Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities.

HER2-positive (HER2+) metastatic breast cancer (mBC) is highly aggressive and a major threat to human health. Despite the significant improvement in patients' prognosis given the drug development efforts during the past several decades, many clinical questions still remain to be addressed such as efficacy when combining different therapeutic modalities, best treatment sequences, interindividual variability as well as resistance and potential coping strategies. To better answer these questions, we developed a mechanistic quantitative systems pharmacology model of the pathophysiology of HER2+ mBC that was extensively calibrated and validated against multiscale data to quantitatively predict and characterize the signal transduction and preclinical tumor growth kinetics under different therapeutic interventions. Focusing on the second-line treatment for HER2+ mBC, e.g., antibody-drug conjugates (ADC), small molecule inhibitors/TKI and chemotherapy, the model accurately predicted the efficacy of various drug combinations and dosing regimens at the in vitro and in vivo levels. Sensitivity analyses and subsequent heterogeneous phenotype simulations revealed important insights into the design of new drug combinations to effectively overcome various resistance scenarios in HER2+ mBC treatments. In addition, the model predicted a better efficacy of the new TKI plus ADC combination which can potentially reduce drug dosage and toxicity, while it also shed light on the optimal treatment ordering of ADC versus TKI plus capecitabine regimens, and these findings were validated by new in vivo experiments. Our model is the first that mechanistically integrates multiple key drug modalities in HER2+ mBC research and it can serve as a high-throughput computational platform to guide future model-informed drug development and clinical translation.

Distribution and identification of Mycobacterium tuberculosis lineage in Kashgar prefecture.

OBJECTIVES: Kashgar prefecture is an important transportation and trade hub with a high incidence of tuberculosis. The following study analyzed the composition and differences in Mycobacterium tuberculosis (M.tb) lineage and specific tags to distinguish the lineage of the M.tb in Kashgar prefecture, thus providing a basis for the classification and diagnosis of tuberculosis in this area. METHODS: Whole-genome sequencing (WGS) of 161 M.tb clinical strains was performed. The phylogenetic tree was constructed using Maximum Likelihood (ML) based on single nucleotide polymorphisms (SNPs) and verified through principal component analysis (PCA). The composition structure of M.tb in different regions was analyzed by combining geographic information. RESULTS: M.tb clinical strains were composed of lineage 2 (73/161, 45.34%), lineage 3 (52/161, 32.30%) and lineage 4 (36/161, 22.36%). Moreover, the 3 lineages were subdivided into 11 sublineages, among which lineage 2 included lineage 2.2.2/Asia Ancestral 1 (9/73, 12.33%), lineage 2.2.1-Asia Ancestral 2 (9/73, 12.33%), lineage 2.2.1-Asia Ancestral 3 (18/73, 24.66%), and lineage 2.2.1-Modern Beijing (39/73, 53.42%). Lineage 3 included lineage 3.2 (14/52, 26.92%) and lineage 3.3 (38/52, 73.08%), while lineage 4 included lineage 4.1 (3/36, 8.33%), lineage 4.2 (2/36, 5.66%), lineage 4.4.2 (1/36, 2.78%), lineage 4.5 (28/36, 77.78%) and lineage 4.8 (2/36, 5.66%), all of which were consistent with the PCA results. One hundred thirty-six markers were proposed for discriminating known circulating strains. Reconstruction of a phylogenetic tree using the 136 SNPs resulted in a tree with the same number of delineated clades. Based on geographical location analysis, the composition of Lineage 2 in Kashgar prefecture (45.34%) was lower compared to other regions in China (54.35%-90.27%), while the composition of Lineage 3 (32.30%) was much higher than in other regions of China (0.92%-2.01%), but lower compared to the bordering Pakistan (70.40%). CONCLUSION: Three lineages were identified in M.tb clinical strains from Kashgar prefecture, with 136 branch-specific SNP. Kashgar borders with countries that have a high incidence of tuberculosis, such as Pakistan and India, which results in a large difference between the M.tb lineage and sublineage distribution in this region and other provinces of China.

Bevacizumab concomitant with chemotherapy is effective in treating Chinese patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVES: To retrospectively review the safety and clinical efficacy of bevacizumab concomitant with chemotherapy in Chinese patients with advanced non-squamous non-small cell lung cancer (NSNSCLC). METHODS: Clinical data for 79 patients with NSNSCLC who received bevacizumab concomitant with chemotherapy in Chinese PLA General Hospital from April 28th 2009 to May 5th 2013 were retrospectively reviewed to analyze the clinical efficacy including disease control rate (DCR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), the Eastern Cooperative Oncology Group (ECOG) score and the safety. RESULTS: The Eastern Cooperative Oncology Group (ECOG) score was 0-2. By the final cutoff date (June 9, 2013), 54 (68.4%) patients had disease progression and 37 (46.8%) died. The ORR was 32.9% and the DCR was 83.5%. The ORR of the first-, second-, and third- or later-line treatments were 51.4%, 25.0% and 12.5%, while the DCR were 94.3%, 80.0% and 70.8%, respectively. The median OS (mOS) and PFS (mPFS) were 13.5 and 5.83 months, respectively. The mOS of patients with the first-, second-, and third- or later-line treatments were 16.2, 10.9 and 8.30 months, while the mPFS were 7.27, 5.90 and 5.17 months, respectively. Chemotherapy-related adverse events included myelosuppression, vomiting, hepatic dysfunction and renal dysfunction, while the common serious bevacizumab-related adverse events were thromboembolic problems, gastrointestinal perforation and reversible posterior leukoencephalopathy syndrome, which could be well managed. CONCLUSIONS: Bevacizumab concomitant with chemotherapy is effective and the related toxicity can be well tolerated in Chinese patients with NSNSCLC.

Analysis on survival and prognostic factors for cancer patients with malignancy-associated hypercalcemia.

OBJECTIVE: To explore the incidence, clinical characteristics, diagnosis and treatment strategies, prognosis of patients with malignancy-associated hypercalcemia (MAH). METHODS: The data of 115 patients with MAH who were treated at the Medical Oncology Department of Chinese PLA General Hospital from Jan., 2001 to Dec., 2010 was retrospectively reviewed. Survival analysis was performed using the Kaplan-Meier method and the Cox proportional hazard model with statistic software SPSS 18.0. RESULTS: The patients had blood calcium levels ranging from 2.77 to 4.87 mmol/L. Except for 9 cases who died or were discharged within 5 days after admission, all other patients recovered to normal blood calcium level after treatment with bisphosphonates or intravenous hydration and diuretics; their survival after occurrence of MAH was from 1 day to 4,051 days, and the median survival time was only 50 days. In the log-rank test, the male, renal metastasis, central nervous system symptoms and hypercalcemia occurring over 140 days after cancer diagnosis were predictors of poor survival (P=0.002, P=0.046, P=0.000, P=0.009). In the COX analysis, being male, central nervous system symptoms and hypercalcemia lasting over 140 days after cancer diagnosis were independent prognostic factors for survival time (RR=2.131, P=0.027; RR=3.054, P=0.002; RR=2.403, P=0.001). According to these factors, a score system was established to predict the patient prognosis and adjust the treatment. CONCLUSION: Cancer patients with MAH have an extremely poor median survival. Some independent factors indicate poor prognosis, including male gender, central nervous system symptoms and hypercalcemia lasting over 140 days after cancer diagnosis. The prognostic score can serve as a reference for MAH prognosis and treatment, worthy of further investigation.

Expression and significance of ER, PR, VEGF, CA15-3, CA125 and CEA in judging the prognosis of breast cancer.

OBJECTIVE: To explore the expression and significance of estrogen receptor (ER), progestrone receptor (PR), vascular endothelial growth factor (VEGF), CA15-3, CA125 and carcinoma embryonic antigen (CEA) expression in judging the prognosis of breast cancer. MATERIALS AND METHODS: Sixty-five patients with breast cancer undergoing operations in the general surgery department were considered as the observation group, and 50 healthy outpatients of our hospital as the control group. Cubital venous blood was drawn in the morning from fasting patients in the two groups and chemiluminescence immunoassays were used to detect the levels of CA15-3, CA125 and CEA in serum. The follow-up duration was from 4 months to 2 years, and change in levels of the indicators was detected by dynamically drawing blood. After surgery, cancer tissue samples of patients in observation group remained on file (the non-recurrent patients were biopsied). Immunohistochemistry was applied to determine the expression of ER, PR and VEGF in tissue. RESULTS: The effective rate of 12 patients with negative ER and PR expression was 33.3% in the observation group, being associated with prognosis to varying extents. Serum CA15-3, CA125 and CEA in the observation group were all significantly higher than in control group (p<0.01). With increase in pathological staging, levels of serum CA15-3, CA125 and CEA gradually increased (p<0.01). Levels in patients with lymph node metastasis were markedly higher than in those without (p<0.01). In addition, values with distal lymph node metastasis were notably higher than with adjacent lymph node metastasis (p<0.01). The postoperative follow-up results revealed that positive VEGF and levels of serum VEGF, CA15-3, CA125 and CEA in recurrence group were obviously higher than in non-recurrence group (p<0.01). CONCLUSIONS: Joint detection of ER and PR expression as well as levels of serum VEGF, CA15-3, CA125 and CEA is meaningful and can guide the diagnosis and treatment for breast cancer.

Extraskeletal Ewing sarcomas in late adolescence and adults: a study of 37 patients.

BACKGROUND: Extraskeletal Ewing sarcoma (EES)/primitive neuroectodermal tumours (PNET) are rare soft tissue sarcomas. Prognostic factors and optimal therapy are still unconfirmed. MATERIALS AND METHODS: We performed a retrospective analysis on patients to explore the clinic characteristics and prognostic factors of this rare disease. A total of 37 patients older than 15 years referred to our institute from Jan., 2002 to Jan., 2012 were reviewed. The characteristics, treatment and outcome were collected and analyzed. RESULTS: The median age was 28 years (range 15-65); the median size of primary tumours was 8.2 cm (range 2-19). Sixteen patients (43%) had metastatic disease at the initial presentation. Wide surgical margins were achieved in 14 cases (38%). Anthracycline or platinum-based chemotherapy was performed on 29 patients (74%). Radiotherapy was delivered in 13 (35%). At a median follow-up visit of 24 months (range 2-81), the media event-free survival (EFS) and overall survival (OS) were 15.8 and 30.2 months, respectively. The 3-year EFS and OS rates were 24% and 43%, respectively. Metastases at presentation and wide surgical margins were significantly associated with OS and EFS. Tumour size was significantly associated with OS but not EFS. There were no significant differences between anthracycline and platinum based chemotherapy regarding EFS and OS. CONCLUSIONS: EES/PNET is a malignant tumour with high recurrence and frequent distant metastasis. Multimodality therapy featuring wide surgical margins, aggressive chemotherapy and adjuvant local radiotherapy is necessary for this rare disease. Platinum-based chemotherapy can be used as an adjuvant therapy.

[Clinical characteristics and prognostic factors of malignancy-associated hypercalcemia in squamous cell carcinoma].

OBJECTIVE: To explore the clinical characteristics and prognostic factors of patients diagnosed with squamous cell carcinoma (SCC) and presented malignancy-associated hypercalcemia (MAH). METHODS: We retrospectively analyzed the clinical data of 36 patients with biopsy-proven SCC and presented MAH who were treated at the our department from January 2001 to December 2010. The survival were analyzed using the Kaplan-Meier method and Cox analysis. RESULTS: Among these 36 patients, the median blood calcium level was 2.94 mmol/L (2.77-4.87 mmol/L), and the median survival time was only 45 days (1-839 d). Log-rank test showed that central nervous system symptoms, bone metastasis, and hypercalcemia occurring over 160 days after cancer diagnosis were predictors for poor survival(p=0.003, P=0.049, P=0.005). In the COX proportional hazard model analysis, central nervous system symptoms and hypercalcemia occurring over 160 days after cancer diagnosis were independent prognostic factors for survival time (RR=5.721, P=0.000; RR=4.624, P=0.001). CONCLUSIONS: Patients with squamous cell carcinoma (SCC) and presented MAH have poor prognosis. Central nervous system symptoms and hypercalcemia occurring over 160 days after cancer diagnosis are independent predictors of the prognosis.

[Clinical observation on nanometer acupoint mounting method for alleviation of myospasm complicated by spinal injury].

OBJECTIVE: To observe clinical effect of nanometer acupoint mounting method for alleviation of myospasm complicated by spinal injury. METHODS: Sixty cases were randomly divided into an observation group and a control group, 30 cases in each group. The observation group were treated by nanometer mounting at 4 Jiaji (EX-B 2) points each on both sides of the affected spine and Shenshu (BL 23), Shangliao (BL 31), Ciliao (BL 32), Yang-lingquan (GB 34), Xuanzhong (GB 39); and the control group by mounting zinc oxide sticking tablets at the above acupoints. The mounting was replaced once each two days, 7 times constituting one course. One week and one month after the end of 3 courses, their results were recorded, respectively. RESULTS: Before treatment, there was no significant difference between the two groups in grades of the myospasm degree (P > 0.05). One week after the end of treatment, 15 cases were grade I of myospasm, 9 cases were grade II, 5 cases were grade III and 1 case was grade IV in the observation group, and 1 cases grade I, 7 cases grade II, 14 cases grade III, 8 cases grade IV in the control group. Ridit analysis on the data indicated that there were significant differences before and after treatment in the myospasm degree (P < 0.01) and between the two groups after treatment (P < 0.01). One month after the end of treatment, the results were similar to those one week after the end of treatment. CONCLUSION: Nanometer acupoint mounting method is a new one for alleviation of myospasm complicated by spinal injury, with convenience, safety and no side effect.