Role of transforming growth factor-ß1 pathway in angiogenesis induced by chronic stress in colorectal cancer.

BACKGROUND: Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood. METHODS: Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or ß-adrenergic receptor (ß-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-ß (TGF-ß) receptor Type I kinase (Ly2157299) in vitro. TGF-ß1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested. RESULTS: Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-ß1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion. CONCLUSIONS: Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-ß1 signaling during this process. In addition, ß-AR/TGF-ß1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.

WZB117 enhanced the anti-tumor effect of apatinib against melanoma via blocking STAT3/PKM2 axis.

Background: Melanoma is the most lethal skin malignant tumor with a short survival once stepping into the metastatic status and poses a therapeutic challenge. Apatinib (a tyrosine kinase inhibitor) is a promising antiangiogenic agent for the treatment of metastatic melanoma. However, antiangiogenic monotherapy is prone to acquired drug resistance and has a limited therapeutic effect. The persistence dependence of glycolytic metabolism in antiangiogenic therapy-resistant cells provides evidence that glycolysis inhibitors may enhance the effect of antiangiogenic therapy. So, this study aimed to investigate whether WZB117 (a specific GLUT1 inhibitor) could enhance the anti-tumor effect of apatinib against melanoma and its potential mechanisms. Methods: We investigated the anti-tumor effects of apatinib alone or in combination with WZB117 on human melanoma cell lines (A375 and SK-MEL-28). The MTT assay determined cell viability and the half-maximal inhibitory concentration (IC50). Multiple drug effect/combination indexes (CI) analysis was conducted to assess interactions between apatinib and WZB117. Signal transducer and activator of transcription 3 (STAT3) pathway measured by western blotting and immunofluorescence staining. RNA expression analyses were performed using the reverse transcription-quantitative PCR method. Results: Apatinib and WZB117 showed dose and time-dependent growth inhibitory effects in both melanoma cells. The IC50 of apatinib at 48 h in A375 and SK-MEL-28 cells was 62.58 and 59.61 µM, respectively, while the IC50 of WZB117 was 116.85 and 113.91 µM, respectively. The CI values of the two drugs were 0.538 and 0.544, respectively, indicating a synergistic effect of apatinib combined with WZB117. We also found that glucose consumption and lactate production were suppressed by apatinib plus WZB117 in a dose-dependent manner, paralleled by reducing glycolytic enzyme pyruvate kinase M2 (PKM2). The potential mechanism of the combination was to suppress the phosphorylation of STAT3. Knockdown of STAT3 by siRNA inhibited the expression of PKM2, while the activation of STAT3 by IL-6 increased the expression of PKM2. The effects of IL-6 were attenuated by apatinib combined with WZB117 treatment. Conclusion: WZB117 enhanced the anti-tumor effect of apatinib against melanoma via modulating glycolysis by blocking the STAT3/PKM2 axis, which suggested the combination of apatinib with WZB117 could be a potential therapeutic candidate for melanoma.

The real-world clinical outcomes and treatment patterns of patients with unresectable locally advanced or metastatic soft tissue sarcoma treated with anlotinib in the post-ALTER0203 trial era.

BACKGROUND: The ALTER0203 clinical trial showed that anlotinib, a multitargeted tyrosine kinase inhibitor, had antitumor effects on advanced soft tissue sarcoma (STS) after the failure of standard chemotherapy. We aimed to evaluate the real-world efficacy and explore prognostic factors and treatment patterns of anlotinib in patients with advanced STS. METHODS: We retrospectively analyzed the data of patients with unresectable locally advanced or metastatic STS who received at least one dose of anlotinib from June 2018 to March 2021. The survival data were analyzed using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was performed for multivariate analysis. RESULTS: A total of 209 patients were included. The median age was 48 (range 11-85) years. The median follow-up, progression-free survival, and overall survival were 18.7 months, 6.1 months [95% confidence interval (CI): 4.9-7.2], and 16.4 months (95% CI: 13.6-19.1), respectively. The objective response rate was 13.4%. Nutritional status, Eastern Cooperative Oncology Group (ECOG) performance status, and anlotinib treatment patterns (combination therapy or switch maintenance therapy vs. monotherapy) were significantly associated with progression-free survival. Besides, pathological grade, nutritional status, ECOG performance status, and anlotinib treatment patterns were predictive of overall survival. Due to anlotinib-related toxicity, 31 (14.8%) patients, and 25 (12.0%) patients experienced dose reduction and treatment discontinuation, respectively. CONCLUSION: These findings confirmed the efficacy of anlotinib in patients with advanced STS in a real-world setting. The patterns of anlotinib treatment deserve further exploration.

Anlotinib treatment in elderly patients with unresectable or metastatic soft tissue sarcoma: a retrospective study.

Palliative chemotherapy can improve outcomes in most patients with advanced soft tissue sarcoma (STS), but the treatment of elderly patients remains a challenge because of older age, comorbidities and poor performance status. This study retrospectively analyzed the efficacy and safety of the multi-targeted tyrosine kinase inhibitor anlotinib in elderly patients with advanced STS. Eligible patients included those of age at least 60 years, diagnosed with unresectable or metastatic STS, and treated with at least one cycle of anlotinib between June 2018 and September 2020 in our center. Clinical characteristics, treatment response, survival status and adverse events were analyzed by reviewing medical records. The median age of 35 eligible patients was 65 (range, 61-85) years, and the median Charlson Comorbidity Index score was 8 (range, 4-11). Anlotinib as first-line systemic treatment was in 24 (68.6%) patients, and as second-line or third-line treatment in the remaining 11 (31.4%) patients. The objective response rate was 8.6%. The median progression-free survival was 5.5 [95% confidence interval (CI), 1.4-9.6] months and the median overall survival was 14.3 (95% CI, 9.6-19.0) months. Thirteen (37.1%) patients developed at least one grade 3/4 adverse event during anlotinib treatment. Our findings suggest that anlotinib treatment has promising efficacy and an acceptable toxicity profile in elderly patients with unresectable or metastatic STS. Prospective controlled trials are needed to compare the safety and efficacy of anlotinib and chemotherapy as first-line treatment in elderly patients with advanced STS.

Rechallenge with Multi-Targeted Tyrosine Kinase Inhibitors in Patients with Advanced Soft Tissue Sarcoma: A Single-Center Experience.

PURPOSE: Chemotherapy and multi-targeted tyrosine kinase inhibitors (TKI) are important treatments for advanced soft tissue sarcomas, but the following treatment remains unclear after the failure of these drugs. This retrospective study investigated the efficacy and safety of multi-targeted TKI rechallenge in patients with advanced soft tissue sarcoma after the failure of previous TKI treatment. PATIENTS AND METHODS: Gastrointestinal stromal tumors, dermatofibrosarcoma protuberans and anaplastic lymphoma kinase translocation-positive inflammatory myofibroblastic tumor were excluded. Eligible patients included those diagnosed with advanced soft tissue sarcoma, progressed after the initial TKI treatment, and received the same or other TKI therapies. Treatment response, adverse events, median progression-free survival and overall survival were analyzed. RESULTS: Twenty-six eligible patients were included. Nineteen patients had previously received chemotherapy, and all patients had received at least 1.5 months of initial TKI treatment. During the TKI rechallenge, patients were treated with anlotinib (n =16), lenvatinib (n =3), apatinib (n =2), pazopanib (n =2), axitinib (n =2) or regorafenib (n =1). No patients achieved responses. Nine (34.6%) patients had stable disease confirmed by a second imaging scan, and 5 (19.2%) patients had stable disease that was not confirmed by a second scan. The estimated median progression-free survival and overall survival were 3.3 months and 11.7 months, respectively. Grade 3/4 adverse events occurred in 6 (23.1%) patients and were manageable. CONCLUSION: Our findings suggest that multi-targeted TKI rechallenge may provide potential clinical benefits for patients with advanced soft tissue sarcoma after their previous TKI treatment.

Locally advanced malignant solitary fibrous tumour successfully treated with conversion chemotherapy, operation and postoperative radiotherapy: a case report.

Preoperative diagnosis of solitary fibrous tumour (SFT) may not provide a complete tumour picture and may be inaccurate. There is no standard treatment for locally advanced or metastasised malignant SFT (MSFT). Here, the case of a 17-year-old male patient with final pathology diagnosis of MSFT is reported. Preoperative biopsy pathology results suggested an Ewing sarcoma that was positive for CD99 antigen, vimentin, friend leukaemia integration 1 transcription factor, apoptosis regulator Bcl-2, and synaptophysin; and negative for CD34 antigen, S-100 protein (S-100), smooth muscle antigen, cytokeratin, and Wilms tumour 1 associated protein. The Ki67 positive rate was 8%, so the patient initially received eight cycles of conversion chemotherapy (vincristine, etoposide, ifosfamide and pirarubicin for one cycle, and vincristine, doxorubicin, and cyclophosphamide/ifosfamide and etoposide for 7 cycles in total). The tumour shrunk significantly and was surgically removed. The final pathology diagnosis was MSFT that was positive for CD99 and signal transducer and activator of transcription 6, and negative for CD34, tumour protein 63, S-100, desmin, and epithelial membrane antigen. Fluorescence in situ hybridization showed no gene translocation in EWS RNA binding protein 1, SS18 subunit of BAF chromatin remodelling complex or FUS RNA binding protein. The patient finally accepted adjuvant radiotherapy of 5600 cGy. Disease-free survival has been > 1 year, with no recurrence or metastasis detected to date. MSFT is rare and treatment for locally advanced or metastatic MSFT remains controversial. The efficacy of the present therapeutic strategy requires further research.

Efficacy and safety of anlotinib in patients with unresectable or metastatic well-differentiated/dedifferentiated liposarcoma: a single-center retrospective study.

Treatment options for unresectable local recurrence or metastatic well-differentiated/dedifferentiated liposarcoma (WDLS/DDLS) remain limited. Different liposarcoma subtypes have varying clinical features and sensitivities to treatment regimens. The multitarget tyrosine kinase inhibitors (TKIs), such as pazopanib and regorafenib, have been approved for use in nonadipocytic soft tissue sarcomas (STS). Anlotinib, another TKI, has been approved in China for treating metastatic STS that has progressed after the use of anthracycline-based regimens. In this study, we aimed to evaluate the role of anlotinib in the treatment of local recurrence or metastatic WDLS/DDLS. From August 2018 to June 2020, 17 patients with unresectable local recurrence or metastatic WDLS/DDLS treated with anlotinib in our center were included. The follow-up cutoff time was set as 20 October 2020. Baseline and observation indicators were collected and analyzed. Estimated median progression-free survival (PFS) was 27.9 weeks, the PFS rate at 24 weeks was 58.8%, overall survival (OS) was 56.6 weeks, the disease control rate was 64.7% and no complete response or partial response was detected. Grade 3/4 adverse events occurred in four cases and could be managed. Anlotinib is a potential treatment option for unresectable local recurrence or metastatic WDLS/DDLS.

Switch maintenance therapy with anlotinib after chemotherapy in unresectable or metastatic soft tissue sarcoma: a single-center retrospective study.

Background Chemotherapy is an important first-line treatment option in patients with advanced soft tissue sarcoma (STS). Whether maintenance therapy improves survival after chemotherapy is still controversial. Methods We retrospectively analyzed the data of 21 adults diagnosed with unresectable or metastatic STS between May 2018 and September 2019 in our center. They achieved an objective response or stable disease after chemotherapy and then received at least one cycle of switch maintenance therapy with anlotinib, a novel multi-targeted tyrosine kinase inhibitor. The objective response rate (ORR), disease control rate (DCR), adverse events, and median progression-free survival (PFS) after anlotinib maintenance (PFSa), and the median PFS after chemotherapy (PFSc) were analyzed. Results Nineteen patients received first-line chemotherapy and 2 received second-line chemotherapy. Five patients achieved a partial response and 16 had stable disease after chemotherapy. The median number of anlotinib maintenance cycles was five (range, 2-31). One patient achieved a complete response and two patients exhibited a partial response during anlotinib maintenance, with an ORR of 14.3%. The DCR was 81.0%. After a median follow-up of 14.0 months, the median PFSa and PFSc were 7.3 and 13.6 months, respectively. Grade 3/4 adverse events occurred in six (28.6%) patients and were managed through symptomatic treatment, dose reduction or anlotinib discontinuance. Conclusion Our results indicate that switch maintenance therapy with anlotinib is a promising strategy for the treatment of patients with unresectable or metastatic STS who have benefited from chemotherapy. Toxicities were manageable. Prospective clinical trials are needed to confirm this finding.

The do-not-resuscitate order for terminal cancer patients in mainland China: A retrospective study.

With the development of palliative care, a signed do-not-resuscitate (DNR) order has become increasingly popular worldwide. However, there is no legal guarantee of a signed DNR order for patients with cancer in mainland China. This study aimed to estimate the status of DNR order signing before patient death in the cancer center of a large tertiary affiliated teaching hospital in western China. Patient demographics and disease-related characteristics were also analyzed.This was a retrospective chart analysis. We screened all charts from a large-scale tertiary teaching hospital in China for patients who died of cancer from January 2010 to February 2015. Analysis included a total of 365 records. The details of DNR order forms, patient demographics, and disease-related characteristics were recorded.The DNR order signing rate was 80%. Only 2 patients signed the DNR order themselves, while the majority of DNR orders were signed by patients' surrogates. The median time for signing the DNR order was 1 day before the patients' death. Most DNR decisions were made within the last 3 days before death. The time at which DNR orders were signed was related to disease severity and the rate of disease progression.Our findings indicate that signing a DNR order for patients with terminal cancer has become common in mainland China in recent years. Decisions about a DNR order are usually made by patients' surrogates when patients are severely ill. Palliative care in mainland China still needs to be improved.

A phase II prospective study of the "Sandwich" protocol, L-asparaginase, cisplatin, dexamethasone and etoposide chemotherapy combined with concurrent radiation and cisplatin, in newly diagnosed, I/II stage, nasal type, extranodal natural killer/T-cell lymphoma.

Nasal-type, extranodal NK/T cell lymphoma (ENKTCL) is a special type of lymphomas with geographic and racial specificity. Up to now, the standard first-line treatment is still not unified. In our previous report, the "sandwich" protocol produced good results. Continuing to use the "sandwich" mode, a new chemotherapy composed of L-asparaginase, cisplatin, etoposide and dexamethasone (LVDP) plus concurrent chemoradiotherapy (CCRT) was conducted in more patients with newly diagnosed, I/II stage ENKTCL. The results showed that 66 patients were enrolled. Overall response rate was 86.4% including 83.3% complete response and 3.0% partial remission. With the median follow-up of 23.5 months, 3-year overall survival and 3-year progression-free survival were 70.1% and 67.4%, respectively. The survival rate in stage II and extra-cavity stage I was significantly less than that in limited stage I (p < 0.05). Therefore, we thought that the "sandwich" mode was worthy of being generalized and LVDP combined with CCRT was an effective protocol for I/II stage ENKTCL. But this regimen was not suitable for all stage I/II patients and warrants larger sample and layering investigation. This study was a registered clinical trial with number ChiCTR-TNC-12002353.

A multicenter study on the validation of the Burnout Battery: a new visual analog scale to screen job burnout in oncology professionals.

OBJECTIVES: The objective of the study is to develop a novel tool-the Burnout Battery-for briefly screening burnout among oncology professionals in China and assessing its validity. METHODS: A multicenter study was conducted in doctors and nurses of the oncology departments in China from November 2014 to May 2015. The Burnout Battery was administered with the Maslach Burnout Inventory-Human Services Survey (MBI-HSS) and the Doctors' Job Burnout Questionnaire. RESULTS: Of 538 oncology doctors and nurses who completed all the survey, using MBI-HSS as the standard tool for measuring burnout, 52% had emotional exhaustion, 39.4% had depersonalization, and 59.3% had a low sense of personal accomplishment. Receiver operating characteristic curve analyses showed that the best cut-off of the Burnout Battery was the battery with 3 bars, which yielded best sensitivity and specificity against all the 3 subscales of MBI-HSS. With this cut-off, nearly half of Chinese oncology professionals (46.8%) had burnout. The Burnout Battery correlated significantly with subscales of the MBI-HSS and the Doctors' Job Burnout Questionnaire. In multiple logistic regression analysis, those who worked more than 60 hours per week and who thought clinical work was the most stressful part of their job were more likely to experience burnout. CONCLUSION: Chinese oncology professionals exhibit high levels of burnout. The Burnout Battery appears to be a simple and useful tool for screening burnout. Working long hours and perceiving clinical work as the most stressful part of the job were the main factors associated with burnout.

Body mass index as a prognostic factor in patients with extranodal natural killer/T-cell lymphoma, nasal type.

Epidemiological evidence has shown that body mass index (BMI) can predict survival in several types of cancer. However, the role of BMI in extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is still unclear. This retrospective single-center study included 251 newly diagnosed patients to determine the prognostic value of BMI in ENKTL. Of these, 203 patients received chemoradiotherapy, 37 received chemotherapy alone, 8 received radiotherapy alone, and 3 received only best supportive care. With a median follow-up of 28 months, the estimated 3-year overall survival (OS) and progression-free survival (PFS) rates were 64.4% and 60.9%, respectively. The receiver-operating characteristic curve showed that 20.8 kg/m2 was the optimal cut-off of BMI to predict survival. BMI < 20.8 kg/m2 was associated with lower 3-year OS (52.8% vs. 72.9%, P = 0.001) and PFS (48.8% vs. 69.8%, P < 0.001) rates. Multivariate analysis indicated that BMI, performance status, lactate dehydrogenase (LDH) levels, chemotherapy, and radiotherapy were independent prognostic factors for OS. Furthermore, BMI, number of extranodal sites, performance status, LDH, and radiotherapy were predictive of PFS. These results suggest that BMI at the cut-off of 20.8 kg/m2 might be a prognostic factor in patients with ENKTL.

Attitudes of Chinese Oncology Physicians Toward Death with Dignity.

BACKGROUND: Death with dignity (DWD) refers to the refusal of life-prolonging measures for terminally ill patients by "living wills" forms in advance. More and more oncology physicians are receiving DWD requests from advance cancer patients in mainland China. OBJECTIVE: The study objective was to investigate the attitudes of Chinese oncology physicians toward the legalization and implementation of DWD. METHODS: A questionnaire investigating the understanding and attitudes toward DWD was administered to 257 oncology physicians from 11 hospitals in mainland China. RESULTS: The effective response rate was 86.8% (223/257). The majority of oncology physicians (69.1%) had received DWD requests from patients. Half of the participants (52.5%) thought that the most important reason was the patients' unwillingness to maintain survival through machines. One-third of participants (33.0%) attributed the most important reason to suffering from painful symptoms. Most oncology physicians (78.9%) had knowledge about DWD. A fifth of respondents did not know the difference between DWD and euthanasia, and a few even considered DWD as euthanasia. The majority of oncology physicians supported the legalization (88.3%) and implementation (83.9%) of DWD. CONCLUSIONS: Many Chinese oncology physicians have received advanced cancer patients' DWD requests and think that DWD should be legalized and implemented. Chinese health management departments should consider the demands of physicians and patients. It is important to inform physicians about the difference between DWD and euthanasia, as one-fifth of them were confused about it.

The discordance of information needs between cancer patients and their families in China.

OBJECTIVE: We aimed at studying information needs of patients and their families, and their attitude towards the counterparts' information needs. Factors influencing psychological status of patients were investigated. METHODS: Self-designed questionnaires for information needs and attitude were delivered to participants. Patient Health Questionnaire 9-item and Generalized Anxiety Disorder 7-item scale were used to evaluate psychological status of patients. RESULTS: 183 eligible pairs of patients and families were involved. Except for the patients' expected life span, most patients and families needed information for all other subscales of disease-related information. Most patients wished families know more information; however, caregivers tended to prevent this. The occurrence of patients' psychiatric disorders was related to their needs for expected life span (OR 3.06 95%CI 1.36-6.93), as well as the attitude of caregivers about whether to provide more information about treatment outcomes (OR 0.24 95% CI 0.10-0.63). CONCLUSIONS: Information discordance between cancer patients and their families tended to happen when it came to patients' prognostic information. The psychological status of cancer patients was found in association with their information needs and families' attitude towards it. PRACTICE IMPLICATIONS: To guide oncology professionals and cancer patients' families for information provision.

Norepinephrine induced epithelial-mesenchymal transition in HT-29 and A549 cells in vitro.

PURPOSE: Norepinephrine (NE) has been implicated in epithelial-mesenchymal transition (EMT) of cancer cells. However, the underlying mechanism is poorly understood. The goal of this study was to explore the effect of NE on cancer cell EMT and to investigate the potential mechanism. METHODS: HT-29 and A549 cells were treated with NE, ß-adrenergic receptor (ß-AR) antagonist (propranolol) or inhibitor of transforming growth factor-ß (TGF-ß) receptor type I kinase (Ly2157299). Morphology of cells was observed with optical and electron microscope and immunofluorescence staining. Cellular migration and invasion were tested with transwell migration assay and Matrigel invasion assay, respectively. TGF-ß1 and cyclic adenosine monophosphate (cAMP) were quantified. EMT markers and signaling pathway were measured by RT-PCR and western blot. RESULTS: NE stimulated TGF-ß1 secretion and intracellular cAMP synthesis, induced morphological alterations in HT-29 and A549 cells, and enhanced their ability of migration and invasion. EMT markers induction was observed in NE-treated cancer cells. The effect of NE could be inhibited by propranolol or Ly2157299. ß-AR/TGF-ß1 signaling/p-Smad3/Snail and ß-AR/TGF-ß1 signaling/HIF-1α/Snail were two signaling pathways. CONCLUSION: These findings demonstrated that TGF-ß1 signaling pathway was a significant factor of NE-induced cancer cells EMT. The data also suggested that psychological stress might be a risk factor which enhances the ability of migration or invasion of cancer cells.

Mannan-modified adenovirus targeting TERT and VEGFR-2: A universal tumour vaccine.

Antigen-presenting cells including dendritic cells (DCs) express mannan receptors (MR) on their surface, which can be exploited in cancer therapy by designing immune-stimulatory viruses coated with mannan-modified capsids that then bind to DCs and initiate a potent immune response. Although the combination of anti-angiogenesis and cancer immunotherapy agents has a synergistic antitumor effect, more effective strategies for delivering such combinations are still required. Here we report the design and application of mannan-modified adenovirus that expresses both telomerase reverse transcriptase (TERT) and vascular endothelial growth factor receptor-2 (VEGFR-2). Cytotoxic T lymphocytes that are reactive to TERT and VEGFR-2 are capable of mounting an anti-tumour response in murine breast and colon tumour models and in a lung metastatic model. Compared with mannan-modified TERT adenovirus vaccine or mannan-modified VEGFR-2 adenovirus vaccine alone, the combined vaccine showed remarkably synergistic anti-tumour immunity in these models. Both TERT- and VEGFR-2-specific cytotoxic T lymphocytes (CTL) were identified in an in vitro cytotoxicity assay, and the CTL activity against tumour cells was significantly elevated in the combined vaccine group. Furthermore, CTL-mediated toxicity was blocked by anti-CD8 monoclonal antibodies. Thus, the combined mannan-modified TERT and VEGFR-2 adenovirus confers potent anti-tumour immunity by targeting both tumour cells and intratumoural angiogenesis.

The effect of chronic stress on anti-angiogenesis of sunitinib in colorectal cancer models.

Epidemiological and experimental evidence has shown that psychological stress can propel cancer progression. However, its role in anti-angiogenic therapy is not well understood. We previously found that exogenous norepinephrine attenuated the effect of sunitinib, a multi-targeted anti-angiogenic agent, in a mouse melanoma model. Here, we further evaluated the effects of chronic stress on sunitinib therapy in colorectal cancer models. We found that chronic restraint stress markedly weakened the efficacy of sunitinib, primarily through promoting the expression of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) to stimulate tumor angiogenesis in vivo. This effect could be sufficiently mimicked by exogenous norepinephrine and blocked by the ß-antagonist propranolol. In vitro, norepinephrine up-regulated expression of VEGF and IL-8 in sunitinib-treated cancer cells mainly through the ß-adrenoceptor-cAMP-PKA signaling pathway. Norepinephrine also abrogated sunitinib-induced inhibition of cancer cell migration, but had no effect on direct anti-proliferative activity of sunitinib on cancer cells. These findings suggest that psychological stress might attenuate anti-angiogenic therapy primarily through activating beta-adrenergic signaling to promote tumor angiogenesis. It is also suggested that ß-blockers might improve anti-angiogenic outcome under psychological stress.

Mannan-modified adenovirus encoding VEGFR-2 as a vaccine to induce anti-tumor immunity.

PURPOSE: Dendritic cell (DC) vaccines are a promising immunotherapeutic approach for treatment and prevention of cancer. While this methodology is widely accepted, it also has some limitations. Antigen-presenting cells including DCs express the mannan receptor (MR). The delivery of a mannan-modified tumor antigen to the MR has been demonstrated to be efficient. Vascular endothelial growth factor receptor-2 (VEGFR-2) is mainly responsible for angiogenesis and tumor growth. The goal of our study was to deliver VEGFR-2 to DCs by means of mannan-modified adenovirus. METHODS: VEGFR-2 recombinant adenovirus modified with oxidized mannan was constructed as a tumor vaccine to immunize mice in vivo. IFN-γ in mouse sera and spleen was detected by ELISA and ELISPOT. The killing activity of cytotoxic T lymphocyte (CTL) against VEGFR-2 was measured with a lactate dehydrogenase assay. Vessel densities in tumor tissues were detected by immunohistochemistry. Flow cytometry was used to test CD4(+) and CD8(+) T-cell counts in tumor tissues. RESULTS: The vaccine exhibited both protective and therapeutic efficacy in the inhibition of tumor growth and markedly prolonged survival in mice. Protection against metastasis was also observed. Furthermore, vaccination led to greater IFN-γ and VEGFR-2-specific CTLs. The specific immunity resulted in the suppression of angiogenesis and an increase in CD8(+) cells in tumor tissues. CONCLUSION: Oxidized mannan-modified adenovirus expressing VEGFR-2 could extraordinarily stimulate both protective and therapeutic immune response in a mice model. Our data suggest that the combination of cancer immunity and anti-angiogenesis via modified mannan is a promising strategy in tumor prophylaxis and therapy.

Measurement of distress and its alteration during treatment in patients with nasopharyngeal carcinoma.

BACKGROUND: We examined the criterion-related validity of the Distress Thermometer (DT) for screening distress in patients with nasopharyngeal carcinoma (NPC) and investigated prospectively how distress changes. METHODS: In the cross-sectional study, the DT was tested against the Hospital Anxiety and Depression Scale (HADS) in 295 patients with NPC. In the prospective study, 61 newly diagnosed patients with NPC completed the DT and HADS 6 times. RESULTS: Adopting HADS as the standard tool for screening distress, 31.5% of the patients with NPC had distress. A DT cutoff score ≥ 4 had best sensitivity (0.73) and specificity (0.85). In the prospective study, the proportion of patients with distress rose significantly during treatment. CONCLUSION: Receiver operating characteristic (ROC) findings provide initial support for the validity of the DT among patients with NPC. Nearly one third of patients with NPC exceeded cutoff values for distress in the cross-sectional study. In the prospective study, the level of distress increased significantly during concurrent chemoradiotherapy for patients with NPC.