Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.

BACKGROUND: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. PATIENTS AND METHODS: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. RESULTS: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. CONCLUSION: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

Submacular hemorrhage and grape-like polyp clusters: factors associated with reactivation of the lesion in polypoidal choroidal vasculopathy.

PurposeThe purpose of this study is to investigate the factors associated with reactivation of the lesion during the first year in patients with polypoidal choroidal vasculopathy (PCV) treated with intravitreal ranibizumab.Patients and methodsThis retrospective observational study included 84 eyes diagnosed with PCV and treated with 3-monthly ranibizumab injections. Only those patients who exhibited complete resolution of fluid after initial treatment and were followed up at least 12 months were included. The baseline characteristics of the patients, including their age and sex, location of the polyps, greatest linear dimensions of the lesions, largest polyp diameter, choroidal vascular hyperpermeability, submacular hemorrhages ≥1 disc area in size, presence of grape-like polyp clusters, central foveal thickness, and best-corrected visual acuity were compared between patients with and without reactivation of the lesion.ResultsDuring the 12-month follow-up period, reactivation of the lesion was observed in 60 patients (71.4%). The first reactivation was noted at a mean duration of 3.9±1.7 months after the third ranibizumab injection. Cox regression analysis revealed that the absence of submacular hemorrhages ≥1 disc area (P=0.009), presence of grape-like polyp clusters (P=0.002), and greatest linear dimension of the lesions (P=0.019) were associated with reactivation of the lesion.ConclusionThe absence of submacular hemorrhages, presence of grape-like polyp clusters, and large lesion size at diagnosis were associated with a high risk of reactivation of PCV in patients treated with intravitreal ranibizumab. Patients exhibiting these characteristics may require close monitoring.

Acute endophthalmitis after cataract surgery: 164 consecutive cases treated at a referral center in South Korea.

PurposeTo identify prognostic factors in patients referred with endophthalmitis after cataract surgery, and to evaluate the efficacy of primary vitrectomy as an initial management.MethodsOver an eight-year study period, we retrospectively reviewed the medical records of 164 patients who were referred with endophthalmitis following cataract surgery. Treatment generally conformed to standard guidelines, although primary vitrectomy was performed in several eyes with a visual acuity of hand motion or better, depending on the patient's status. Using multivariate analysis, we analyzed outcomes to determine the effect on final visual outcome.ResultsA final visual acuity of ≥20/40 was achieved in 92/164 (56.1%) cases after treatment. Bacterial cultures showed bacterial growth in 89/164 cases (54.3%). Among the various baseline characteristics, old age (P=0.028), poor visual acuity at presentation (P=0.004), gram-negative bacterial infection (P=0.030), and short time between cataract surgery and signs of endophthalmitis (P=0.021) were associated with poor visual outcome. The visual outcome showed no significant difference, in terms of initial treatment feature, between the primary vitrectomy with intraocular antibiotics injection (IOAI) and IOAI-only groups. However, reintervention was significantly less frequent in the primary vitrectomy group than in the IOAI group (12.5 and 32.7%, respectively; P=0.002).ConclusionOld age, poor visual acuity at presentation, type of cultured organism (gram-negative bacteria), and early onset of endophthalmitis after cataract surgery were significantly related to poor visual outcome after endophthalmitis treatment. Primary vitrectomy may decrease the need for reintervention to control infection, although the treatment showed no benefits with regard to visual outcome.

Cytokeratin19 induced by HER2/ERK binds and stabilizes HER2 on cell membranes.

Cytokeratin19 (KRT19) is widely used as a biomarker for the detection of disseminated tumors. Using an LC-MS/MS proteomics approach, we found that KRT19 was upregulated in HER2-overexpressing cells and tissues. KRT19 expression was induced by HER2-downstream ERK at the transcriptional level. Another HER2-downstream kinase, Akt, was found to phosphorylate KRT19 on Ser35 and induce membrane translocation of KRT19 and remodeling of KRT19 from filamentous to granulous form. KRT19 phosphorylated by Akt could bind HER2 on the plasma membrane and stabilized HER2 via inhibition of proteasome-mediated degradation of HER2. Silencing of KRT19 by shRNA resulted in increased ubiquitination and destabilization of HER2. Moreover, treatment of KRT19 antibody resulted in downregulation of HER2 and reduced cell viability. These data provide a new rationale for targeting HER2-positive breast cancers.

Effects of high-intensity intermittent running exercise in overweight children.

This study examined the effects of a 6-week intermittent exercise training, at different intensities, on body composition, functional walking and aerobic endurance in overweight children. Forty-eight overweight children (age: 10.4 ± 0.9 years) were randomly assigned to either intervention or control group. Lower and higher intensity intermittent exercise groups (LIIE and HIIE) performed intermittent running three times a week. LIIE performed more intervals at a lower intensity [16 intervals at 100% of individual maximal aerobic speed (MAS), 8 minutes in total], and HIIE performed fewer intervals at a higher intensity (12 intervals at 120% of MAS, 6 minutes in total). Each interval consisted of a 15-second run at the required speed, followed by a 15-second passive recovery. After 6 weeks, HIIE had a significantly (p < 0.05) higher percentage reduction in sum of skinfolds (i.e. calf and triceps), and significantly (p < 0.05) fewer steps during the functional obstacle performance, as compared with LIIE and control group. Significant improvement (p < 0.05) was found in intermittent aerobic endurance for HIIE as compared to the control group. Higher intensity intermittent training is an effective and time-efficient intervention for improving body composition, functional walking and aerobic endurance in overweight children.

Planar Hall magnetoresistive aptasensor for thrombin detection.

The use of aptamer-based assays is an emerging and attractive approach in disease research and clinical diagnostics. A sensitive aptamer-based sandwich-type sensor is presented to detect human thrombin using a planar Hall magnetoresistive (PHR) sensor in cooperation with superparamagnetic labels. A PHR sensor has the great advantages of a high signal-to-noise ratio, a small offset voltage and linear response in the low-field region, allowing it to act as a high-resolution biosensor. In the system presented here, the sensor has an active area of 50 µm × 50 µm with a 10-nm gold layer deposited onto the sensor surface prior to the binding of thiolated DNA primary aptamer. A polydimethylsiloxane well of 600-µm radius and 1-mm height was prepared around the sensor surface to maintain the same specific area and volume for each sensor. The sensor response was traced in real time upon the addition of streptavidin-functionalized magnetic labels on the sensor. A linear response to the thrombin concentration in the range of 86 pM-8.6 µM and a lower detection limit down to 86 pM was achieved by the proposed present method with a sample volume consumption of 2 µl. The proposed aptasensor has a strong potential for application in clinical diagnosis.

Long-term metformin use reduces gastric cancer risk in type 2 diabetics without insulin treatment: a nationwide cohort study.

BACKGROUND: Metformin use has been associated with a decreased incidence and mortality of various cancers. AIM: To evaluate the association between metformin use and gastric cancer. METHODS: We randomly selected 100 000 type 2 diabetic patients from the 2004 Korean National Health Insurance claim database, and assessed gastric cancer incidence among 39 989 patients (aged 30-97 years) who were regularly treated with anti-diabetic drugs and followed-up from 2004 to 2010. In total, 26 690 patients had used metformin out of 32 978 diabetics who had not regularly used insulin (insulin non-users), and 5855 patients had used metformin out of 7011 regular insulin users. RESULTS: Patients who used metformin showed a lower incidence of gastric cancer than those who did not use metformin, in insulin non-users (P = 0.047, log-rank test). However, in patients on regular insulin, there was no difference of gastric cancer incidence according to metformin use. In insulin non-users, the adjusted hazard ratio (AHR) for metformin use was 0.73 (95% confidential interval [CI], 0.53-1.01) with borderline statistical significance (P = 0.059). Duration of metformin use was associated with the reduction in gastric cancer risk (AHR, 0.88; 95% CI 0.81-0.96, P = 0.003), especially in patients who used metformin for more than 3 years (AHR, 0.57; 95% CI, 0.37-0.87; P = 0.009). CONCLUSION: Metformin use >3 years in type 2 diabetics who do not use insulin is associated with a significantly reduced gastric cancer risk.

Lentiviral modification of enriched populations of bovine male gonocytes.

Undifferentiated germ cells have the capacity to develop into sperm capable of fertilizing oocytes and contributing genetic material to subsequent generations. The most primitive prepubertal undifferentiated germ cells include gonocytes and undifferentiated spermatogonia, including spermatogonial stem cells (SSC). Gonocytes, present in the testis at birth, differentiate into SSC, which maintain spermatogenesis for the remainder of the male's life. Because of their capacity to contribute to lifelong spermatogenesis, undifferentiated germ cells are attractive targets for genetic modification to produce transgenic animals, including cattle. To maximize the efficiency of genetic modification of bovine gonocytes and SSC, effective enrichment techniques need to be developed. Selection of bovine gonocytes using differential plating was improved 8-fold (P < 0.001) when using a combination of extracellular matrix proteins, including laminin, fibronectin, collagen type IV, and gelatin, compared to using laminin and gelatin alone. Selected cells labeled with PKH26 formed colonies of donor-derived germ cells after transplantation into recipient mouse testes, indicating putative stem cell function. Significantly more colonies (P < 0.001) per 1 × 10(5) viable transplanted cells were formed from isolated nonadherent cells (203 ± 23.2) compared to adherent (20 ± 2.7) or Percoll (45.5 ± 4.5) selected cells. After selection, some gonocytes were transduced using a lentiviral vector containing the transgene for the enhanced green fluorescent protein. Transduction efficiency was 17%. Collectively, these data demonstrate effective methods for the selection and genetic modification of bovine undifferentiated germ cells.

Staging of intestinal- and diffuse-type gastric cancers with the OLGA and OLGIM staging systems.

BACKGROUND: Operative link on gastritis assessment (OLGA) and Operative link on gastric intestinal metaplasia assessment (OLGIM) staging systems have been proposed for gastric cancer (GC) risk estimation. AIM: To validate the OLGA and OLGIM staging systems in a region with high risk of GC. METHODS: This retrospective study included 474 GC patients and age- and sex-matched health screening control persons in a cancer centre hospital. We classified gastritis patterns according to the OLGA and OLGIM systems using the histological database that a pathologist prospectively evaluated using the updated Sydney system. GC risk according to the OLGA and OLGIM stages was evaluated using logistic regression analysis. RESULTS: More GC patients had OLGA stages III-IV (46.2%) than controls (26.6%, P < 0.001), particularly among patients with intestinal-type GCs (62.2%) compared with diffuse-type GCs (30.9%). OLGA stages III and IV were significantly associated with increased risk of GC [odds ratios (ORs), 2.09; P = 0.008 and 2.04; P = 0.014 respectively] in multivariate analysis. The association was more significant for intestinal-type (ORs, 4.76; P = 0.001 and 4.19; P = 0.002 respectively), but not diffuse-type GC. OLGIM stages from I to IV were significantly associated with increased risk of both intestinal-type (ORs, 3.64, 5.15, 7.89 and 13.20 respectively) and diffuse-type GC (ORs, 1.84, 2.59, 5.08 and 6.32 respectively) with a significantly increasing trend. CONCLUSION: As high OLGA and OLGIM stages are independent risk factors for gastric cancer, the staging systems may be useful for risk assessment in high-risk regions, especially for intestinal-type gastric cancer.

Randomised clinical trial: the effects of Helicobacter pylori eradication on glandular atrophy and intestinal metaplasia after subtotal gastrectomy for gastric cancer.

BACKGROUND: Helicobacter pylori eradication is recommended for early gastric cancer (GC) patients after resection. AIM: To evaluate whether H. pylori eradication improves glandular atrophy and intestinal metaplasia (IM) in GC patients undergoing subtotal gastrectomy. METHODS: This randomised, double-blind trial was performed in tertiary care setting. Distal GC patients with H. pylori infection were randomised to receive proton pump inhibitor-based triple therapy or placebo. The histology was evaluated using the updated Sydney system before and at 36 months after surgery. The endpoints were the comparison of atrophy and IM score changes between the allocated groups and according to final H. pylori status. RESULTS: Overall, 190 patients were randomised to the treatment and placebo groups. For lesser curvature of the corpus, mean atrophy and IM scores did not differ between the treatment and placebo groups. However, the H. pylori-eradicated patients had significantly lower mean scores than the H. pylori-persistent patients regarding atrophy (0.55 ± 0.95 vs. 1.05 ± 1.10 respectively; P = 0.0046) and IM (0.66 ± 0.99 vs. 1.05 ± 1.16 respectively; P = 0.0284). The percentage change from baseline was more marked in the H. pylori-negative than in the H. pylori-positive groups (-58.6% vs. -11.0% for atrophy and -60.5% vs. -35.6% for IM respectively). For greater curvature, mean atrophy score was lower in the H. pylori-negative group than in the H. pylori-positive group (0.14 ± 0.50 vs. 0.41 ± 0.75 respectively; P = 0.0281). The percentage change was -36.4% vs. 86.3%. CONCLUSION: Helicobacter pylori eradication in GC patients is beneficial, as reflected by lower scores of atrophy and IM at 36 months after subtotal gastrectomy. (ClinicalTrials.gov number, NCT01002443).