Fadu head and neck squamous cell carcinoma induces hyperexcitability of primary sensory neurons in an in vitro coculture model.

Introduction: Currently, cancer pain is viewed as a process orchestrated by the release of pronociceptive molecules and the invasion of neural structures, referred to as perineural invasion (PNI). Cancer pain resulting from PNI is well-documented, but the mechanisms leading to peripheral sensitization because of tumor growth are not fully known. Methods: A retrospective study was used to examine how the use of anti-inflammatory medications affected preoperative pain in patients with oral squamous cell carcinoma cancer. We then used an in vitro coculture model in which dorsal root ganglion (DRG) neurons were incubated together with Fadu human head and neck squamous cell carcinoma cancer cells to explore how cancer cells affect the electrical membrane properties of sensory neurons. Results: We found that inflammation contributes to preoperative pain in patients with oral squamous cell carcinoma. After coculture with Fadu human head and neck squamous cell carcinoma cancer cells, we identified markers of inflammation in coculture media and found evidence of neuronal sensitization, including spontaneous activity, reduced current thresholds, depolarized resting membrane potential, and enhanced responses to current stimulation in human and rat DRG neurons. In rats, these effects were influenced by sex and age: neurons from young adult female rats were resistant to changes in neuronal activity, in contrast to neurons from older adult female rats or male rats of either age group. Conclusions: Pro-inflammatory substances released in cancer cell-DRG coculture promoted neuronal hyperexcitability and may contribute to cancer pain after PNI, and these effects may differ across age groups and sexes.

Lack of association between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and pain improvement in patients with oral cancer.

BACKGROUND: There is a growing body of literature implicating angiotensin II in the modulation of tumour-associated inflammation and pain. However, the impact of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) on pain and inflammation has not yet been studied in oral cancers. The objective is to investigate the role of ACEi and ARB pharmacotherapy on preoperative pain and inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR), in patients with oral cancer. METHODS: We performed a retrospective study on patients who underwent oral cancer surgery. The Wilcoxon rank-sum test or Kruskal-Wallis analysis was used to evaluate differences in demographic, tumour-related and preoperative characteristics and amongst patients using ARBs, ACEis and no treatment. Multivariable analysis was fitted to estimate the effects of important covariates on severe preoperative pain. RESULTS: A total of 162 patients with oral malignancies were included in the study. After adjusting for significant covariates, patients with perineural invasion were found to have higher levels of pain (p = 0.0278). Similarly, patients taking ARBs were found to have lower levels of perineural invasion (p = 0.035). The analysis did not demonstrate a significant difference in pain levels when comparing ARBs or ACEis to the no treatment group (p = 0.250). Furthermore, the use of ARB or ACEi did not significantly alter preoperative NLR (p = 0.701) or MLR (p = 0.869). CONCLUSIONS: When compared to no treatment, ARBs and ACEis are not associated with significant analgesic effect or decreased inflammatory scores (NLR, PLR and MLR).

Persistent and Chronic Postoperative Opioid Use in a Cohort of Patients with Oral Tongue Squamous Cell Carcinoma.

BACKGROUND: Recently, the concept of persistent postsurgical opioid use has been described for patients undergoing cancer surgery. Our hypothesis was based on the premise that patients with oral tongue cancer require high dosages of opioids before, during, and after surgery, and thus a large percentage of patients might develop persistent postsurgical opioid use. METHODS: After institutional review board approval, we conducted a retrospective study that included a cohort of patients with oral tongue cancers who underwent curative-intent surgery in our institution. Multivariable logistic regression models were fit to study the association of the characteristics of several patients with persistent (six months after surgery) and chronic (12 months after surgery) postoperative opioid use. RESULTS: A total of 362 patients with oral tongue malignancies were included in the study. The rate of persistent use of opioids after surgery was 31%. Multivariate analysis showed that patients taking opioids before surgery and those receiving adjuvant therapy were 2.9 and 1.78 times more likely to use opioids six months after surgery. Fifteen percent of the patients were taking opioids 12 months after surgery. After adjusting for clinically relevant covariates, patients complaining of moderate tongue pain before surgery and those taking opioids preoperatively had at least three times higher risk of still using these analgesics one year after surgery. CONCLUSIONS: Patients with oral tongue cancers have a high risk of developing persistent and chronic postsurgical opioid use.

Effects of Intraoperative Opioid Use on Recurrence-Free and Overall Survival in Patients With Esophageal Adenocarcinoma and Squamous Cell Carcinoma.

BACKGROUND: Perioperative opioid use is associated with poor survival in patients with esophageal squamous cell carcinoma. The most common histological type of esophageal cancer in western countries is adenocarcinoma. The objective of this study was to evaluate the association between intraoperative opioid consumption and survival in patients with adenocarcinoma and squamous cell carcinoma of the esophagus. METHODS: Records of patients who had undergone esophageal cancer surgery between January 2000 and January 2017 were reviewed. Comparisons were made between patients who received high versus low intraoperative doses of opioids. Groups were divided using the recursive partitioning method. Multicovariate Cox proportional hazards models were fitted to evaluate the impact of intraoperative opioid use on recurrence-free survival (RFS) and overall survival (OS). RESULTS: For patients with esophageal squamous cell carcinoma, the univariable analysis indicated that lower opioid dosages (<710 µg fentanyl equivalents) were significantly associated with worse RFS (P = .009) and OS (P = .002). With the adjustment of age, stage, and adjuvant chemotherapy, multivariable analysis confirmed significant associations between higher dosages of intraoperative fentanyl equivalents and better RFS (P = .002; hazard ratio [HR], 0.376; 95% confidence interval [CI], 0.201~0.704). Likewise, higher intraoperative fentanyl equivalents administered was associated with improved OS (P = .002; HR, 0.346; 95% CI, 0.177~0.676). In the adenocarcinoma population, the association between intraoperative opioid dosage and RFS (P = .15) or OS (P = .36) was not significant from univariable analysis. With the adjustment of age, body mass index, tumor staging, neoadjuvant chemotherapy, and adjuvant chemotherapy, multivariable analysis demonstrated marginal significant association between intraoperative fentanyl equivalents and RFS (P = .0866; HR, 0.806; 95% CI, 0.629~1.032). The association between intraoperative fentanyl equivalents and OS was not significant (P = .51). CONCLUSIONS: The results of this study indicate that the amounts of intraoperative opioids used are associated with recurrence and OS in patients with esophageal squamous cell carcinoma. The association between the dose of intraoperative opioids used and RFS was marginally significant in patients with adenocarcinoma. Until confirmation on our findings by future studies, opioids should continue to be a key component of balanced anesthesia in patients with esophageal cancer.