Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials

Objective: Report efficacy findings from three clinical trials (one phase 2 and two phase 3 [OPUS-1, OPUS-2]) of lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease (DED).

Research design and methods: Three 84-day, randomized, double-masked, placebo-controlled trials. Adults (≥18 years) with DED were randomized (1:1) to lifitegrast 5.0% or matching placebo. Changes from baseline to day 84 in signs and symptoms of DED were analyzed.

Main outcome measures: Phase 2, pre-specified endpoint: inferior corneal staining score (ICSS; 0–4); OPUS-1, coprimary endpoints: ICSS and visual-related function subscale (0–4 scale); OPUS-2, coprimary endpoints: ICSS and eye dryness score (EDS, VAS; 0–100).

Results: Fifty-eight participants were randomized to lifitegrast 5.0% and 58 to placebo in the phase 2 trial; 293 to lifitegrast and 295 to placebo in OPUS-1; 358 to lifitegrast and 360 to placebo in OPUS-2. In participants with mild-to-moderate baseline DED symptomatology, lifitegrast improved ICSS versus placebo in the phase 2 study (treatment effect, 0.35; 95% CI, 0.05–0.65; p?=?0.0209) and OPUS-1 (effect, 0.24; 95% CI, 0.10–0.38; p?=?0.0007). Among more symptomatic participants (baseline EDS ≥40, recent artificial tear use), lifitegrast improved EDS versus placebo in a post hoc analysis of OPUS-1 (effect, 13.34; 95% CI, 2.35–24.33; nominal p?=?0.0178) and in OPUS-2 (effect, 12.61; 95% CI, 8.51–16.70; p?<?0.0001).

Limitations: Trials were conducted over 12 weeks; efficacy beyond this period was not assessed.

Conclusions: Across three trials, lifitegrast improved ICSS in participants with mild-to-moderate baseline symptomatology in two studies, and EDS in participants with moderate-to-severe baseline symptomatology in two studies. Based on the overall findings from these trials, lifitegrast shows promise as a new treatment option for signs and symptoms of DED.     

Prognostic Nutritional Index and Clinical Response in Locally Advanced Cervical Cancer

Abstract

Background: The prognostic nutritional index (PNI), a marker of immune-nutrition balance, has predictive value in the survival and prognosis of various cancers. However, the impact of PNI on response to chemoradiation is poorly understood.

Materials and Methods: A total of 583 women with locally advanced cervical cancer from two centers were clinically assessed for complete response after chemoradiation. The baseline PNI was individually recorded, and the significance of association between PNI and complete response was analyzed using logistic regression. ROC (receiver operating characteristics) curves were analyzed to determine the cutoff value of PNI that significantly predicted complete response.

Results: Logistic regression analysis demonstrated that the PNI was significantly associated with complete response following chemo radiation (p?<?0.0001). Analysis of the ROC curve for PNI demonstrated an optimal cut off value of 44.8 (p?<?0.0001, sensitivity 66.7, and specificity 88.5); the area under the ROC curve was 0.813 (Youden’s index J, 0.7519).

Conclusions: The PNI is significantly associated with clinical complete response to chemoradiation in locally advanced cervical cancer. Low baseline PNI may lower the likelihood of complete response after chemoradiation. In particular, those with PNI values below 44 should be carefully monitored during treatment; nutritional interventions may offer benefit in these women.     

不同器官细胞因子在多细菌感染性炎症时的基因表达和临床意义

目的探讨肝、肺细胞因子基因表达与腹腔吞噬细胞上清液、循环血中细胞因子含量的关系,为临床诊治多细菌感染引发的炎症提供实验依据.方法将30只小鼠分为假手术对照组(sham组)和盲肠结扎组(CLP组).采用RT-PCR法检测肝脏和肺脏肿瘤坏死因子α(TNF-α)和白细胞介素10(IL-10)的基因表达情况,采用ELISA法检测腹腔巨噬细胞上清液和循环血液中相应细胞因子含量.结果CLP组的TNF-α、IL-10基因表达和腹腔巨噬细胞上清液、循环血液中的相应细胞因子含量均高于sham组.CLP后18h组与4h组比较,TNF-α在腹腔巨噬细胞上清液、循环血液中的活性均有显著性差异(P＜0.05),在肝、肺中基因表达有非常显著性差异(P＜0.01);IL-10在腹腔巨噬细胞上清液和循环血液中的含量无显著性差异,而在肝、肺中基因表达有显著性差异.结论发生多细菌感染性炎症时,肝、肺参与细胞因子的表达;血液中细胞因子含量不能完全代表组织器官内的基因表达情况;多细菌感染性炎症治疗应考虑靶器官细胞因子的表达状态.     

Hyperfractionated radiation therapy and concurrent 5-fluorouracil, cisplatin and mitomycin-C in head and neck carcinoma. A pilot study.

Seventeen patients were entered into a Phase I/II trial of concurrent hyperfractionated radiation therapy (7,440 cGy total dose; 120 cGy b.i.d.) combined with constant infusion of 5-fluorouracil (5-FU) (1,000 mg/m2/24 hours for 72 hours) and cisplatin (DDP) (50 mg/m2) for a total of three cycles. Thirteen patients had Stage IV disease; three, Stage III disease; and one, Stage II hypopharyngeal disease. Thirteen of 17 patients had positive cervical lymph nodes, and the mean size of the largest lymph node was 5.5 x 5.1 cm. The patients were not treated with planned adjunctive surgery except for one patient who had a radical neck dissection for massive, rapidly growing cervical adenopathy, which recurred promptly within 1 month before the initiation of protocol therapy. After the initial six patients were entered, mitomycin-C (Mito 8 mg/m2) was added during the second cycle. All the patients completed the planned course of radiotherapy with a median dose of 7,440 cGy and a mean dose of 7,248 cGy except for two patients who died--one from toxicity and the other, suicide. The predominant toxicity was mucositis, which was grade 3/4 in 11 of 15 patients, resulting in an average interruption of radiation therapy of 12 days. Weight loss was significant and was on the average 12% of baseline weight. Hematological toxicity was mild in the 5-FU/DDP group (only one grade 3 toxicity of six) and severe in the 5-FU/DDP/Mito-treated patients (five of eight patients having grade 3/4 toxicity including one leukopenic pneumonitis death). Additional toxicity included one parapharyngeal cellulitis, which responded to antibiotics. Noncompliance with the complex regimen was only seen in three patients. One patient refused b.i.d. radiation therapy, and one patient refused further chemotherapy after the first cycle. Additionally, one patient who had a severe ethanol withdrawal reaction during the first cycle of 5-FU/DDP did not receive further chemotherapy. The complete response rate of both primary site and neck by the protocol regimen alone was 71%. However, two patients, one from each group, did undergo salvage neck dissection, and the locoregional control is currently 73%, with a mean follow-up time of 18.4 months. The feasibility of combining hyperfractionated radiation therapy with aggressive concurrent chemotherapy was demonstrated. The response and local control rate justifies the added toxicity of concurrent chemotherapy and radiation therapy.     

New strategies are needed in diffuse malignant mesothelioma.

BACKGROUND. Medical records of 50 patients with malignant mesothelioma were reviewed to determine the clinical features and factors influencing survival. METHODS. Charts of all patients whose conditions were diagnosed as malignant mesothelioma were abstracted and analyzed by statistical software. RESULTS. The male-to-female ratio was 4:1. The age distribution was younger than 45 years of age, 10%; 45-54 years of age, 12%; 55-64 years of age, 37%; 65-74 years of age, 33%; and 75 years of age or older, 8%. Both mean and median ages were 58 years. Among the 32 patients in whom asbestos exposure was recorded, 24 had documented exposure. The sites were pleura, 73%; peritoneum, 20%; and both, 6%. The histologic types were epithelial, 51%; sarcomatous, 10%; mixed, 15%; and not specified, 24%. The stage at presentation was Stage I, 37%; II, 39%; III, 12%; IV, 6%; and unknown, 6%. The common symptoms in pleural disease were dyspnea and pain; in peritoneal disease, abdominal distension and pain were common. The median time from first symptom to diagnosis was 3 months (range, 0-23 months). The median survival after the appearance of symptoms, the diagnosis, and the treatment were 13, 10, and 8 months, respectively. CONCLUSIONS. The survival was independent of age, sex, and smoking behavior. It was longer in patients with earlier-stage disease, a good performance status, a longer duration of symptoms, an absence of pain, and who were treated with combined surgery and chemotherapy. Chemotherapy using anthracyclines yielded more remissions (9 of 21) than that using nonanthracyclines (0 of 13). The remission rate after primary chemotherapy with anthracyclines (7 of 16) may be higher than in recurrent tumor (2 of 14). In future trials, stratification into primary chemotherapy and chemotherapy of recurrent cancer is suggested. There is a need for multitechnique trials incorporating primary chemotherapy.     

Spirometric indices of early airflow obstruction.

Thirty cigarette smokers and 25 non-smoking controls, all men were evaluated by history, physical examination and simple spirometry. The history and physical examination were not of much use in predicting airflow obstruction. Forced mid-expiratory flow (FEF 25-75%) was abnormally low in 23 of the 30 subjects, while forced expiratory volume in 1 second (FEV1) and FEV1/FVC (forced vital capacity) were less sensitive. Thus simple spirometry is a useful screening tool to detect early airflow obstruction even when it is clinically undetectable.     

Resting energy expenditure and nutritional state of patients with increased oxygen cost of breathing due to emphysema, scoliosis and thoracoplasty.

BACKGROUND--Weight loss is a well recognised feature of patients with emphysematous chronic obstructive pulmonary disease (COPD). It has been suggested that this weight loss could be due to a hypermetabolic state resulting from the increased oxygen cost of breathing (OCB). To clarify the relation between resting energy expenditure (REE), nutritional state, and OCB these indices were measured in patients with respiratory impairment and an increased OCB due to COPD, scoliosis, and thoracoplasty. METHODS--Eighteen patients (six COPD, six scoliosis, six thoracoplasty) of mean (SD) age 59.9 (8.6) years (8M, 10F) and six controls (45.5 (9.9) years; 2M, 4F) were studied. OCB was estimated by the addition of dead space to the breathing circuit and REE was measured by indirect calorimetry using a ventilated canopy system. Height, arm span, weight, triceps skin fold thickness (TSF), mid-arm muscle circumference (MAMC), forced expiratory volume in one second (FEV1), and vital capacity (VC) were measured in all study subjects. RESULTS--OCB was elevated in all patient groups (mean 7.0 ml/l) compared with controls (1.9 ml/l). All patients with COPD, four with scoliosis, three with thoracoplasty, and none of the controls were < 90% ideal body weight. Mean (SD) measured REE as % predicted (Harris-Benedict equation) was 103.8 (7.6) in patients with COPD, 105.5 (10.9) in those with scoliosis, 106.3 (6.9) in the thoracoplasty patients, and 103.3 (3.4) in controls. One patient with COPD, two with scoliosis, two with thoracoplasty, but no controls were hypermetabolic (REE > 110% predicted). In all groups there was a negative relation between OCB and lung function (OCB v FEV1 r = -0.83 in COPD, -0.62 in scoliosis, -0.67 in thoracoplasty, and -0.76 in controls). There was no correlation between REE and OCB or MAMC. CONCLUSIONS--In patients with respiratory disease OCB (augmented ventilation) is related to lung function but not to REE. This is evidence against the hypothesis that hypermetabolism due to increased oxygen cost of breathing at rest is the sole or major cause of malnutrition in patients with lung disease.