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.

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.

Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Platinum chemotherapy has a role in the treatment of metastatic triple-negative breast cancer but its full potential has probably not yet been reached. We assessed whether a cisplatin plus gemcitabine regimen was non-inferior to or superior to paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer. METHODS: For this open-label, randomised, phase 3, hybrid-designed trial undertaken at 12 institutions or hospitals in China, we included Chinese patients aged 18-70 years with previously untreated, histologically confirmed metastatic triple-negative breast cancer, and an ECOG performance status of 0-1. These patients were randomly assigned (1:1) to receive either cisplatin plus gemcitabine (cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) or paclitaxel plus gemcitabine (paclitaxel 175 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) given intravenously every 3 weeks for a maximum of eight cycles. Randomisation was done centrally via an interactive web response system using block randomisation with a size of eight, with no stratification factors. Patients and investigator were aware of group assignments. The primary endpoint was progression-free survival and analyses were based on all patients who received at least one dose of assigned treatment. The margin used to establish non-inferiority was 1·2. If non-inferiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine was achieved, we would then test for superiority. The trial is registered with ClinicalTrials.gov, number NCT01287624. FINDINGS: From Jan 14, 2011, to Nov 14, 2013, 240 patients were assessed for eligibility and randomly assigned to treatment (120 in the cisplatin plus gemcitabine group and 120 in the paclitaxel plus gemcitabine group). 236 patients received at least one dose of assigned chemotherapy and were included in the modified intention-to-treat analysis (118 per group). After a median follow-up of 16·3 months (IQR 14·4-26·8) in the cisplatin plus gemcitabine group and 15·9 months (10·7-25·4) in the paclitaxel plus gemcitabine group, the hazard ratio for progression-free survival was 0·692 (95% CI 0·523-0·915; pnon-inferiority<0·0001, psuperiority=0·009, thus cisplatin plus gemcitabine was both non-inferior to and superior to paclitaxel plus gemcitabine. Median progression-free survival was 7·73 months (95% CI 6·16-9·30) in the cisplatin plus gemcitabine group and 6·47 months (5·76-7·18) in the paclitaxel plus gemcitabine group. Grade 3 or 4 adverse events that differed significantly between the two groups included nausea (eight [7%] vs one [<1%]), vomiting (13 [11%] vs one [<1%]), musculoskeletal pain (none vs ten [8%]), anaemia (39 [33%] vs six [5%]), and thrombocytopenia (38 [32%] vs three [3%]), for the cisplatin plus gemcitabine compared with the paclitaxel plus gemcitabine groups, respectively. In addition, patients in the cisplatin plus gemcitabine group had significantly fewer events of grade 1-4 alopecia (12 [10%] vs 42 [36%]) and peripheral neuropathy (27 [23%] vs 60 [51%]), but more grade 1-4 anorexia (33 [28%] vs 10 [8%]), constipation (29 [25%] vs 11 [9%]), hypomagnesaemia (27 [23%] vs five [4%]), and hypokalaemia (10 [8%] vs two [2%]). Serious drug-related adverse events were seen in three patients in the paclitaxel plus gemcitabine group (interstitial pneumonia, anaphylaxis, and severe neutropenia) and four in the cisplatin plus gemcitabine group (pathological bone fracture, thrombocytopenia with subcutaneous haemorrhage, severe anaemia, and cardiogenic syncope). There were no treatment-related deaths. INTERPRETATION: Cisplatin plus gemcitabine could be an alternative or even the preferred first-line chemotherapy strategy for patients with metastatic triple-negative breast cancer. FUNDING: Shanghai Natural Science Foundation.

Recurrent herpes simplex virus mimicking vulvar carcinoma in patient with Human Immunodeficiency Virus: A case report.

Patients with human immunodeficiency virus (HIV) are at increased risk for developing other gynecologic conditions, including herpes simplex virus (HSV) and vulvar intraepithelial neoplasia (VIN)/carcinoma. We describe the case of a woman with a history of microinvasive vulvar squamous cell carcinoma who presented with hypertrophic ulcerated vulvar and peri-anal masses concerning for malignancy. This case highlights the need to maintain a high index of suspicion for malignancy and herpes simplex virus, even with negative polymerase chain reaction (PCR) test, as well as the difficulty of treating this often-resistant lesion.

GLI1 -Rearranged Enteric Tumor : Expanding the Spectrum of Gastrointestinal Neoplasms With GLI1 Gene Fusions.

GLI1 encodes a transcription factor that targets cell cycle regulators affecting stem cell proliferation. GLI1 gene fusions were initially described in pericytomas with a t[7;12] translocation and more recently in gastric plexiform fibromyxomas and gastroblastomas. This study describes the clinicopathologic, immunohistochemical, and molecular features of three intestinal-based neoplasms harboring GLI1 gene fusions. We studied three unique mesenchymal small bowel tumors. Paraffin embedded tumor tissues from these cases and 62 additional tumor samples that included a plexiform fibromyxoma were sequenced using a targeted RNAseq method to detect fusion events. The study patients included two women and one man who were 52, 80, and 22 years of age at the time of diagnosis. The tumors involved the submucosa and muscularis propria of the duodenum, jejunum, and ileum. All 3 tumors contained a proliferation of monotonous oval or spindle cells with scattered, somewhat dilated vessels. Two cases showed epithelioid structures such as glands, tubules, or nests. Immunohistochemical analysis revealed cytokeratin expression in the epithelioid components of both tumors displaying these features, and variable numbers of mesenchymal cells. Diffuse CD56 positivity was seen in the mesenchymal component of 2 tumors and desmin and smooth muscle actin staining in the other tumor. Immunostains for S-100 protein, DOG-1, and CD117 were negative in all cases. GLI1 fusions with different partner genes were detected in all tumors, and in the plexiform fibromyxoma, used as a control. Validation by fluorescence in situ hybridization was performed. None of the tumors have recurred or metastasize after surgery. We describe novel GLI1 fusions in 3 mesenchymal neoplasms of the small intestine, including 2 with biphenotypic features. Thus far, all cases have pursued indolent clinical courses. We propose the term " GLI1 -rearranged enteric tumor" to encompass this group of unique neoplasms of the small intestine that harbor GLI1 gene fusions and expand the spectrum of gastrointestinal neoplasms with these alterations.

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.

The pathological and clinical landscape of refractory metastatic triple negative breast cancer: a narrative review.

Background and Objective: Triple negative breast cancer (TNBC) refers to a special subtype of breast cancer that is negative for the estrogen receptor, the progesterone receptors, and human epidermal growth factor receptor 2. As a group of diseases, it has strong heterogeneity. Refractory metastatic triple negative breast cancer (mTNBC) has even greater heterogeneity, more susceptibility to drug resistance, and faster progression, which makes it more difficult to treat effectively and significantly reduces a patient's overall survival. Therefore, in order to overcome this difficulty in clinical practice, we need to deeply understand the special subgroup by analyzing definition and prognostic factors of refractory mTNBC and describing the therapeutic status and future treatment directions. Methods: Recent domestic and foreign guidelines, as well as clinical studies related to refractory mTNBC on PubMed and the China National Knowledge Infrastructure (CNKI) databases were retrospectively analyzed. The six keywords we selected were used for literature search. Two authors performed database searches independently, and disagreements over the results were mediated by a third reviewer. Key Content and Findings: According to the guidelines, refractory mTNBC has not been clearly defined. Related studies indicated that tumor heterogeneity may be one of the main mechanisms of early relapse or drug resistance in refractory mTNBC. The clinical treatment options for refractory mTNBC are very limited. Although chemotherapy is the standard treatment, it is limited by poor efficacy and intolerance in the clinical stage. Therefore, in recent years, many studies have explored novel treatment options. Both immunotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors have been selected as first-line treatment in clinical studies, but gained limited benefits. Indeed, clinical studies have shown good efficacy with novel ADCs, which may be promising in the clinical treatment of refractory mTNBC. Conclusions: Currently, improving the survival time and quality of life of refractory mTNBC are major challenges for clinicians. Novel therapies including immunosuppressive agents, PARP inhibitors, and ADCs rather than chemotherapy alone have achieved good results in the exploration of first-line treatment for refractory TNBC patients, but this warrants further research and investigation.

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.

The regimen of gemcitabine and cisplatin combined with radio frequency hyperthermia for advanced non-small cell lung cancer: a phase II study.

PURPOSE: This phase II randomised trial was designed to evaluate the therapeutic efficacy and feasibility of radio frequency regional hyperthermia in combination with chemotherapy for patients with advanced non-small lung cancer (NSCLC). METHODS: Eighty patients with pathologically proven advanced NSCLC, were enrolled and divided into two groups. Group A patients were treated by radio frequency regional hyperthermia in combination with the regimen of gemcitabine and cisplatin (GP). Group B patients were treated with the GP regimen alone. RESULTS: In group A, one patient achieved a complete response (CR), 18 achieved a partial response (PR), 18 achieved a stable disease and three experienced a progression of the disease. Thirty-three patients had a positive Clinical Benefit Response (CBR). In group B, no patient achieved CR, 17 achieved PR, 19 achieved a stable disease and four experienced a progression of the disease. Nineteen patients had a positive CBR. Significant differences between the two groups were observed for the CBR (P < 0.05), but not for RR. Major toxicities included bone marrow depression, nausea, vomiting, without significant differences between the two groups (P > 0.05). CONCLUSIONS: Radio-frequency regional hyperthermia in combination with chemotherapy (GP) is a safe, well tolerated, and effective therapeutic modality for patients with advanced NSCLC. The addition of hyperthermia improved quality of life.

[Expression of HER-2 and leptin in gastric cancer and their clinical significance].

OBJECTIVE: To assess the expression of HER-2 and leptin in gastric cancer and evaluate their relationship with VEGF expression and clinicopathological features, and their prognostic value for gastric cancer patients. METHODS: One hundred and ten gastric cancer specimens and the corresponding metastatic lymph nodes were detected for HER-2 by immunohistochemistry (IHC). All primary cancer tissues were detected for leptin, OB-Rb and VEGF. Ninty-six specimens of normal gastric mucosa served as the control. RESULTS: The expression level of HER-2, leptin and OB-Rb in gastric cancer tissues were significantly higher than those in normal tissues (19.1% vs. 8.0%, 49.1% vs. 34.0%, and 60.9% vs. 46.0%, P < 0.05). HER-2 overexpression was moderately homogenous in primary gastric cancer and matastatic lymph nodes (P = 0.607, Kappa = 0.581). There was a correlation between the expression of HER-2 and leptin, both of which were significantly correlated with tumor invasion depth, metastatic lymph nodes ratio (NR), distal metastasis, TNM stage and VEGF expression. However, there was no significant correlation between OB-Rb expression and the clinicopathological features evaluated. Cox regression multivariate analysis showed that tumor size, histological grade, NR, stage, chemotherapy and HER-2 expression were independent prognostic factors. CONCLUSIONS: HER-2 is stably expressed in primary gastric cancer and metastatic lymph nodes. HER-2 and leptin play an important role in the progression and angiogenesis of gastric cancer. High expression of HER-2 is a prognostic factor for poor outcome.

Effect of breast-conserving surgery plus radiotherapy versus mastectomy on breast cancer-specific survival for early-stage contralateral breast cancer.

BACKGROUND: Breast-conserving surgery followed by radiotherapy is recommended in most women with early-stage unilateral breast cancer. However, its role in contralateral breast cancer (CBC) patients remains unclear. This retrospective study aimed to evaluate the breast cancer-specific survival (BCSS) outcomes after breast-conserving surgery plus radiotherapy compared with mastectomy in women with early-stage (T1-2N0-1M0) CBC. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database. BCSS was analyzed using the log-rank method, competing risks regression model, and propensity score matching method. RESULTS: A total of 9,336 early-stage CBC patients were included. After multivariable adjustment, no significant difference in BCSS was found between early-stage CBC patients undergoing breast-conserving surgery plus radiotherapy and those undergoing mastectomy [hazard ratio (HR) 1.11, 95% confidence interval (CI): 0.90-1.37, P=0.329]. BCSS was similar in both treatment groups and in the subgroups stratified by age at first primary breast cancer or CBC diagnosis (≤50, 51-60, and >60 years), time interval between cancers (<0.25, 0.25-4, 5-9, and ≤10 years), stage of first primary breast cancer, T classification of CBC, histology and hormone receptors status of both cancers (all P>0.05). Among patients with N1 disease at CBC diagnosis, breast-conserving surgery plus radiotherapy was associated with a boundary significantly improved BCSS (HR 1.45, 95% CI: 1.00-2.12, P=0.050). Among patients who underwent breast-conserving surgery for first primary cancer, bilateral mastectomy for contralateral cancer did not improve BCSS compared with breast-conserving surgery plus radiotherapy (P>0.05). There was no significant difference in BCSS between breast-conserving surgery plus radiotherapy and mastectomy plus radiotherapy (P>0.05). Stable results were obtained after propensity score matching. CONCLUSIONS: Breast-conserving surgery plus radiotherapy did not significantly influence BCSS outcomes of patients with early-stage CBC. Bilateral mastectomy and mastectomy plus radiotherapy did not confer a survival advantage over breast-conserving surgery plus radiotherapy in these patients. Future prospective studies are necessary to expand on these results.

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.

Restoration of gefitinib efficacy following chemotherapy in a patient with metastatic non-small cell lung cancer.

BACKGROUND: Gefitinib has shown evidence of antitumor activity in advanced non-small cell lung cancer (NSCLC). CASE REPORT: A female Asian nonsmoker with adenocarcinoma was given gefitinib as first-line treatment with significant efficacy. However, after approximately 1.5 years, progression occurred. She then received chemotherapy (pemetrexed/carboplatin) until progression, followed by treatment with gefitinib to which the patient responded a second time. After progression, treatment with chemotherapy (docetaxel/cisplatin) was instituted and again followed by gefitinib. A recent positron emission tomography/computed tomography (PET/CT) scan showed complete remission under gefitinib. CONCLUSIONS: This case report indicates that resistance to gefitinib in NSCLC can be reversed after chemotherapy. Thus, re-exposure to gefitinib may be justified in selected cases.

Amphiregulin and epiregulin expression in colorectal carcinoma and the correlation with clinicopathological characteristics.

BACKGROUND: Amphiregulin (AREG) and epiregulin (EREG) have been found to play pivotal roles in several malignancies. However, the correlation between their expression and clinicopathological factors in colorectal carcinoma (CRC) is yet to be further investigated. To clarify the clinical significance of AREG and EREG expression in CRC, we detected serum and tissue levels of AREG and EREG. PATIENTS AND METHODS: We detected serum AREG and EREG levels by ELISA, and tissue levels by immunohistochemical test in 73 patients with CRC. The correlation between each independent clinicopathological characteristic and AREG and EREG levels was examined. RESULTS: There was significant correlation between serum AREG level and vascular invasion. There was no correlation between EREG serum level and any clinicopathological characteristics. Among the 73 primary lesions, 51 were AREG-positive, and 48 were EREG-positive. AREG-positive status was significantly correlated with depth of tumor invasion, distant metastases, and nerve invasion. EREG-positive status was significantly correlated with depth of tumor invasion and distant metastases. Coexpression analysis showed that 46 patients were both AREG-positive and EREG-positive. CONCLUSIONS: High serum and tissue levels of AREG and high tissue level of EREG are predictors of a poor prognosis in patients with CRC.

Docetaxel-Loaded Chitosan-Cholesterol Conjugate-Based Self-Assembled Nanoparticles for Overcoming Multidrug Resistance in Cancer Cells.

Cholesteryl hemisuccinate (CHS)-conjugated chitosan (CS)-based self-assembled nanoparticles (NPs) were developed for enhancing the intracellular uptake of docetaxel in multidrug resistance (MDR)-acquired cancer cells. CHS-CS was successfully synthesized and self-aggregation, particle size, zeta potential, drug entrapment efficiency, and in vitro drug release of docetaxel-loaded CHS-CS NPs were tested. The optimized NPs had a mean hydrodynamic diameter of 303 nm, positive zeta potential of 21.3 mV, and spherical shape. The in vitro release of docetaxel from the optimized CHS-CS NPs in different pH medium (pH 6.0 and 7.4) revealed that the release was improved in a more acidic condition (pH 6.0), representing a tumor cell's environment. The superior MDR-overcoming effect of docetaxel-loaded CHS-CS NPs, compared with docetaxel solution, was verified in anti-proliferation and cellular accumulation studies in MDR-acquired KBV20C cells. Thus, CHS-CS NPs could be potentially used for overcoming the MDR effect in anticancer drug delivery.

MONARCH plus: abemaciclib plus endocrine therapy in women with HR+/HER2- advanced breast cancer: the multinational randomized phase III study.

AIM: To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa. METHODS: This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A. RESULTS: In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346-0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm (p < 0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6 months; hazard ratio 0.376; 95% CI 0.240-0.588; p < 0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm (p < 0.0001, measurable disease population). The most frequent grade ⩾3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B). CONCLUSION: The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population.Trial Registration: ClinicalTrials.gov identifier: NCT02763566.

Glycogenic hepatopathy: A narrative review.

Glycogenic hepatopathy (GH) is a rare complication of the poorly controlled diabetes mellitus characterized by the transient liver dysfunction with elevated liver enzymes and associated hepatomegaly caused by the reversible accumulation of excess glycogen in the hepatocytes. It is predominantly seen in patients with longstanding type 1 diabetes mellitus and rarely reported in association with type 2 diabetes mellitus. Although it was first observed in the pediatric population, since then, it has been reported in adolescents and adults with or without ketoacidosis. The association of GH with hyperglycemia in diabetes has not been well established. One of the essential elements in the pathophysiology of development of GH is the wide fluctuation in both glucose and insulin levels. GH and non-alcoholic fatty liver disease (NAFLD) are clinically indistinguishable, and latter is more prevalent in diabetic patients and can progress to advanced liver disease and cirrhosis. Gradient dual-echo MRI can distinguish GH from NAFLD; however, GH can reliably be diagnosed only by liver biopsy. Adequate glycemic control can result in complete remission of clinical, laboratory and histological abnormalities. There has been a recent report of varying degree of liver fibrosis identified in patients with GH. Future studies are required to understand the biochemical defects underlying GH, noninvasive, rapid diagnostic tests for GH, and to assess the consequence of the fibrosis identified as severe fibrosis may progress to cirrhosis. Awareness of this entity in the medical community including specialists is low. Here we briefly reviewed the English literature on pathogenesis involved, recent progress in the evaluation, differential diagnosis, and management.

Small nucleolar host gene 6 promotes esophageal squamous cell carcinoma cell proliferation and inhibits cell apoptosis.

Esophageal cancer (ESCC) is one of the most common causes of cancer-associated mortality in China. The present investigation reveals that non-coding RNAs (ncRNAs), including long ncRNAs (lncRNAs), exert a significant effect on the initiation, development and metastasis of malignant tumors, including ESCC. However, to the best of our knowledge, the function of non-protein-coding genes that host small nucleolar RNAs has not been investigated in cancer, particularly in ESCC. The expression of small nucleolar host gene 6 (SNHG6) in 70 ESCC tissues and paired adjacent tissues was measured by reverse transcription quantitative polymerase chain reaction. Analysis demonstrated that SNHG6 expression was significantly increased in ESCC tissues, and associated with tumor size (P=0.040) and Tumor-Node-Metastasis stage (P<0.01). Knockdown of SNHG6 may inhibit proliferative and colony-forming abilities, and induce apoptosis, in ESCC cells. To the best of our knowledge, the data from the present study indicated for the first time that SNHG6 was upregulated in ESCC tissues and cell lines. This novel lncRNA may exert a marked effect on the generation and progression of ESCC, potentially providing a novel perspective on ESCC diagnosis and management.

Clinical significance of CD44s, CD44v3 and CD44v6 in breast cancer.

OBJECTIVES: To evaluate levels of CD44 standard variant (CD44s), CD44 variant exon 3 (CD44v3) and CD44 variant exon 6 (CD44v6) protein in breast cancer tissue, and investigate their relationships with clinicopathological characteristics of the disease. METHODS: Immunohistochemistry for CD44s, CD44v3 and CD44v6 was retrospectively performed on formalin-fixed paraffin wax-embedded breast cancer tissue samples. RESULTS: Tumour tissue samples from 60 patients with breast cancer were included. There was a significant relationship between CD44s positivity and tumour diameter and lymph node involvement. CD44v6 positivity was significantly associated with tumour-node-metastasis (TNM) stage and lymph node involvement. There were significant negative correlations between CD44s immunopositivity, tumour diameter and TNM stage, and significant positive correlations between CD44v6 immunopositivity, tumour diameter and TNM stage. CONCLUSIONS: CD44s and CD44v6 appear to play opposing roles in the development of breast cancer, but their precise functions and mechanisms of action remain unclear.

Regulation of CD44 expression by tumor necrosis factor-α and its potential role in breast cancer cell migration.

CD44 molecule plays critical role in distant malignant metastasis. It is expressed in standard form (CD44s) or variant form (CD44v). Tumor necrosis factor-α (TNF-α) is highly expressed in the cancer microenvironment. TNF-α was reported to modulate CD44 expression in several kinds of cancer. However, little is known about pathological role of TNF-α in breast cancer (BC) cells. In the current investigation, we investigated the effect of TNF-α on BC cells (MCF-7 and MDA-MB-231) viability, CD44 expression, and in vitro migration. We found that TNF-α down-regulated CD44s expression, up-regulated CD44v3 and CD44v6 expression through JNK pathway in MCF-7 cells. In MDA-MB-231 cells, TNF-α up-regulated CD44s, CD44v3 and CD44v6 expression via p38 pathway. These data indicate important role of CD44 molecule in BC pathology.