Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in many developed countries. Mitochondrial oxidative stress is considered to be the predominant cellular event in APAP-induced liver injury. Accordingly, N-acetyl cysteine, a known scavenger of reactive oxygen species (ROS), is recommended as an effective clinical antidote against APAP-induced acute liver injury (AILI) when it is given at an early phase; however, the narrow therapeutic window limits its use. Hence, the development of novel therapeutic approaches that can offer broadly protective effects against AILI is clearly needed. To this end, it is necessary to better understand the mechanisms of APAP hepatotoxicity. Up to now, in addition to mitochondrial oxidative stress, many other cellular processes, including phase I/phase II metabolism, endoplasmic reticulum stress, autophagy, sterile inflammation, microcirculatory dysfunction, and liver regeneration, have been identified to be involved in the pathogenesis of AILI, providing new targets for developing more effective therapeutic interventions against APAP-induced liver injury. In this review, we summarize intracellular and extracellular events involved in APAP hepatotoxicity, along with emphatic discussions on the possible therapeutic approaches targeting these different cellular events.

Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions.

Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR). Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death.

https://www.mdpi.com/1422-0067/18/5/1018/pdf

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

Drug-induced toxicity is a key issue for public health because some side effects can be severe and life-threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug-induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug-induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug-induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

https://hal-univ-rennes1.archives-ouvertes.fr/hal-01269898/document

Role of endoplasmic reticulum stress in drug‐induced toxicity

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.27939

Receptor interacting protein kinase 1 mediates murine acetaminophen toxicity independent of the necrosome and not through necroptosis

Endoplasmic reticulum stress and liver diseases

CHOP is a critical regulator of acetaminophen-induced hepatotoxicity

Percutaneous dilational tracheostomy (PDT) is a commonly used technique in intensive care units (ICUs) for persistent respiratory failure. Early complications of placement includeairway loss, bleeding, and tracheal ring fracture. Tracheostomy tube fracture is a rarely reported complication that can lead to loss of airway and require emergent intervention. We present two case reports of tracheostomy flange fracture and dislocation after PDT. Shortly after insertion, the tracheostomy flange was incidentally noted to have irreparably fractured and separated from the outer cannula. Both patients were orotracheally intubated and converted to open revisional surgical tracheostomy. Outer cannula separation from the flange is a rare but important complication of PDT due to the risk of occult airway loss. The tracheostomy tube supplied in the PDT set is manufactured in three parts and the plastic outer cannula is snapped to the silicone flange during manufacturing. The flange is not meant to be separated during insertion or use. PDT insertion requires significant force to be exerted, as the catheter has to travel through the subcutaneous tissue of the neck before entering the trachea. These cases suggest that the junction of the flange and the outer cannula may be a weak point and that fracture and dislocation at that site may occur due to excessive or misdirected force. Dislocation may cause loss of airway and a need for orotracheal intubation as performed in our cases. Understanding this complication and carefully examining the flange after placement is essential for early recognition to avoid loss of airway.

Flange Fracture and Dislocation: An Unusual Complication of Percutaneous Tracheostomy

BACKGROUND
The neutrophil to lymphocyte ratio (NLR) has demonstrated prognostic value in various malignant conditions, including gastric adenocarcinoma. However, chemotherapy may affect NLR.


OBJECTIVES
To evaluate the prognostic value of NLR as an accessory decision-making tool in terms of operating patients after neoadjuvant chemotherapy in patients with resectable gastric cancer.


METHODS
We collected oncologic, perioperative, and survival data of patients with gastric adenocarcinoma who underwent curative intent gastrectomy and D2 lymphadenectomy between 2009 and 2016. The NLR was calculated from preoperative laboratory tests and classified as high (> 4) and low (≤ 4). The t-test, chi-square, Kaplan-Meier analysis, and Cox multivariate regression models were used to assess associations of clinical, histologic, and hematological variables with survival.


RESULTS
For 124 patients the median follow-up was 23 months (range 1-88). High NLR was associated with greater rate of local complication (r=0.268, P < 0.01). The rate of major complications (Clavien-Dindo ≥ 3) was higher in the high NLR group (28% vs. 9%, P = 0.022). Among the 53 patients who received neoadjuvant chemotherapy, those with low NLR had significantly improved disease-free survival (DFS) (49.7 vs. 27.7 months, P = 0.025). Low NLR was not significantly associated with overall survival (mean survival, 51.2 vs. 42.3 months, P = 0.19). Multivariate regression identified NLR group (P = 0.013), male gender (P = 0.04), and body mass index (P = 0.026) as independently associated with DFS.


CONCLUSIONS
Among gastric cancer patients planned for curative intent surgery who underwent neoadjuvant chemotherapy, NLR may have prognostic value, particularly regarding DFS and postoperative complications.

Neutrophil to Lymphocyte Ratio in Patients Who Received Neoadjuvant Treatment before Gastrectomy.

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Papers

CHOP is a critical regulator of acetaminophen-induced hepatotoxicity

Flange Fracture and Dislocation: An Unusual Complication of Percutaneous Tracheostomy

Neutrophil to Lymphocyte Ratio in Patients Who Received Neoadjuvant Treatment before Gastrectomy.