Pneumonitis and pneumonitis-related death in cancer patients treated with programmed cell death-1 inhibitors: a systematic review and meta-analysis.

PURPOSE: We conducted a meta-analysis of published clinical trials to determine the relationship between the risks of pneumonitis and pneumonitis-related death and programmed cell death-1 (PD-1) inhibitor treatment in patients with cancer. MATERIALS AND METHODS: We examined clinical trials from the Medline and Google Scholar databases. Data from original studies and review articles were also cross-referenced and evaluated. Randomized Phase II and Phase III trials of pembrolizumab and nivolumab treatment in patients with cancer were eligible for the analysis. Information about the participants, all-grade and high-grade pneumonitis, and pneumonitis-related death was extracted from each study and analyzed. RESULTS: After the exclusion of ineligible studies, 12 clinical trials were included in the analysis. The odds ratio (OR) for all-grade pneumonitis after PD-1 inhibitor treatment was 4.59 (95% confidence interval [CI]: 2.51-8.37; P<0.00001), and the OR for high-grade pneumonitis after PD-1 inhibitor treatment was 3.83 (95% CI: 1.54-9.48; P=0.004). The OR for pneumonitis-related death after PD-1 inhibitor treatment was 2.47 (95% CI: 0.41-14.81; P=0.32). Moreover, the OR for all-grade pneumonitis after nivolumab/ipilimumab combination therapy versus nivolumab monotherapy was 3.54 (95% CI: 1.52-8.23; P=0.003), and that for high-grade pneumonitis after nivolumab/ipilimumab combination therapy versus nivolumab monotherapy was 2.35 (95% CI: 0.45-12.13; P=0.31). Treated cancer appeared to have no effect on the risk of pneumonitis. CONCLUSION: Our data showed that PD-1 inhibitors were associated with increased risks of all-grade and high-grade pneumonitis compared with chemotherapy or placebo controls in patients with cancer. However, we noted no significant difference between patients treated with a PD-1 inhibitor and patients treated with control regimens with respect to the risk of pneumonitis-related death.

Expression of HSPA2 in human hepatocellular carcinoma and its clinical significance.

Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide. HSPA2 has been highlighted as an important marker in many types of cancers. However, little is known about the role of HSPA2 in HCC. The objective of the current study was to investigate the expression pattern and clinicopathological significance of HSPA2 in patients with HCC. Quantitative reverse-transcriptase ploymerase chain reaction (qRT-PCR) was applied to examine HSPA2 messenger RNA (mRNA) expression in 52 pairs of HCC tissues and adjacent noncancerous tissues. Immunohistochemistry (IHC) was performed to examine HSPA2 protein expression in paraffin-embedded tissues from 119 HCC patients. Statistical analyses were applied to evaluate the diagnostic value and associations of HSPA2 expression with clinicopathological characteristics. We identified abnormally elevated mRNA expression of HSPA2 in HCC tissues compared to paired adjacent noncancerous tissues (P < 0.001). Clinicopathological analysis showed that HSPA2 expression was significantly correlated with tumor size (P = 0.013), histological differentiation (P = 0.04), and tumor stage (P = 0.001). Patients with higher HSPA2 expression had shorter overall survival time, whereas those with lower HSPA2 expression had longer survival time. Furthermore, Cox regression analyses showed that HSPA2 expression was an independent predictor of overall survival. In conclusion, our findings provide evidences that positive expression of HSPA2 in HCC may be important in the acquisition of an aggressive phenotype and it is an independent biomarker for poor prognosis of patients with HCC.

Curcumin inhibits lung cancer progression and metastasis through induction of FOXO1.

Recent population studies provide clues that the use of curcumin may be associated with reduced incidence and improved prognosis of certain cancers. In the present study, we demonstrated that curcumin acted as a growth inhibitor for lung cancer cells. Our results found that curcumin inhibited cell proliferation, which was associated with upregulation of the cyclin-dependent kinase inhibitors, p27 and p21, and downregulation of cyclin D1. In addition, we showed that curcumin induced the expression of forkhead box protein O1 (FOXO1) through activation of extracellular signal-regulated kinase 1/2 signaling. These findings provide evidence for a mechanism that may contribute to the antineoplastic effects of curcumin and justify further work to explore potential roles for activators of FOXO1 in the prevention and treatment of lung cancer.

Influence of intensive insulin therapy on vascular endothelial growth factor in patients with severe trauma.

The influence of early-stage intensive insulin therapy on the plasma levels of vascular endothelial growth factor (VEGF) and the related parameters in patients with severe trauma and the clinical implication were investigated. Sixty-four cases of severe trauma (injury severity score ≥20) with stress hyperglycemia (blood glucose >9 mmol/L) were randomly divided into intensive insulin therapy group and conventional therapy group. ELISA method, radioimmunoassay and density gradient gradation one-step process were used to determine plasma VEGF, endothelin-1 (ET-1), and the number of circulating endothelial cells (CECs) at the day of 0, 2, 3, 5 and 7 after admission. Simultaneously, the changes of CRP concentration in plasma were monitored to evaluate inflammatory response. The results showed that plasma levels of observational indexes in patients receiving early-stage intensive insulin therapy were all significantly lower than those in conventional therapy groups 2, 3, 5 and 7 days after admission [for VEGF (ng/L), 122.2±23.8 vs. 135.9±26.5, 109.6±27.3 vs. 129.0±18.4, 88.7±18.2 vs. 102.6±27.3, 54.2±26.4 vs. 85.7±35.2, P<0.05, 0.01, 0.05, 0.05 respectively; for ET-1 (ng/L), 162.8±23.5 vs. 173.7±13.2, 128.6±17.5 vs. 148.8±22.4, 96.5±14.8 vs. 125.7±14.8, 90.7±16.9 vs. 104.9±22.5, P<0.05, 0.01, 0.01, 0.01 respectively; for CRP (mg/L), 23.2±13.8 vs. 31.9±16.5, 13.6±17.3 vs. 23.5±18.4, 8.7±10.2 vs. 15.6±13.3, 5.2±9.4 vs. 10.7±11.2, all P<0.05; for CECs (/0.9 µL), 10.9±5.6 vs. 13.9±6.2, 8.5±4.9 vs. 11.3±5.3, 6.3±6.4 vs. 9.4±5.7, 4.8±7.1 vs. 7.8±4.8, all P<0.05]. It was concluded that intensive insulin therapy could antagonize the endothelium injury after trauma and reduce inflammation response quickly, which was one of important mechanisms by which intensive insulin therapy improves the prognosis of trauma patients.

[Effect of early intensive insulin therapy on high mobility group box 1 protein levels and prognosis of patients with severe trauma].

OBJECTIVE: To study the effect of intensive insulin therapy on serum high mobility group box 1 (HMGB1) levels and its relationship with the prognosis in early phase of severe trauma. METHODS: Eighty severe trauma patients [injury severity score (ISS)≥ 16] were divided into groups according to injury to matched anatomical regions. Forty patients of intensive therapy group were given early intensive insulin therapy, while another 40 patients of the conventional treatment group received routine treatment based on clinical experience with insulin treatment. The insulin dose and the blood glucose levels were recorded within 72 hours after treatment. The relationship between HMGB1 levels and prognosis was analyzed by testing serum HMGB1 levels at 24, 36, 48, 60 or 72 hours after treatment, and clinical terminal events such as multiple organ dysfunction syndrome (MODS) and death rate within 1 week were recorded. Results The insulin dose of intensive therapy group was significantly greater than that of conventional treatment group following the blood glucose levels were significantly lower than those of the conventional treatment group after treatment for 72 hours. The levels of HMGB1 (µg/L) lowered after intensive insulin therapy for 36 hours , and were significantly lower than those of conventional treatment group at 36, 48, 60 and 72 hours after intensive treatment (36 hours: 41.3 ± 9.5 vs. 52.7 ± 11.5, 48 hours: 48.6 ± 17.6 vs. 124.1 ± 22.9, 60 hours: 47.7 ± 23.3 vs. 132.9 ± 33.4, 72 hours: 54.3 ± 26.3 vs. 140.6 ± 16.5, P <0.05 or P <0.01). The incidence of MODS and mortality in intensive therapy group was respectively significantly lower than that of the conventional treatment group (20.0% vs. 55.0%, 10.0% vs. 30.0%, both P <0.05). In conventional treatment group the patients with HMGB1 ≥ 132.26 µg/L ( n =22) occurred MODS, and those with HMGB1<132.26 µg/L ( n =18) did not occur MODS. The HMGB1 levels in death patients ( n =12) were ≥ 132.26 µg/L. CONCLUSION: Early intensive insulin treatment could probably reduce MODS and mortality by inhibiting stress hyperglycemia and serum HMGB1 levels effectively. Serum HMGB1 of severe trauma patients can be used for the clinical indicator of prognosis.

[Effects of intensive insulin therapy on serum immunoglobulin, complement levels and phagocytosis of monocytes in patients with severe trauma].

OBJECTIVE: To investigate the influence of intensive insulin therapy on serum immunoglobulin (Ig), complement levels and phagocytosis of monocytes in patients with severe trauma. METHODS: Severe injured patients with injury severity score (ISS)>20 in surgical intensive care unit (ICU) were randomly divided into two groups, intensive insulin therapy and conventional therapy. Blood glucose levels in intensive insulin therapy and conventional therapy groups were maintained at 4-6 mmol/L and <11.1 mmol/L, respectively. Blood samples were obtained on 0, 2, 4, 6 and 8 days after admission. Dynamic changes of immunological parameters including serum IgA, IgG, IgM, complements (C3, C4) levels were determined in each group at various intervals following trauma. Phagocytosis of monocytes was also measured by use of phagotest kits after blood cells were incubated with fluorescein isothiocyanate (FITC)-labeled E. coli in a heated water bath at 37 centigrade. RESULTS: Serum IgA, IgG, IgM, C3 and C4 levels were low in two groups at admission, and elevated after treatment with recovery to normal range on 6-8 days. Serum C3 and C4 levels in intensive insulin therapy group were much lower than those in conventional therapy group (both P<0.05) with delayed recovery to normal range. There were no significant differences in serum IgA, IgG and IgM levels between two groups (all P>0.05). For the patients with intensive insulin therapy, phagocytosis of monocytes was markedly enhanced on 4 and 6 days compared with those at admission (both P<0.05), and E. coli-FITC positive rates were significantly higher than those with conventional therapy on 2, 4 and 6 days after admission (all P<0.05). CONCLUSION: Intensive insulin therapy can markedly improve immune function and enhance phagocytosis of monocytes, which might be used as one of effective methods to increase the host defense ability in traumatic patients.

[Suggestive guideline for respiratory support in emergency--stepwise breath management].

OBJECTIVE: To propose a guideline of respiratory support for emergency patients. METHODS: To summarize the experiences gained in giving stepwise respiratory support (SRS) in 2,548 patients for emergency care (including 1,823 trauma patients and 725 non-trauma patients) between 1992 to 2002. RESULTS: There were 1,876 male and 672 female patients with the ratio of male to female 2.79:1. The age of patients ranged between 4 to 86 years, and the mean age of traumatic patients was (32.3+/-19.8) years, and the dominant ages were between 20 to 39. The mean age of non-traumatic patients was (65.2+/-17.3) years, and the dominant ages were between 50 to 69. The traumatic and non-traumatic patients accounted for 60.2% and 32.0% of all patients, respectively. The respiratory management included resuscitation positioning in 816 (32.0%), open airway and suctioning in 314 patients (12.3%), oxygenation through nostril or nasal intubation in 2,311 patients (90.7%), oxygenation by mask in 124 patients (4.9%), endotracheal intubation in 254 patients (10.0%), thyrocricocentesis or cricothyrotomy in 25 patients (1.0%), tracheotomy in 195 patients (7.7%), percutaneous tracheotomy in 58 patients (2.3%). SRW management included two types, four steps and ten ways. The two types included traumatic and non-traumatic; the four steps and ten ways included first step of manual treatment (including (1) resuscitation positioning, (2) open airway and suction and (3) chest-back press), second step oxygenation (including (4) oxygenation through nostril or nasal intubation, (5) oxygenation by mask, (6) endotracheal intubation), third step invasive airway support (including (7) thyrocricocentesis or cricothyrotomy and (8) tracheotomy or percutaneous tracheostomy), fourth step mechanic ventilation (covering (9) manual ventilation and (10) mechanical ventilator). CONCLUSION: The series of SRS management plan and principles can improve the respiratory support in rescuing emergency patients efficiently.