 20, 180 d after treatment, including pain of neck and shoulder, limitation of motion of neck, tenderness of neck, numbness and muscle weakness of upper limb. RESULTS: (1) At the 10th day after treatment, the total score of treatment group was (15.43 +/- 3.46) scores, which was obviously higher than that of control group's (13.17 +/- 3.18) scores (P < 0.01). In different symptoms, treatment group also was better than that of control group (P < 0.05), so as in the tenderness of neck, and especially in the limitation of motion of neck and muscle weakness of upper limb decreased obviously (P < 0.01). (2) At the 20th day after treatment, the total score of treatment group was (18.00 +/- 2.94) scores, which was obviously better than that of control group's (15.90 +/- 2.89) scores (P < 0.01). In different symptoms, treatment group also was better than that of control group (P < 0.05), so as in the pain of neck and shoulder, numbness and muscle weakness of upper limb (P < 0.05), and especially in the limitation of motion of neck, tenderness of neck decreased obviously (P < 0.01). (3) At the 180th day after treatment, the total score of treatment group was (16.63 +/- 3.32) scores, which was obviously better than that of control group's (12.67 +/- 3.42) scores (P < 0.01); In different symptoms, treatment group also was better than that of control group (P < 0.05), so as in the numbness of upper limb (P < 0.05), and especially in the pain of neck and shoulder, muscle weakness of upper limb, limitation of motion of neck, tenderness of neck decreased obviously (P < 0.01). CONCLUSION: Compared with method of traditional traction, Blade needle closed loosing and traction in treating cervical spondylotic radiculopathy can significantly obtain clinical effects,which can quickly improve symptoms, relieve pain of neck and shoulder, limitation of motion of neck, tenderness of neck, numbness and muscle weakness of upper limb.

[Efficacy of erlotinib after the failure of gefitinib in patients with metastasis of non-small cell lung cancer with unknown EGFR mutation status].

OBJECTIVE: To evaluate the efficacy of erlotinib in patients with metastasis of non-small cell lung cancer who had benefits from initial gefitinib treatment but finally demonstrated resistance, especially in those of unknown EGFR mutation status, and to compare the efficacy of erlotinib between patients who received erlotinib immediately after gefitinib failure and those who received chemotherapy before erlotinib. METHODS: Forty Chinese patients who had been treated with erlotinib (150 mg daily) after gefitinib (250 mg daily) failure were evaluated retrospectively. All of these patients had achieved gefitinib treatment for at least three months with response of partial remission or stable disease. Among them, 16 patients shifted to erlotinib immediately after progression (Group G-E), and the other 24 patients inserted chemotherapy between gefitinib and erlotinib (Group G-C-E). RESULTS: In the whole group, the disease control rate (DCR) of erlotinib was 52.5% (21/40) while the objective response rate (RR) was only 10.0% (4/40). The RR of the group G-E was 6.2% and the group G-C-E was 12.5%, and the DCR was 56.2% and 50.0% in the two groups, respectively, both without significant differences (P = 0.638 and P = 0.755). There was no correlation between the efficacy of erlotinib and that of initial gefitinib in both group G-E and group G-C-E (P = 0.365 and P = 0.658). The median progression-free survival (PFS) and overall survival (OS) for the erlotinib treatment were 3.0 and 12.0 months in the 40 patients. Statistically no significant difference was observed in PFS (4 months in the group G-E and 2 months in the group G-C-E, P = 0.768) and OS (12 months in both Groups, P = 0.510). CONCLUSIONS: Erlotinib can be considered either immediately after gefitinib failure or following the insertion of chemotherapy after gefitinib failure in progressive non-small cell lung cancer patients who initially benefited from gefitinib.

[Classification and regression tree analysis of 154 patients with cancer of unknown primary].

OBJECTIVE: To explore the prognostic factors and their impact on survival of patients with cancer of unknown primary (CUP). METHODS: The clinical and follow up data of 154 CUP patients referred to the Cancer Hospital & Institute, Chinese Academy of Medical Sciences from January 1, 2003 to December 31, 2007 were analyzed. Multivariate analysis of survival was performed using recursive partitioning referred to as classification and regression tree (CART) analysis. RESULTS: The median survival for 154 eligible consecutive CUP patients was 18.2 months, and the 5-year survival rate was 1.3%. CART was performed with an initial split on age of 34, and 5 terminal subgroups were formed. The median survival of the 5 subsets ranged from 5.5 months (younger than 34 years old subgroup) to 61.8 months for patients at age of 34 to 60, with one or two organ sites involved, and non-adenocarcinoma histology subsets. CONCLUSIONS: CART can be used to identify previously unappreciated patient subsets and is a useful method for dissecting complex clinical situations and identifying homogeneous patient populations in clinical practice and future clinical trials.

[A randomized phase II trial of docetaxel and doxorubicin in treatment for patients with non-small-cell lung cancer who have failed previous platinum-based chemotherapy].

OBJECTIVE: The aim of this study was to evaluate the efficacy, toxicity and safety of doxorubicin combined with domestically produced docetaxel versus with taxotere, and to investigate whether these two regimens result in similar outcomes in the treatment for non-small-cell lung cancer (NSCLC) patients who failed previous platinum-based chemotherapy. METHODS: Eighty-eight NSCLC patients were enrolled into this clinical phase II trial. The patients randomly received either domestic docetaxel (study arm) or taxotere (control arm) at a dose of 70 mg/m2 on D2, while doxorubicin at a dose of 40 mg/m2 on D1 was administered in both groups. It was repeated every 3 weeks, totally for three cycles. No granulocyte colony-stimulating factor was used to prevent granulocytopenia. The response rate and toxicity were evaluated using World Health Organization toxicity scale and Karnofsky performance status scale. RESULTS: Of the 88 patients, 81 were evaluable in terms of efficacy. There was no complete responder in this series. The response rate (RR) was 17.1% in the study arm versus 7.5% in the control arm, and the clinical benefit rate (CBR) was 80.5% in the study group versus 72.5% in the control group. The most frequent grade 3 or 4 toxicities were neutropenia, leucopenia and gastrointestinal symptoms. Other toxicities such as alopecia and vomiting were mild and generally well tolerated. No fluid retention was noticed. CONCLUSION: The administration of doxorubicin 40 mg/m2 on D1 combined with domestic docetaxel 70 mg/m2 on D2 is proved to be as effective and tolerable as with taxotere. The domestic drug docetaxel may be considered as an alternative for patients with non-small-cell lung cancer who failed previous platinum-based chemotherapy.

[Docetaxel in the treatment of advanced breast cancer ].

OBJECTIVE: To evaluate the efficacy, toxicity and safety of an new domestic docetaxel in the treatment of pretreated advanced breast cancer. METHODS: Fourty-four breast cancer patients who had failed in first-line chemotherapy were included in this trial. They received docetaxel as the second-line chemotherapy. Docetaxel was administered alone at a dose of 70 mg/m2 every 3 weeks. The use of granulocyte colony-stimulating factor to prevent granulocytopenia was not permitted. The response rate and toxicity were evaluated by World Health Organization toxicity scale and performance status by Karnofsky scale. RESULTS: Of the 41 evaluable patients, 4 achieved complete response and 14 partial remission, with a response rate and clinical benefit rate of 43.9% and 85.4%, respectively. Grade 3 or grade 4 neutropenia developed in 42.9%, alopecia in 7.1% and vomiting in 4.8% of these patients. Fluid retention was not observed in this series. CONCLUSION: Three-week administration of docetaxel alone at a dose of 70 mg/m2 is effective and tolerable. It provides an alternative for the pretreated advanced breast cancer patients.

[Inflammatory breast cancer: 38 cases clinical report].

BACKGROUND & OBJECTIVE: Inflammatory breast cancer (IBC) is a special form of rapidly progressive breast cancer with poor prognosis. The purpose of this study was to investigate the clinical characters, treatment, and prognosis of inflammatory breast cancer. METHODS: Thirty-eight patients with inflammatory breast cancer who were diagnosed and treated from March 20, 1970 to December 21, 2001 in our hospital were analyzed retrospectively. RESULTS: All IBC patients presented clinically with an erythematous or swollen and tender breast, no fever. The mean age of 38 patients was 45 years old. Twenty-four patients were in stage III b and 14 in stage IV. Eighteen patients received local treatment (radiotherapy or surgery) firstly and 20 patients underwent chemotherapy firstly. Median survival was 17 months. The 1 year and the 5 year survival rates were 57.7% and 14.0%, respectively. The administration of chemotherapy first improved the outcome of IBC. Earlier stage showed more favorable prognosis. CONCLUSIONS: Combination therapy with chemotherapy first was an effective treatment for IBC.