Compound 275# Induces Mitochondria-Mediated Apoptosis and Autophagy Initiation in Colorectal Cancer Cells through an Accumulation of Intracellular ROS.

Colorectal cancer (CRC) is the most common intestinal malignancy, and nearly 70% of patients with this cancer develop metastatic disease. In the present study, we synthesized a novel compound, termed N-(3-(5,7-dimethylbenzo [d]oxazol-2-yl)phenyl)-5-nitrofuran-2-carboxamide (compound 275#), and found that it exhibits antiproliferative capability in suppressing the proliferation and growth of CRC cell lines. Furthermore, compound 275# triggered caspase 3-mediated intrinsic apoptosis of mitochondria and autophagy initiation. An investigation of the molecular mechanisms demonstrated that compound 275# induced intrinsic apoptosis, and autophagy initiation was largely mediated by increasing the levels of the intracellular accumulation of reactive oxygen species (ROS) in CRC cells. Taken together, these data suggest that ROS accumulation after treatment with compound 275# leads to mitochondria-mediated apoptosis and autophagy activation, highlighting the potential of compound 275# as a novel therapeutic agent for the treatment of CRC.

Single Nucleotide Polymorphisms of Paclitaxel-induced Peripheral Sensory Neuropathy in Chinese Han Population.

Objective To study the single nucleotide polymorphisms (SNPs)that predict a patient's risk of grade 2-3 paclitaxel-induced peripheral sensory neuropathy (PSN) in Chinese Han populations.Methods Totally 216 patients received paclitaxel in Peking Union Medical College Hospital from May 2014 to December 2016 were enrolled.DNA was isolated from peripheral blood.Genotyping for eight candidate SNPs was performed on Sequenom-MassARRARYiPLEX platform.Patients were followed up and PSN was assessed by trained physicians according to National Cancer Institute-Common Terminology Criteria for Adverse Events v4.03.Results A total of 209 patients entered the final analysis.Among the candidate SNPs,only rs4141404:A>C(LIMK2) was significantly associated with grade 2/3 PSN (OR:4.32,95%CI:2.37-7.89,P<0.0001).In multivariate logistic regression analysis,both rs4141404:A>C(LIMK2) and history of receiving platinum compound (OR:2.70,95%CI:1.32-5.51,P=0.007) were associated with grade 2/3 PSN.Conclusion rs4141404:A>C(LIMK2) may be the markers of risk of grade 2/3 PSN.

[Infection of human papillomavirus 16/18 DNA in patients with head and neck squamous cell carcinoma and its relationship with expression of Ki-67 and P53 protein].

OBJECTIVE: To detect the infection of human papillomavirus (HPV) 16/18 in patients with head and neck squamous cell carcinoma and explore the relationship between HPV infection and expressions of Ki-67 and P53 proteins in tumor tissue. METHOD: The level of HPV 16/18 DNA was measured by real time polymerase chain reaction, and Ki-67 and P53 proteins were measured by immunohistochemistry in tissues from head and neck squamous cell carcinoma. RESULTS: HPV 16/18 DNA was detected in 62.8% of our patients. In each cancer tissue sample, Ki-67 protein was expressed between 2% to 70%. P53 protein was expressed in 46.15% of our patients. No significant relation was found between HPV 16/18 DNA level and sex, smoking, drinking, and tumor clinical stages. However, level of HPV 16/18 DNA was found to have positive relation with tumor pathological grades and negative relation with P53 protein expression. No relation with Ki-67 protein expression was found. CONCLUSION: Head and neck squamous cell carcinoma may be initiated by HPV 16/18 infection and the mechanism in carcinogenesis involves abnormal expression in P53 protein.

Expanded activated autologous lymphocyte infusions improve outcomes of low- and intermediate-risk childhood acute myeloid leukemia with low level of minimal residual disease.

The presence of minimal residual disease (MRD) is a risk factor for relapse among children with acute myeloid leukemia (AML), and eliminating MRD can usually improve survival rates. To investigate the effect of expanded activated autologous lymphocytes (EAALs) combined with chemotherapy on eliminating MRD and improving survival rates of children with AML, we retrospectively analyzed the results of 115 children with low- or intermediate-risk AML with MRD treated at the Pediatric Hematological Center, Peking University People's Hospital, between January 2010 and January 2016. The patients were assigned to the chemotherapy plus EAAL (combined therapy) group (n = 61) and chemotherapy group (n = 54). The MRD-negativity rates were 95.1% (58/61) in the combined therapy group and 63.0% (34/54) in the chemotherapy group (P < 0.0001) during consolidation treatment. The 5-year event-free survival rate was higher in the combined therapy group than in the chemotherapy group (86.3 ± 4.6% vs. 72.1 ± 6.1%, P = 0.025). No severe adverse event was observed after EAAL infusion. The present study showed that EAAL combined with chemotherapy could improve the MRD-negativity rate and event-free survival rate among children with AML with low level MRD-positive status.

[Predictors of residual lesion in cervix after conization in patients with cervical intraepithelial neoplasia and microinvasive cervical cancer].

OBJECTIVE: To determine the clinicopathological factors predicting residual lesions after conization in patients with cervical intraepithelial neoplasia (CIN) and microinvasive carcinoma of cervix (MIC). METHODS: The clinical data of 77 patients with CIN3, 20 patients with stage Ia1 cervical cancer, and 8 patients with stage 1a2 cervical cancer, totally 105 patients, aged (43 + 6), who received further surgery within 3 months after conization, 95 receiving hysterectomy, 2 receiving repeated conization, and 8 receiving radical hysterectomy and pelvic lymph node dissection, were evaluated. The demographic features, clinical and pathological parameters, and the correlation thereof with the post-conization residual lesions were analyzed retrospectively. RESULTS: Residual lesions were found in the specimens obtained from hysterectomy or repeated conization of 53 of the 105 patients (50.5%), among which 38 were CIN2 or less severe lesions. Univariate analysis showed that menopausal status, procreation status, cervical cytology, method of conization, and range of resection were not correlated with the presence of post-conization residual lesion, while age < or = 45 (P < 0.05, odd ratio [OR] = 4.68) and positive resection margin (P < 0.05, OR = 5.40) were risk factors of residual lesion. There were no differences in the proportion of post-conization residual lesion among the patients with MIC, CIN 3, CIN2 or less severe lesions. Multivariate logistic analysis showed that only the positive resection margin was an independent risk factor of residual lesion after conization (P < 0.05, OR = 4.20). CONCLUSIONS: Although severity of the cervical disease is the most important factor in determining post-conization treatment, it is not a predicting factor for post-conization residual lesion. Only the positive resection margin was an independent risk factor of residual lesion after conization.

Pelvic Exenteration for Recurrent and Persistent Cervical Cancer.

BACKGROUND: Pelvic exenteration (PE) for primary and recurrent cervical cancer has resulted in favorable survival outcomes, but there are controversies about specific prognosis factors, and up to now, there have been no published reports from China. This study aimed to share our experiences of PE, which were performed in a single institution. METHODS: From January 2009 to January 2016, 38 patients with recurrent or persistent cervical cancer were included in the study, and they were followed up until January 2017. Epidemiological and clinicopathological characteristics of patients were compared for survival outcomes in univariate and Cox hazard regression analysis. RESULTS: There were thirty-one and seven patients with recurrent and persistent cervical cancer, respectively. The median age of patients was 45 years (range 29-65 years). Total, anterior, and posterior PE consisted of 52.6%, 28.9%, and 18.4% of cases, respectively. Early and late complications occurred in 21 (55.3%) patients and 15 (39.5%) patients, respectively. Two (5.3%) patients died due to complications related to surgeries within 3 months after PE. The median overall survival (OS) and disease-free survival (DFS) were 28.5 months (range 9-96 months) and 23 months (range 4-96 months), respectively, and 5-year OS and DFS were 48% and 40%, respectively. Cox hazard regression analysis showed that, the margin status of the incision and mesorectal lymph node status were independent risk factors for OS and DFS. CONCLUSION: In our patients with recurrent and persistent cervical cancer, the practice of PE might achieve favorable survival outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03291275; https://clinicaltrials.gov/ct2/show/NCT03291275?term=NCT03291275&rank=1.

[Study of symptoms in terminally ill patients with ovarian carcinoma].

OBJECTIVE: To investigate symptom characteristics and their their prevalence in terminally ill patients with ovarian carcinoma. METHODS: A retrospective study was carried out based on clinical data of 98 terminally ill patients with ovarian carcinoma who died in our hospital during January 1995 to December 2004. Fifteen most common symptoms were analyzed with a focus on the followings: symptom incidence, survival time after symptom occurrence, regularity of symptom cluster, and common causes of death. Fifteen symptoms were: pain, cachexia, pleural effusion and ascites, dyspnea, fever, intestinal obstruction, renal failure, bone marrow depression, lung infection, hemorrhage, deep venous thrombosis (DVT), intestinal or pancreatic fistula, mycotic infection, jaundice and emergency conditions. RESULTS: (1) The most prevalent symptom was pleural effusion and ascites (63%), followed by pain (60%), cachexia (59%), dyspnea (52%) and intestinal obstruction (49%). (2) The symptom which lasted longest survival time was mycotic infection (77 days), followed by intestinal or pancreatic fistula (75 days), intestinal obstruction (67 days), pain (60 days) and cachexia (60 days). Symptoms such as bone marrow depression, renal failure, dyspnea and emergency conditions were comparatively critical associated with shorter survival times (14, 13, 12, 7 days, respectively). (3) Terminal symptoms occurred typically in clusters, with 4.9 +/- 1.5 symptoms per case. Of 98 cases, 84 cases (86%) had 4 or more symptoms, with the median survival time of 63 days from the last day of anti-cancer therapy, and a slow death process. The remaining 14 cases (14%) with 3 or fewer symptoms survived only 25 days, of which 10 cases (71%) died of emergency diseases. The survival time for two groups was significantly different (P<0.01). (4) The first four causes of death were as follows: intestinal obstruction (30%), infection (15%), emergencies (12%) and treatment complications (5%). CONCLUSION: Symptom characteristics and regularity are seen in terminally ill patients with ovarian carcinoma, the understanding of which is helpful for the improvement of symptom management and patients' quality of life.

[Survival prediction for terminal gynecologic cancer patients].

OBJECTIVE: To construct a scoring system of predicting the survival time of terminal gynecologic cancer patients. METHODS: The clinical data of 91 patients with terminal gynecologic cancers, aged 56 (13-83), who were not suitable to specific anti-cancer therapy and died in the hospital with a mean survival time of 27 days (1-240 days) were analyzed retrospectively. Initially univariate analysis was performed to evaluate the relationship between 19 clinico-biochemical indices and survival time. Multiple logistic regression was used to analyze 9 out of the 19 clinico-biochemical indices which had significant effects on the survival time, and a regression model with 5 indices was constructed by backward selection procedure. The regression coefficient of any category was divided by the maximum regression coefficient so as to get the score of this category. The cores were added together so as to get the overall score of an individual patient. RESULTS: Univariate analysis identified 9 factors independently and significantly influencing the survival time: short breath, Karnofsky performance status (KPS), age, high fever, speed of tumor growth, presence or absence of treatment-related complication, blood urea nitrogen (BUN), creatinine, and platelet. A regression equation was composed of 5 factors: short breath, KPS, age, higher fever, and BUN by multiple logistic regression with a correct classification ability of 83.5%. The 91 patients were then divided into 2 groups based on this prognostic score system: Group A (n = 37) with a score < or = 9.5 and the mean survival time of (65 +/- 7) days, and Group B (n = 54) with a score > or = 10 and the mean survival time of (19 +/- 2) days. 31 of the 37 patients in Group A survived > or = 30 days, and 46 of the 54 patients in Group B died within 29 days. The Kaplan-Meier survival curves of these 2 group were significantly different (P < 0.001). CONCLUSION: A simple, valid, and useful prognostic score system has been established.

Clinical analysis of primary malignant melanoma of the cervix.

OBJECTIVE: To investigate the clinical and pathological characteristics of primary cervical malignant melanoma, and its prognosis. METHODS: The clinical and pathological data of four patients with primary malignant melanoma of the cervix were analyzed retrospectively. Nerve tissue protein S-100 and monoclonal antibody to melanoma (HMB-45) were measured in all cases by immunohistochemical method. All four patients received radical hysterectomy. Three of them received chemotherapy preoperation or postoperation, and one of them received biotherapy with interferon-gamma and interleukin-2 at the same time. All the cases were followed up. RESULTS: The average age of four patients was 45 years. Clinical symptoms presented with irregular vaginal bleeding, postcoital bleeding, or increase of vaginal discharge. Gynecologic examination showed polypus papilla cauliflower-shaped or nodulated black-brown or black-blue mass on the cervix. All the four cases were pathologically diagnosed with cervical malignant melanoma. S-100 and HMB-45 were positive in all patients. Two patients died at 6 and 41 months postoperation, respectively. The other two patients survived for 3.5 and 7 years postoperation, respectively. CONCLUSIONS: S-100 protein and HMB-45 play very important roles in the diagnosis of primary malignant melanoma of cervix. Radical hysterectomy, chemotherapy combined with dimethyl triazemo imidazole carboxamide and biological therapies may improve the prognosis of the primary malignant melanoma of cervix if the disease could be diagnosed in an early stage.

[Primary malignant melanoma of the cervix: report of four cases and review of the literature].

OBJECTIVE: To investigate the clinical and pathological characteristics of primary cervical malignant melanoma, the treatment, and prognosis. METHODS: The clinical and pathological data of four patients with primary malignant melanoma of the cervix admitted to our hospital from Sept. 1996 to Aug 2002 were analyzed retrospectively. Their follow-up records were also reviewed. Nerve tissue protein S-100 and monoclonal antibody to melanoma (HMB-45) were examined in all cases by immunohistochemical method. RESULTS: All the patients received radical hysterectomy. In addition, three of them received chemotherapy, and one received immunotherapy simultaneously. One patient died six months and another 41 months after the operation respectively. One patient survived for 3 years, and another over 6 years free of tumor. S-100 protein and HMB-45 were positive in all patients. CONCLUSIONS: The prognosis of primary malignant melanoma of cervix is relatively poor. S-100 protein and HMB-45 play important roles in the diagnosis of primary malignant melanoma of cervix. Radical hysterectomy, chemotherapy combined with dimethyl triazemo imidazole carboxamide (DTIC) and immunotherapy can improve the prognosis if the disease could be diagnosed in early stage.

[Clinical and pathological analysis of intravenous leiomyomatosis].

OBJECTIVE: To investigate the clinical and biological characteristics of intravenous leiomyomatosis and the treatment methods, as well as their effect on prognosis. METHODS: The clinical and pathologic data of 7 patients with intravenous leiomyomatosis of the uterus admitted to our hospital from June 1992 to June 2003 were analyzed retrospectively. All the cases were followed up. RESULTS: All the patients complained of pelvic mass. Three of them had enlarged uterus which was over 12 gestational week, 2 of them had prolonged menstruation and hypermenorrhea, 1 of them presented with postmenopausal bleeding. B-ultrasound examination showed 4 leiomyomas, 1 sarcoma of uterus, and 3 ovarian tumors. No intravenous leiomyomatosis within uterus was diagnosed preoperatively. A resection of the mass and a total abdominal hysterectomy with bilateral salpingo-oophorectomy were performed in 4 cases. CONCLUSIONS: Intravenous leiomyomatosis has special and quasi-malignant biological behavior. The prognosis can be improved if the disease could be correctly diagnosed during the operation and treated with combined modality therapy and intensively followed up after operation.

Effects of anticoagulation protein defect in maternal plasma on spontaneous abortion.

OBJECTIVE: To investigate the mechanism of anticoagulation protein defect in the pathogenesis of unexplained recurrent miscarriage. METHODS: Fifty-seven patients with a history of unexplained abortion were enrolled as the investigation group for tests of protein C, protein S, antithrombin III (AT-III), as well as activated protein C resistance (APC-R). The control group consisted of fifty healthy women with a history of normal pregnancy and delivery. Blood samples were obtained for, measuring serum activity of protein C, protein S, AT-III, and APC-R. Patients with positive APC-R were tested for factor V (FV) Leiden gene mutation by PCR-RFLP method. RESULTS: Of the 57 patients, 12 (21.1%), 1 (1.8%), and 5 (8.8%) cases were found with protein S, protein C, and AT-III deficiency respectively, and 13 (22.8%) cases with positive results of APC-R. Of the control group, no protein C or AT-III deficiency was ever found, whereas 2 (4.0%) volunteers were presented with protein S deficiency and 3 (6.0%) with positive results of APC-R. No FV Leiden gene mutation was identified in all the patients with positive APC-R results. Late spontaneous abortion cases had higher incidence of anticoagulation protein defect than the early cases. CONCLUSION: Anticoagulation protein defect may play a role in the pathogenesis of fetal loss, especially for those occurring in late stage of pregnancy.

[Role of single-breath carbon monoxide-diffusing capacity in monitoring the bleomycin-induced lung toxicity in human].

OBJECTIVE: To investigate if the carbon monoxide-diffusing capacity (D(LCO)) could be the early indictor monitoring the bleomycin-induced lung toxicity (BILT) with retrospection of the influence of bleomycin cumulative dose on the pulmonary functions. METHODS: During June 1985 to October 2000, 42 patients with malignant tumor of ovarian germ cells received chemotherapy containing bleomycin in the department of Obstetrics and Gynecology of Peking Union Medical College Hospital. Twenty three patients (54.76%) among them had >or= 2 courses of chemotherapy with bleomycin and performed >or= 2 measurements of lung function. These 23 patients were included in the study. The forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC), total lung capacity (TLC) and D(LCO) were measured and recorded as % of predicted. The D(LCO) was corrected by hemoglobin concentration [D(LCO) corrected = D(LCO) measured x (9.38 + Hb) divided by (1.76 x Hb)]. All the data were divided into 4 groups according to the cumulative dose of bleomycin (pre-treatment group, < 100 mg group, 101 - 200 mg group and > 201 mg group). The relationship between D(LCO) and bleomycin cumulative dose was examined by linear regression analysis and t-test. RESULTS: The values of FEV(1%)predicted in the 4 groups were 99.83 +/- 16.41 (14), 101.43 +/- 12.32 (42), 99.41 +/- 10.22 (23), and 90.96 +/- 13.63 (12), respectively. The FVC%predicted were 97.74 +/- 18.23 (14), 101.11 +/- 13.95 (42), 96.49 +/- 12.04 (23) and 89.63 +/- 18.20 (12), respectively. The TLC%predicted were 101.22 +/- 10.68 (13), 106.14 +/- 12.16 (40), 102.13 +/- 11.33 (23) and 95.05 +/- 14.06 (11), respectively. There were no statistical significant differences in the parameters among the 4 groups. The D(LCO%)predicted of the 4 groups were 93.27 +/- 12.75 (14), 94.51 +/- 12.50 (40), 80.93 +/- 10.05 (24) and 70.99 +/- 11.69 (15), respectively, and the D(LCO) of the last group (> 201 mg group) was significantly decreased as compared to that of the other groups (P < 0.05). A bleomycin dose-related fall in D(LCO) was observed, y = 100.59 - 0.11x, r = -0.649, P < 0.001. CONCLUSION: The D(LCO) might be the most sensitive indicator of subclinical BILT. However, the cumulative dose of bleomycin did not show significant influence on the FEV(1), FVC and TLC.

Solid malignancies complicated with pulmonary embolism: clinical analysis of 120 patients.

BACKGROUND: Pulmonary embolism, a potentially fatal event, occurs more frequently in cancer patients than in the general population. To offer an accurate diagnosis and effective treatment to such patients in China, we analyzed the incidence rate and clinical features of pulmonary embolism in patients with solid tumor hospitalized in the Peking Union Medical College (PUMC) Hospital. METHODS: A retrospective analysis was made of the hospitalized patients with solid malignancies complicated with pulmonary embolism who had been admitted into the PUMC Hospital from January 2002 to December 2008. RESULTS: The incidence of pulmonary embolism in hospitalized patients with solid malignancies was 0.27% (120/43 967). The median age at diagnosis was 57.5 years. The male to female ratio was 1.0:1.4 (49:71). Patients with non-small-cell lung cancer (NSCLC) constituted the largest proportion of the 120 patients (37.5%), followed by patients with breast (9.2%), ovarian (8.3%), pancreatic (6.7%), and liver cancer (6.7%). Eighty patients (66.7%) had stage IV cancer. Bone was the most common site of distant metastasis (46.3%). D-dimer level was elevated in 90.9% of the 66 tested patients. The incidence of bleeding due to anti-coagulation therapy was 3.6%. Thirty-six (30.0%) of the 120 patients had concurrent deep venous thrombosis in the lower extremities. Seventeen patients developed acute pulmonary embolism within 2 weeks after surgery, 3 of whom died suddenly. Four patients presented with deep venous thrombosis and 1 with pulmonary embolism prior to the identification of malignancy. CONCLUSIONS: Patients with cancer of the lung, ovarian, breast, pancreas, and liver are more likely to be complicated with pulmonary embolism than those with other types of solid tumors. Patients with distant metastasis are at a higher risk of pulmonary embolism. Pulmonary embolism without concurrent deep venous thrombosis is more frequently observed than concurrence of both disorders in the clinical setting.

Predictors and clinical significance of the positive cone margin in cervical intraepithelial neoplasia III patients.

BACKGROUND: Conization is being widely accepted for diagnosis and treatment of cervical intraepithelial neoplasia (CIN). There is controversy as to which factors are most predictive of a positive cone margin and the clinical significance of it. We conducted this study to identify the predictive factors and to evaluate the clinical significance of a positive cone margin in CIN III patients. METHODS: A retrospective review was conducted of 207 patients who had undergone conization due to CIN III from January 2003 to December 2005 at Peking Union Medical College Hospital. Of these, 67 had a subsequent hysterectomy. Univariate and multivariate analysis were utilized to define the predictive factors for a positive cone margin, and to compare the pathologic results of conization with subsequent hysterectomy. RESULTS: One hundred and fifty-one (72.9%) were margin free of CIN I or worse, 37 (17.9%) had CIN lesions close to the margin and 19 (9.2%) had margin involvement. A total of 56 cases (27.1%) had positive cone margins (defined as the presence of CIN at or close to the edge of a cone specimen). Univariate analysis showed that the parity, cytological grade, multi-quadrants of CIN III by punch biopsy, gland involvement, as well as the depth of conization were significant factors correlated with a positive cone margin (P < 0.05). However the age, gravidity, grade of dysplasia in punch biopsy, as well as the cone methods were not significantly correlated (P > 0.05). Multivariate analysis revealed that the cytological grade (OR = 1.92), depth of conization (OR = 2.03), parity (OR = 3.02) and multi-quadrants of CIN III (OR = 4.60) were significant predictors with increased risk for positive margin. The frequency of residual CIN I or worse in hysterectomy specimens was found to be 55.6% (20/36) in patients who were margin free, 71.4% (15/21) in patients with CIN occurring close to margin, and 80.0% (8/10) in patients with margin involvement. The frequency of residual CIN III or worse was found to be 13.9% (5/36), 23.8% (5/21) and 50.0% (5/10) respectively in different groups. CONCLUSIONS: Cytological grade, depth of conization, parity and multi-quadrants of CIN III in punch biopsy were significant factors with increased risk in predicting a positive cone margin. Margin status of conization did not mean the presence or absence of CIN, but rather the varied frequency of residual CIN in specimens of subsequent hysterectomy. In view of this fact, it is suggested that the margin status of conization be a valuable surrogate marker for clinical management of CIN III.