Dorsal root ganglion toll-like receptor 4 signaling contributes to oxaliplatin-induced peripheral neuropathy.

ABSTRACT: Activation of toll-like receptor 4 (TLR4) in the dorsal root ganglion (DRG) and spinal cord contributes to the generation of paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Generalizability of TLR4 signaling in oxaliplatin-induced CIPN was tested here. Mechanical hypersensitivity developed in male SD rats by day 1 after oxaliplatin treatment, reached maximum intensity by day 14, and persisted through day 35. Western blot revealed an increase in TLR4 expression in the DRG of oxaliplatin at days 1 and 7 after oxaliplatin treatment. Cotreatment of rats with the TLR4 antagonist lipopolysaccharide derived from Rhodobacter sphaeroides ultrapure or with the nonspecific immunosuppressive minocycline with oxaliplatin resulted in significantly attenuated hyperalgesia on day 7 and 14 compared with rats that received oxaliplatin plus saline vehicle. Immunostaining of DRGs revealed an increase in the number of neurons expressing TLR4, its canonical downstream signal molecules myeloid differentiation primary response gene 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-ß, at both day 7 and day 14 after oxaliplatin treatment. These increases were blocked by cotreatment with either lipopolysaccharide derived from Rhodobacter sphaeroides or minocycline. Double staining showed the localization of TLR4, MyD88, and TIR-domain-containing adapter-inducing interferon-ß in subsets of DRG neurons. Finally, there was no significant difference in oxaliplatin-induced mechanical hypersensitivity between male and female rats when observed for 2 weeks. Furthermore, upregulation of TLR4 was detected in both sexes when tested 14 days after treatment with oxaliplatin. These findings suggest that the activation of TLR4 signaling in DRG neurons is a common mechanism in CIPN induced by multiple cancer chemotherapy agents.

Abdominal tattoo can be useful to avoid a midline abdominal incision.

We report a case in which abdominal tattoo margins were modified and used to hide the surgical incision for desmoid tumour removal. Our patient is a 37-year-old female with history remarkable for atrial septal defect closure at the age of ten, but not for previous abdominal surgeries or trauma. A desmoid tumour diagnosis was made upon needle biopsy of the 5 × 4 cm2 mass confined to the rectus abdominis. Subsequently, tumour was resected with an incision through the tattoo upper margin and abdominal wall was reconstructed with primary fascial closure mesh reinforced. Excision was radical, scar inconspicuous and no incisional hernia, bulging, nor tumour recurrence were detected at 2-year follow-up. This report highlights the fact that an abdominal tattoo might be considered as incision access instead of typical midline incision.

Lidocaine Stimulates the Function of Natural Killer Cells in Different Experimental Settings.

BACKGROUND: One of the functions of natural killer (NK) cells is to eliminate cancer cells. The cytolytic activity of NK cells is tightly regulated by inhibitory and activation receptors located in the surface membrane. Lidocaine stimulates the function of NK cells at clinically relevant concentrations. It remains unknown whether this effect of lidocaine has an impact on the expression of surface receptors of NK cells, can uniformly stimulate across different cancer cell lines, and enhances the function of cells obtained during oncological surgery. MATERIALS AND METHODS: NK cells from healthy donors and 43 patients who had undergone surgery for cancer were isolated. The function of NK cells was measured by lactate dehydrogenase release assay. NK cells were incubated with clinically relevant concentrations of lidocaine. By flow cytometry, we determined the impact of lidocaine on the expression of galactosylgalactosylxylosylprotein3-beta-glucuronosytranferase 1, marker of cell maturation (CD57), killer cell lectin like receptor A, inhibitory (NKG2A) receptors and killer cell lectin like receptor D, activation (NKG2D) receptors of NK cells. Differences in expression at p<0.05 were considered statistically significant. RESULTS: Lidocaine increased the expression of NKG2D receptors and stimulated the function of NK cells against ovarian, pancreatic and ovarian cancer cell lines. Lidocaine also increased the cytolytic activity of NK cells from patients who underwent oncological surgery, except for those who had orthopedic procedures. CONCLUSION: Lidocaine showed an important stimulatory activity on NK cells. Our findings suggest that lidocaine might be used perioperatively to minimize the impact of surgery on NK cells.

Inflammation and pro-resolution inflammation after hepatobiliary surgery.

BACKGROUND: The magnitude of the perioperative inflammatory response plays a role in surgical outcomes. However, few studies have explored the mechanisms of the resolution of inflammation in the context of surgery. Here, we described the temporal kinetics of interleukin-6, cortisol, lipoxin A4, and resolvin D in patients who underwent oncologic liver resections. METHODS: All patients gave written informed consent. Demographic and perioperative surgical data were collected, along with blood samples, before surgery and on the mornings of postoperative days 1, 3, and 5. Interleukin-6, cortisol, lipoxin-A4, and resolvin D were measured in plasma. A P value < 0.05 was considered statistically significant. RESULTS: Forty-one patients were included in the study. Liver resection for colorectal metastatic disease was the most commonly performed surgery. The plasma concentrations of interleukin-6 were highest on day 1 after surgery and remained higher than the baseline up to postoperative day 1. Postoperative complications occurred in 14 (24%) patients. Cortisol concentrations spiked on postoperative day 1. The concentrations of lipoxin A4 and resolvin D were lowest on day 1 after surgery. CONCLUSIONS: The inflammatory response associated with hepatobiliary surgery is associated with low circulating concentrations of lipoxin A4 and resolvin D that mirror, in an opposite manner, the kinetics of interleukin 6 and cortisol. TRIAL REGISTRATION: NCT01438476.

Impaired Immune Function in Patients Undergoing Surgery for Bone Cancer.

BACKGROUND: Natural killer (NK) cells undergo quantitative and functional changes after oncological surgery. PATIENTS AND METHODS: After Institutional Review Board approval, the count and function of NK cells from patients with malignant bone tumors were assessed only days 1, 3, 5 and during first postoperative visit, and compared with preoperative values. The serum concentrations of interleukins (IL)-2, -4 and -6 were also measured before and after surgery. RESULTS: Complete clinical and laboratory data were analyzed from 17 patients with different bone malignancies. The number of NK cells significantly decreased postoperatively as well as their function. The maximum deterioration in their function occurred 5 days postoperatively. The serum concentrations of IL-2 and IL-4 did not change perioperatively. In contrast, a significant increase in the concentrations of IL-6 was observed on day 1, 3 and 5 postoperatively. CONCLUSION: A significant inflammatory response and innate immune suppression occurred after surgery for malignant bone tumors.