Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC.

Introduction: IMpower110 previously revealed significant overall survival (OS) benefit with atezolizumab versus chemotherapy in patients with treatment-naive EGFR- and ALK-negative (wild type [WT]) metastatic NSCLC with high programmed death-ligand 1 (PD-L1) expression (≥50% on tumor cells [TCs] or ≥10% on tumor-infiltrating immune cells [ICs], per SP142 immunohistochemistry assay; p = 0.0106). We present primary OS analyses in lower PD-L1 expression groups and an updated, exploratory analysis in the high PD-L1 expression group.

Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC.

Background: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known.

Methods: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy.

Lymph node-independent liver metastasis in a model of metastatic colorectal cancer.

Deciphering metastatic routes is critically important as metastasis is a primary cause of cancer mortality. In colorectal cancer (CRC), it is unknown whether liver metastases derive from cancer cells that first colonize intestinal lymph nodes, or whether such metastases can form without prior lymph node involvement. A lack of relevant metastatic CRC models has precluded investigations into metastatic routes.

Increased glucocerebrosidase (GBA) 2 activity in GBA1 deficient mice brains and in Gaucher leucocytes.

Lysosomal glucocerebrosidase (GBA1) deficiency is causative for Gaucher disease. Not all individuals with GBA1 mutations develop neurological involvement raising the possibility that other factors may provide compensatory protection. One factor may be the activity of the non-lysosomal β-glucosidase (GBA2) which exhibits catalytic activity towards glucosylceramide and is reported to be highly expressed in brain tissue.

No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease.

Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by defects in the activity of the lysosomal enzyme, glucocerebrosidase, resulting in intracellular accumulation of glucosylceramide (GlcCer). Neuronopathic forms, which comprise only a small percent of GD patients, are characterized by neurological impairment and neuronal cell death. Little is known about the pathways leading from GlcCer accumulation to neuronal death or dysfunction but defective calcium homeostasis appears to be one of the pathways involved.

Successful low-risk hematopoietic cell therapy in a mouse model of type 1 Gaucher disease.

Hematopoietic stem cell-based gene therapy offers the possibility of permanent correction for genetic disorders of the hematopoietic system. However, optimization of present protocols is required before gene therapy can be safely applied as general treatment of genetic diseases. In this study we have used a mouse model of type 1 Gaucher disease (GD) to demonstrate the feasibility of a low-risk conditioning regimen instead of standard radiation, which is associated with severe adverse effects.

Murine models of acute neuronopathic Gaucher disease.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucosidase, beta, acid (GBA) gene that encodes the lysosomal enzyme glucosylceramidase (GCase). GCase deficiency leads to characteristic visceral pathology and, in some patients, lethal neurological manifestations. Here, we report the generation of mouse models with the severe neuronopathic form of GD.

Effective cell and gene therapy in a murine model of Gaucher disease.

Gaucher disease (GD) is a lysosomal storage disorder due to an inherited deficiency in the enzyme glucosylceramidase (GCase) that causes hepatosplenomegaly, cytopenias, and bone disease as key clinical symptoms. Previous mouse models with GCase deficiency have been lethal in the perinatal period or viable without displaying the clinical features of GD. We have generated viable mice with characteristic clinical symptoms of type 1 GD by conditionally deleting GCase exons 9-11 upon postnatal induction.

Stercoraceous perforation of the right colon.

We have reported a case of stercoraceous perforation of the right colon with peritonitis. Stercoraceous perforation should be considered in patients with an acute condition of the abdomen, radiologic evidence of a perforated viscus, and a long-standing history of constipation. The condition is rare and has a high mortality.

Intestinal obstruction due to schistosomiasis.

We have described a patient with intestinal obstruction caused by schistosomiasis but closely resembling colon carcinoma. The cause, demography, pathologic characteristics, and clinical management of the disease caused by Schistosoma mansoni are reviewed.

A comparison of the open and closed methods of anastomosis for colostomy closure.

A transverse colostomy was performed in dogs and, later, closed by resection and anastomosis. Half the anastomoses were done by the open and half by the closed method. The anastomoses were evaluated by barium enema series and by gross and microscopic examination.

The time at which infected postoperative wounds demonstrate increased strength.

It was again shown in this study that laparotomy wounds purposely infected with a known inoculum of live gram-negative bacteria exhibited greater tensile strength than did those in the normal control group. The organisms used were Escherichia coli and Pseudomonas aeruginosa. The phenomenon was not present during the first ten days after wounding but was quite evident in wounds tested at 14 and 21 days.

A study of the critical bacterial inoculum to cause a stimulus to wound healing.

Results of previous work have shown that wounds infected with gram-negative bacteria may be stronger than uninfected wounds. The inoculum in these studies was about 2 X 10(7) organisms. Laparotomy wounds were swabbed with inocula of from 10(2) to 10(9) organisms, Escherichia coli.

Quantitation of local acidosis and hypoxia produced by infection.

Increased strength of healing incisions infected with E coli was demonstrated in this experiment. Efforts to measure respiratory gas tensions and pH in these incisions were unsuccessful. Therefore, these moieties were measured in normal and infected wound fluid contained in implanted wire cylinders.

Accelerated healing in infected wounds.

The effect of a standardized infection of pure and mixed cultures of gram-negative bacteria and a gram-positive coccus was studied in laparotomy wounds of rats. The infections were significantly stronger than in the control group wounds in 14 of 15 comparisons. This increased strength could not be correlated with an increased wound content of collagen.

Effect of partial constriction of the superior mesenteric artery upon absorption of d-xylose, labeled triolein and labeled albumin.

Intestinal adsorption of triolein, Risa and d-xylose was determined before and after reduction of blood flow in the superior mesenteric artery. Absorption of d-xylose did not change, but absorption of triolein and Risa appeared to be slightly improved after arterial constriction, even if the artery was completely thrombosed. Enhancement in absorption of Risa and triolein was probably the result of extensive collateral formation around the constricted superior mesenteric artery.