A nomogram for predicting severe myelosuppression in small cell lung cancer patients following the first-line chemotherapy.

This study aimed at establishing and validating a nomogram to predict the probability of severe myelosuppression in small cell lung cancer (SCLC) patients following the first-line chemotherapy. A total of 179 SCLC cases were screened as the training group and another 124 patients were used for the validation group. Predictors were determined by the smallest Akaike's information criterion (AIC) in multivariate logistic regression analysis, leading to a new nomogram. The nomogram was validated in both training and validation groups and the predicting value was evaluated by area under the receiver operating characteristics (ROC) curve (AUC), calibration curve, and decision curve analysis (DCA). Age and tumor staging were extracted as predictors to establish a nomogram, which displayed the AUC values as 0.725 and 0.727 in the training and validation groups, respectively. This nomogram exhibited acceptable calibration curves in the two groups and its prediction added more net benefits than the treat-all scheme and treat-none scheme if the range of threshold probability in the DCA was between 15 and 60% in the training and validation groups. Therefore, the nomogram objectively and accurately predict the occurrence of severe myelosuppression in SCLC patients following the first-line chemotherapy.

Immortal Time Bias-Corrected Effectiveness of Traditional Chinese Medicine in Non-Small Cell Lung Cancer (C-EVID): A Prospective Cohort Study.

Background: Relatively little is known about the effect of traditional Chinese medicine (TCM) on prognosis of non-small cell lung cancer (NSCLC). Methods: In this nationwide, multicenter, prospective, cohort study, eligible patients aged 18-75 years with radical resection, and histologically confirmed stage II-IIIA NSCLC were enrolled. All patients received 4 cycles of standard adjuvant chemotherapy. Patients who received Chinese herbal decoction and (or) oral Chinese patent medicine for a cumulative period of not less than 6 months were defined as TCM group, otherwise they were considered as control group. The primary endpoint was DFS calculated using the Kaplan-Meier method. A time-dependent Cox proportional hazards model was used to correct immortal time bias. The secondary endpoints included DFS in patients of different characteristics, and safety analyses. This study was registered with the Chinese Clinical Trial Registry (ChiCTR1800015776). Results: A total of 507 patients were included (230 patients in the TCM group; 277 patients in the control group). The median follow-up was 32.1 months. 101 (44%) in the TCM group and 186 (67%) in the control group had disease relapse. The median DFS was not reached in the TCM group and was 19.4 months (95% CI, 14.2 to 24.6) in the control group. The adjusted time-dependent HR was 0.61 (95% CI, 0.47 to 0.78), equalling to a 39% reduction in the risk of disease recurrence with TCM. the number needed to treat to prevent one patient from relapsing was 4.29 (95% CI, 3.15 to 6.73) at 5 years. Similar results were observed in most of subgroups. Patients had a significant improvement in white blood cell decrease, nausea, decreased appetite, diarrhea, pain, and fatigue in the TCM group. Conclusion: TCM may improves DFS and has a better tolerability profile in patients with stage II-IIIA NSCLC receiving standard chemotherapy after complete resection compared with those receiving standard chemotherapy alone. Further studies are warranted.

Efficacy and Safety of Astragalus-Containing Traditional Chinese Medicine Combined With Platinum-Based Chemotherapy in Advanced Gastric Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Astragalus-containing traditional Chinese medicine (TCM) is widely used as adjunctive treatment to platinum-based chemotherapy (PBC) in patients with advanced gastric cancer (AGC) in China. However, evidence regarding its efficacy remains limited. This study aimed to evaluate the efficacy and safety of Astragalus-containing TCM combined with PBC in AGC treatment. METHODS: We searched for literature (up to July 19, 2020) in eight electronic databases. The included studies were reviewed by two researchers. The main outcomes were the objective response rate (ORR), disease control rate (DCR), survival rate, quality of life (QOL), adverse drug reactions (ADRs), and peripheral blood lymphocyte levels. The effect estimate of interest was the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs). Trial sequential analysis (TSA) was used to detect the robustness of the primary outcome and to calculate the required information size (RIS). Certainty of the evidence was assessed using the GRADE profiler. RESULTS: Results based on available literature showed that, compared with patients treated with PBC alone, those treated with Astragalus-containing TCM had a better ORR (RR: 1.24, 95% CI: 1.15-1.34, P < 0.00001), DCR (RR: 1.10, 95% CI: 1.06-1.14, P < 0.00001), 1-year survival rate (RR: 1.41, 95% CI: 1.09-1.82, P = 0.009), 2-year survival rate (RR: 3.13, 95% CI: 1.80-5.46, P < 0.0001), and QOL (RR: 2.03, 95% CI: 1.70-2.43, P < 0.00001 and MD: 12.39, 95% CI: 5.48-19.30, P = 0.0004); higher proportions of CD3+ T cells and CD3+ CD4+ T cells; higher ratio of CD4+/CD8+ T cells; nature killer cells; and lower incidence of ADRs. Subgroup analysis showed that both oral and injection administration of Astragalus-containing TCM increased tumor response. Whether treatment duration was ≥8 weeks or <8 weeks, Astragalus-containing TCM could increase tumor response in AGC patients. Furthermore, Astragalus-containing TCM combined with oxaliplatin-based chemotherapy could increase the ORR and DCR; when with cisplatin, it could only increase the ORR. CONCLUSION: Current low to moderate evidence revealed that Astragalus-containing TCM combined with PBC had better efficacy and less side effects in the treatment of AGC; however, more high-quality randomized studies are warranted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, identifier CRD42020203486.

Can Src protein tyrosine kinase inhibitors be combined with opioid analgesics? Src and opioid-induced tolerance, hyperalgesia and addiction.

The clinical application of opioids may be accompanied by a series of adverse consequences, such as opioid tolerance, opioid-induced hyperalgesia, opioid dependence or addiction. In view of this issue, clinicians are faced with the dilemma of treating various types of pain with or without opioids. In this review, we discuss that Src protein tyrosine kinase plays an important role in these adverse consequences, and Src inhibitors can solve these problems well. Therefore, Src inhibitors have the potential to be used in combination with opioids to achieve synergy. How to combine them together to maximize the analgesic effect while avoiding unnecessary trouble provides a topic for follow-up research.

The nonreceptor protein tyrosine kinase Src participates in every step of cancer-induced bone pain.

Cancer-induced bone pain (CIBP) is a refractory form of pain that has a high incidence in advanced tumors. Src protein tyrosine kinase is mainly composed of six domains, with two states of automatic inhibition and activation. The modular domain allows Src to conveniently regulate by and communicate with a variety of proteins, directly or indirectly participate in each step of the CIBP process. Src is beneficial to the growth and proliferation of tumor cells, and it can promote the metastases of primary tumors to bone. In the microenvironment of bone metastasis, it mainly mediates bone resorption, activates related peripheral receptors to participate in the formation of pain signals, and may promote the generation of pathological sensory nerve fibers. In the process of pain signal transmission, it mainly mediates NMDAR and central glial cells to regulate pain signal intensity and central sensitization, but it is not limited to these two aspects. Both basic experimentation and clinical research have shown encouraging potential, providing new ideas and inspiration for the prevention and treatment of CIBP.

PAR2-mediated upregulation of BDNF contributes to central sensitization in bone cancer pain.

BACKGROUND: Bone cancer pain is currently a major clinical challenge for the management of cancer patients, and the cellular and molecular mechanisms underlying the spinal sensitization remain unclear. While several studies demonstrated the critical role of proteinase-activated receptor (PAR2) in the pathogenesis of several types of inflammatory or neuropathic pain, the involvement of spinal PAR2 and the pertinent signaling in the central sensitization is not determined yet in the rodent model of bone cancer pain. FINDINGS: Implantation of tumor cells into the tibias induced significant thermal hyperalgesia and mechanical allodynia, and enhanced glutamatergic strength in the ipsilateral dorsal horn. Significantly increased brain-derived neurotrophic factor (BDNF) expression was detected in the dorsal horn, and blockade of spinal BDNF signaling attenuated the enhancement of glutamatergic strength, thermal hyperalgesia and mechanical allodynia in the rats with bone cancer pain. Significantly increased spinal PAR2 expression was also observed, and inhibition of PAR2 signaling ameliorated BDNF upsurge, enhanced glutamatergic strength, and thermal hyperalgesia and mechanical allodynia. Inhibition of NF-κB pathway, the downstream of PAR2 signaling, also significantly decreased the spinal BDNF expression, glutamatergic strength of dorsal horn neurons, and thermal hyperalgesia and mechanical allodynia. CONCLUSION: The present study demonstrated that activation of PAR2 triggered NF-κB signaling and significantly upregulated the BDNF function, which critically contributed to the enhancement of glutamatergic transmission in spinal dorsal horn and thermal and mechanical hypersensitivity in the rats with bone cancer. This indicated that PAR2 - NF-κB signaling might become a novel target for the treatment of pain in patients with bone cancer.

A systematic review and meta-analysis on the use of traditional Chinese medicine compound kushen injection for bone cancer pain.

PURPOSE: Bone cancer pain presents a clinical challenge with limitations of current treatments. Compound kushen injection (CKI) is a well-known traditional Chinese medicine (TCM) formulation in treatment of patients with bone cancer pain. The objective of this study is to assess the efficacy and safety of CKI for bone cancer pain. METHODS: A systematic literature search was conducted in nine databases until December 2012 to identify randomized controlled trials (RCTs) of CKI versus current western therapies for bone cancer pain. The primary outcome was total pain relief rate. The secondary outcomes were the quality of life and adverse events at the end of treatment course. The methodological quality of RCTs was assessed independently using six-item criteria according to the Cochrane Collaboration, and the level of evidence was assessed by the GRADE approach. All data were analyzed using Review Manager 5.1.0. RESULTS: Seven RCTs with 521 patients from 2010 to 2012 were identified. Compared with radiotherapy or bisphosphonates, seven RCTs showed significant effects of CKI for improving pain relief in patients with bone cancer pain (n = 521, risk ratio (RR) = 1.25, 95 % CI (95 % confidence intervals (CI)), 1.13 to 1.38, p < 0.0001)), three RCTs for improving Karnofsky scoring (KPS) increase rate (n = 305, RR = 1.62, 95 % CI, 1.32 to 1.99, p < 0.00001), 1 RCT for increasing KPS scores (n = 78, mean difference (MD) = 10.43, 95 % CI 4.76 to 16.10, p = 0.0003). 4 RCTs reported adverse effects in both the treatment and control groups. The patients treated with CKI achieved statistically significant reductions of incidences of leukopenia (n = 276, RR = 0.32, 95 % CI, 0.21 to 0.47, p < 0.00001) and nausea (n = 78, RR = 0.15, 95 % CI, 0.06 to 0.34, p < 0.00001). No severe adverse events were found and no treatment was stopped because of adverse events of CKI in the treatment groups. However, the studies were deemed to have a high risk of bias. CONCLUSION: This systematic review showed positive but weak evidence of CKI for bone cancer pain because of the poor methodological quality and the small quantity of the included trials. Future rigorously designed RCTs are required.

Involvement of protease-activated receptor 2 in nociceptive behavior in a rat model of bone cancer.

Treatment for bone cancer pain remains a clinical challenge due to a poor understanding of the underlying mechanisms. Protease-activated receptor 2 (PAR2), a receptor for inflammatory proteases, has been implicated in nociceptive signaling under both normal and pathologic pain states. However, little is known of the role of PAR2 in cancer-induced bone pain. Here we investigated the potential role of PAR2 in a rat model of bone cancer pain. The model of bone cancer pain was induced by inoculating Walker 256 into the tibia bone cavity of rats and verified by X-ray imaging, pathology, and behavior assessments. The rats with bone cancer exhibited marked mechanical allodynia, thermal hyperalgesia, and signs of spontaneous nocifensive behavior. Subcutaneous administration of the PAR2 antagonist FSLLRY-NH2 almost completely abolished mechanical allodynia and thermal hyperalgesia but had no effects on spontaneous pain behavior in the rats with bone cancer. Immunohistochemical study revealed that the expression of PAR2 was significantly increased in large- and medium-sized dorsal root ganglia (DRG) neurons but not in small-sized neurons after Walker 256 inoculation. These results suggest that the increased expression of PAR2 in the DRG may contribute to the development of mechanical allodynia and thermal hyperalgesia associated with bone cancer rats. PAR2 might become a novel target for the treatment of pain in patients with bone cancer.