Natural Killer Cells Degenerate Intact Sensory Afferents following Nerve Injury.

Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves.

Lack of correlation between spinal microgliosis and long-term development of tactile hypersensitivity in two different sciatic nerve crush injury.

Microglia activation following peripheral nerve injury has been shown to contribute to central sensitization of the spinal cord for the development of neuropathic pain. In a recent study, we reported that the amount of nerve damage does not necessarily correlate with chronic pain development. Here we compared the response of spinal microglia, using immunohistochemistry as a surrogate of microglial activation, in mice with two different types of crush injury of the sciatic nerve. We confirmed that incomplete crush of the sciatic nerve (partial crush injury, PCI) resulted in tactile hypersensitivity after the recovery of sensory function (15 days after surgery), whereas the hypersensitivity was not observed after the complete crush (full crush injury, FCI). We observed that immunoreactivity for Iba-1, a microglial marker, was greater in the ipsilateral dorsal horn of lumbar (L4) spinal cord of mice 2 days after FCI compared to PCI, positively correlating with the intensity of crush injury. Ipsilateral Iba-1 reactivity was comparable between injuries at 7 days with a significant increase compared to the contralateral side. By day 15 after injury, ipsilateral Iba-1 immunoreactivity was much reduced compared to day 7 and was not different between the groups. Our results suggest that the magnitude of the early microgliosis is dependent on injury severity, but does not necessarily correlate with the long-term development of chronic pain-like hypersensitivity after peripheral nerve injury.

Promising aberrant DNA methylation marker to predict gastric cancer development in individuals with family history and long-term effects of H. pylori eradication on DNA methylation.

OBJECTIVE: It remains unknown whether individuals with a family history (FH) of gastric cancer (GC) are associated with aberrant DNA methylation. The aim of this study was to investigate the association between aberrant DNA methylation and FH of GC. DESIGN: Using quantitative MethyLight assay, MOS, miR124a-3, NKX6-1, EMX1, CDH1, and TWIST1 methylation levels in the noncancerous gastric mucosa was compared between subjects with and without FH based on GC and Helicobacter pylori (Hp) infection. Changes in the methylation levels were evaluated over time after Hp eradication. RESULTS: In Hp-positive GC patients, MOS (P < 0.001), CDH1 (P < 0.001), and TWIST1 (P = 0.004) methylation were decreased in subjects with FH (n = 64) than in those without FH (n = 58). In Hp-positive controls, MOS methylation was lower in subjects with FH (n = 73) than in those without FH (n = 50) (P = 0.042), while miR124a-3 (P = 0.006), NKX6-1 (P < 0.001), and CDH1 (P < 0.001) methylation were higher in subjects with FH. CDH1 methylation constantly decreased from 2 years in GC patients and 3-4 years in controls after Hp eradication (all P < 0.001). A persistent decrease in methylation over time was not observed in other genes after eradication. CONCLUSION: The methylation of MOS and CDH1 provided an association between aberrant DNA methylation and gastric carcinogenesis in FH of GC, a useful marker for GC risk in individuals with FH. Furthermore, CDH1 methylation decreased after Hp eradication.

Optimal procedure-related hospitalization using clinical pathway protocols following gastric endoscopic submucosal dissection.

BACKGROUND: The clinical pathway (CP) protocols simplified a systematic process from hospitalization to discharge, and were conducted to achieve standardization of the treatment process as well as improve outcomes. Thus, we investigated the optimal procedure-related hospitalization period following gastric endoscopic submucosal dissection (ESD) by comparing the rate of delayed bleeding (DB) and perforation according to CP protocols. METHODS: We retrospectively enrolled 630 patients who underwent ESD for gastric dysplasia or early gastric cancer (EGC); Group A (368 patients) followed Protocol A for a hospital stay of a single night; Group B (262 patients) followed Protocol B for a hospital stay of two nights. RESULTS: The patient characteristics were comparable between the two groups, except for pathologic diagnosis (42.1% in Group A vs. 32.1% in Group B for EGC). DB occurred in 21 patients, and there was no significant difference in the overall DB rates between Group A (12/368 = 3.3%) and Group B (9/262 = 3.4%) (P = 0.904). The DB rates were 2.5% (8/315) and 7.5% (4/53) in Group A, and 2.7% (6/223) and 7.7% (3/39) in Group B, without and with the use of antiplatelets, respectively, and 33.3% (1/3) in Group A and 50.0% (1/2) in Group B with the use of dual antiplatelets. DB developed at various intervals post-discharge from 2 to 17 days, and was successfully controlled by endoscopic hemostasis in most cases. There were no deaths or surgeries required as a result of uncontrolled DB and no postoperative delayed perforation occurred. CONCLUSIONS: The CP protocols with a one-night hospitalization following gastric ESD decreased the hospital stay and did not influence postoperative complications compared to those with two-night hospitalizations.

Ischemic colitis induced by indigo naturalis in a patient with ulcerative colitis: a case report.

BACKGROUND: Indigo naturalis is a Chinese herbal medicine that has currently been used to treat various inflammatory diseases, including ulcerative colitis. Recently, there are several reports concerning severe adverse events associated with indigo naturalis. CASE PRESENTATION: We described a case of a 44-year-old female with ulcerative colitis who presented with lower abdominal pain and hematochezia. She stopped taking her medicine for ulcerative colitis and started oral indigo naturalis 3 months before admission. Computed tomography showed segmental edematous wall thickening of the descending and sigmoid colon. Colonoscopy findings revealed erythema, edema, and submucosal hemorrhage, the surface of which presented a dark blue pigmentation. The histologic finding was consistent with ischemic colitis. We therefore considered an ischemic colitis induced by indigo naturalis, and the patient improved after supportive care and withdrawal of indigo naturalis. CONCLUSION: Indigo naturalis has currently been used in the patients with ulcerative colitis as an alternative therapy. However, physicians should be aware of possible severe adverse events such as ischemic colitis.

Disparities in gastric cancer screening among people with disabilities: a national registry-linkage study in South Korea.

BACKGROUND AND AIM: Using the national disability registration linked to the cancer screening database in Korea, we examined (1) trends in the gastric cancer screening rate among people with disabilities over time, and (2) whether gastric cancer screening participation and modalities differed according to presence, severity, and type of disability. METHODS: We examined gastric cancer screening participation rates among individuals with registered disability, from 2006 to 2015. RESULTS: The age- and sex-adjusted rate for gastric cancer screening in people with disabilities increased from 25.9% in 2006 to 51.9% in 2015 (change: + 26.0%). During the same period, screening rates among people without disability improved from 24.7 to 56.5% (change: + 31.8%). Disability was associated with a screening rate [adjusted odds ratio (aOR) 0.89, 95% confidence interval (CI), 0.88-0.89]. Screening rates were markedly lower among people with severe disabilities (aOR 0.58, 95% CI 0.57-0.58) and people with autism (aOR 0.36, 95% CI 0.25-0.52), renal failure (aOR 0.39, 95% CI 0.38-0.39), brain injury (aOR 0.41, 95% CI 0.40-0.41), ostomy problems (aOR 0.53, 95% CI 0.51-0.55), intellectual disabilities (aOR 0.54, 95% CI 0.53-0.54), or mental disorders (aOR 0.55, 95% CI 0.54-0.56). The use of gastroscopy as the initial screening modality in people with disabilities was lower than in people without a disability. CONCLUSIONS: In spite of the availability of national gastric cancer screening program, we found significant disparities in gastric cancer screening participation, especially among people with severe disabilities and those with renal failure or brain-related/mental disabilities.

It is necessary to exam bottom and top slide smears of EUS-FNA for pancreatic cancer.

BACKGROUND: Despite many reports on the diagnostic yield of cytology from endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), inter-slide differences are unknown. This prospective study aimed to compare diagnostic yield and cellular characteristics of bottom slides (BS) and top slides (TS) from EUS-FNA cytology performed without an on-site cytopathologist. METHODS: In patients with suspected pancreatic cancer on previous imaging explorations, a single endoscopist performed EUS-FNA and obtained 2 sets of cytology slide (8 BS and 8 TS), 1 cellblock slide, and 1 biopsy slide. Both slide sets were randomly assigned. A cytopathologist with more than 10 years of expertise in pancreatic cytopathology blindly inspected and compared two slide sets. RESULTS: In total, 73 specimens [42 head (57.5%), 16 body (21.9%), and 15 tail (20.5%)] were acquired for final analysis. Seventy-one cases were finally diagnosed with pancreatic cancer. The sensitivity and specificity of BS were 80.3% and 100.0%; and of TS 78.9% and 100.0%, respectively. In analyzing inter-slide difference, 66 cases (90.4%) showed consistent results between BS and TS. However, seven (9.6%) were positive only in one slide sets (4 BS and 3 TS). The proportions of specimens more than moderate and high cellularity were 75.3% and 60.3% in both slide sets (P> 0.99), and the proportion of artifact-free sets were 50.7%, and 52.1% for the BS and TS, respectively (P= 0.869). CONCLUSIONS: Although BS and TS exhibited highly consistent diagnostic yields in cytologic smears from EUS-FNA, the proportion of inter-slide discordance is clinically considerable. Both slide sets need to be examined if there is no on-site cytopathologist.

Percutaneous transhepatic versus EUS-guided gallbladder drainage for malignant cystic duct obstruction.

BACKGROUND AND AIMS: Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) has been proposed as an alternative management strategy for acute cholecystitis caused by malignant cystic duct obstruction in patients for whom surgery is not an option. This study aimed to compare the results of EUS-GBD with those of percutaneous transhepatic gallbladder drainage (PTGBD) for palliative management of malignant cystic duct obstruction with acute cholecystitis or symptomatic gallbladder hydrops. METHODS: Between November 2013 and November 2015, 14 patients with acute cholecystitis or symptomatic gallbladder hydrops as a result of malignant cystic duct obstruction underwent EUS-GBD with covered metal stents. Nineteen patients with acute cholecystitis as a result of malignant cystic duct obstruction who received PTGBD served as a control group. Patients' medical records were reviewed retrospectively. RESULTS: The technical and clinical success rates of EUS-GBD were 85.7% (12/14) and 91.7% (11/12) and of PTGBD were 100% (19/19) and 86.4% (17/19), respectively. The groups had similar adverse event rates (28.5% and 21.1%, respectively). The average duration of stent patency in patients with EUS-GBD was 130.3 ± 35.3 days, and no patient required an additional procedure before death. In 6 of 17 patients (35.3%) with clinically successful PTGBD, the catheter was not removed until the end stage of life. CONCLUSIONS: EUS-GBD is a feasible, safe, and effective modality for the treatment of malignant cystic duct obstruction in patients who are not indicated for surgery. It enables improved long-term quality of life in patients with advanced-stage cancer.

The Efficacy of Clinical Predictors for Patients with Intermediate Risk of Choledocholithiasis.

BACKGROUND/AIMS: For the suspected choledocholithiasis, the American Society for Gastrointestinal Endoscopy has proposed guidelines to assign risk based on clinical predictors. The study aimed to assess the usefulness of clinical predictors of choledocholithiasis set forth by the guidelines in patients with intermediate risk of choledocholithiasis. METHODS: In 2014, 109 patients with intermediate risk of choledocholithiasis underwent endoscopic ultrasound. Their medical records were retrospectively reviewed. The gold standard for choledocholithiasis was endoscopic retrograde cholangiopancreatography or clinical follow-up. RESULTS: Based on endoscopic ultrasound findings, choledocholithiasis was suspected in 18 patients, and it was removed in 17 patients. Choledocholithiasis was absent in the remaining 91 who did not show any signs from endoscopic ultrasound. Among the 2 strong (common bile duct (CBD) diameter >6 mm and bilirubin 1.8-4 mg/dl) and 3 moderate (abnormal liver biochemical test other than bilirubin, age >55 years and gallstone pancreatitis) clinical predictors, 28.8% of patients with one of the strong predictors had choledocholithiasis; however, only 3.5% of patients with any one of the moderate predictors had choledocholithiasis. As a result, only strong clinical predictors showed predictability: increased bilirubin level (OR 3.23; 90% CI 0.85-12.28) and dilated CBD diameter (OR 5.83; 90% CI 1.93-17.57). CONCLUSION: Only strong clinical predictors of choledocholithiasis showed predictability for patients with intermediate risk of choledocholithiasis.

Mortality of elderly patients with acute kidney injury undergoing continuous renal replacement therapy: is age a risk factor?

BACKGROUND: Whether advanced age is associated with poor outcomes of elderly patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) is controversial. This study aimed to evaluate age effect and predictors for mortality in elderly AKI patients undergoing CRRT. METHODS: Data of 480 elderly AKI patients who underwent CRRT were retrospectively analyzed. Subjects were stratified into two groups according to age: younger-old (age, 65-74 years; n = 205) and older-old (age, ≥75 years; n = 275). Predictors for 28-day and 90-day mortality and age effects were analyzed using multivariable Cox regression analysis and propensity score matching. RESULTS: Urine output at the start of CRRT (adjusted hazard ratio [aHR], 0.99; 95% confidence interval [CI], 0.99-1.00; p = 0.04), operation (aHR, 0.53; 95% CI, 0.30-0.93; p = 0.03), and use of an intra-aortic balloon pump (aHR, 3.60; 95% CI, 1.18-10.96; p = 0.02) were predictors for 28-day mortality. Ischemic heart disease (aHR, 1.74; 95% CI, 1.02-2.98; p = 0.04) and use of a ventilator (aHR, 0.56; 95% CI, 0.36-0.89; p = 0.01) were predictors for 90-day mortality. The older-old group did not exhibit a higher risk for 28- day or 90-day mortality than the younger-old group in multivariable or propensity score-matched models. CONCLUSION: Advanced age was not a risk factor for mortality among elderly AKI patients undergoing CRRT, suggesting that advanced age should not be considered for therapeutic decisions in critically ill elderly patients with AKI requiring CRRT.

Creatinine-cystatin C ratio and death with a functioning graft in kidney transplant recipients.

Death with a functioning graft is important cause of graft loss after kidney transplantation. However, little is known about factors predicting death with a functioning graft among kidney transplant recipients. In this study, we evaluated the association between post-transplant creatinine-cystatin C ratio and death with a functioning graft in 1592 kidney transplant recipients. We divided the patients into tertiles based on sex-specific creatinine-cystatin C ratio. Among the 1592 recipients, 39.5% were female, and 86.1% underwent living-donor kidney transplantation. The cut-off value for the lowest creatinine-cystatin C ratio tertile was 0.86 in males and 0.73 in females. The lowest tertile had a significantly lower 5-year patient survival rate and was independently associated with death with a functioning graft (adjusted hazard ratio 2.574, 95% confidence interval 1.339-4.950, P < 0.001). Infection was the most common cause of death in the lowest tertile group, accounting for 62% of deaths. A low creatinine-cystatin C ratio was significantly associated with an increased risk of death with a functioning graft after kidney transplantation.

The therapeutic potential of natural killer cells in neuropathic pain.

Novel disease-modifying treatments for neuropathic pain are urgently required. The cellular immune response to nerve injury represents a promising target for therapeutic development. Recently, the role of natural killer (NK) cells in both CNS and PNS disease has been the subject of growing interest. In this opinion article, we set out the case for NK cell-based intervention as a promising avenue for development in the management of neuropathic pain. We explore the potential cellular and molecular targets of NK cells in the PNS by contrasting with their reported functional roles in CNS diseases, and we suggest strategies for using the beneficial functions of NK cells and immune-based therapeutics in the context of neuropathic pain.

Long-term tactile hypersensitivity after nerve crush injury in mice is characterized by the persistence of intact sensory axons.

ABSTRACT: Traumatic peripheral nerve injuries are at high risk of neuropathic pain for which novel effective therapies are urgently needed. Preclinical models of neuropathic pain typically involve irreversible ligation and/or nerve transection (neurotmesis). However, translation of findings to the clinic has so far been unsuccessful, raising questions on injury model validity and clinically relevance. Traumatic nerve injuries seen in the clinic commonly result in axonotmesis (ie, crush), yet the neuropathic phenotype of "painful" nerve crush injuries remains poorly understood. We report the neuropathology and sensory symptoms of a focal nerve crush injury using custom-modified hemostats resulting in either complete ("full") or incomplete ("partial") axonotmesis in adult mice. Assays of thermal and mechanically evoked pain-like behavior were paralleled by transmission electron microscopy, immunohistochemistry, and anatomical tracing of the peripheral nerve. In both crush models, motor function was equally affected early after injury; by contrast, partial crush of the nerve resulted in the early return of pinprick sensitivity, followed by a transient thermal and chronic tactile hypersensitivity of the affected hind paw, which was not observed after a full crush injury. The partially crushed nerve was characterized by the sparing of small-diameter myelinated axons and intraepidermal nerve fibers, fewer dorsal root ganglia expressing the injury marker activating transcription factor 3, and lower serum levels of neurofilament light chain. By day 30, axons showed signs of reduced myelin thickness. In summary, the escape of small-diameter axons from Wallerian degeneration is likely a determinant of chronic pain pathophysiology distinct from the general response to complete nerve injury.

In Vitro Visualization of Cell-to-Cell Interactions Between Natural Killer Cells and Sensory Neurons.

Cell-to-cell interactions between the immune and nervous systems are increasingly recognized for their importance in health and disease. Assessment of cellular neuro-immune interactions can be aided by co-culture of two (or more) cells in an in vitro model system that preserves the morphology of neuronal cells. Here we describe methods to investigate the cytotoxic effector functions of natural killer cells on sensory neurons isolated from syngeneic embryonic and adult mice. We present methods for the morphological analysis of axon fragmentation (pruning) and dynamic cell function via live confocal calcium imaging. These techniques can easily be adapted to study interactions between other combinations of immune cell subsets and neuronal populations.

[Inflammatory Bowel Disease and Vitamin D].

Vitamin D contributes to bone metabolism and acts as an immune modulator for both innate and adaptive immunity. The serum level of vitamin D has been associated with inflammatory diseases, such as inflammatory bowel disease (IBD). In epidemiologic studies, IBD patients have been shown to have low levels of vitamin D. The suboptimal circulating levels of vitamin D in IBD patients may be caused by low exposure to sunlight, dietary malabsorption, and the impaired conversion of active metabolites (1,25[OH]2D). Recent studies have demonstrated that vitamin D deficiency in IBD can increase the chance of disease recurrence, IBD-related hospitalization or surgery, and deterioration of quality of life. Supplementation with vitamin D is therefore thought to reduce the risk of flare-ups and the improvement of the quality of life in IBD patients. This review aims to summarize the latest knowledge on the effects of vitamin D deficiency on IBD and the possible benefits of vitamin D supplementation in IBD patients.

Postoperative muscle mass restoration as a prognostic factor in patients with resected pancreatic cancer.

BACKGROUND: Recent studies have found that muscle depletion may be a prognostic predictor in patients with pancreatic cancer (PC). However, in these studies, limited data were used to assess the relationship between the serial change in body composition and outcomes after PC resection. Hence, we evaluated the changes in body composition during the perioperative period in patients with PC and their association with the overall survival (OS). METHODS: A total of 89 patients with PC who received surgery with curative intent between 2006 and 2015 were included in this study retrospectively. These patients underwent serial computed tomography (CT) scans: preoperatively, immediately after surgery (4 weeks), and 12 and 24 weeks after resection. The muscle and visceral fat areas were measured at the third lumbar vertebra level on cross-sectional CT images using sliceOmatic V5.0 program (TomoVision, Canada). The body composition ratio was determined by dividing the post-resection body composition at each point (4, 12, and 24 weeks) by the pre-resection body composition. Patients were divided into two groups-higher and lower groups-based on this body composition ratio (skeletal muscle mass ratio [SMR], visceral fat mass ratio [VFR]). The OS was compared between the two groups using the log-rank test. RESULTS: The median age of patients was 63 (27-84) years, and the baseline body mass index was 23.0 (17.0-35.8) kg/m2. In the comparison of the SMR, there was no significant difference in the OS between the two groups at 4 and 12 weeks (4 weeks, P = 0.488; 12 weeks, P = 0.397). However, the higher group showed a longer OS than the lower group at 24 weeks (39 vs. 20 months, P = 0.008). Similarly, in the VFR, there was no significant difference in the OS between the two groups at 4 and 12 weeks (4 weeks, P = 0.732; 12 weeks, P = 0.060). However, the OS was longer in the higher group at 24 weeks (35 vs. 22 months, P = 0.023). When we analyzed the effect of muscle restoration at 24 weeks after resection on the OS by gender, there was no significant difference between the OS and SMR in the male group (P = 0.213), but a significant difference was noted in the female group (P = 0.002). In the multivariate Cox regression analysis, the SMR at 24 weeks after resection was significantly associated with the OS (P = 0.023) but not VFR at 24 weeks. In 69 patients without recurrence at 6 months, the SMR at 24 weeks was related to longer OS but without statistical significance (P = 0.07). CONCLUSIONS: This study suggests that the restoration of muscle mass at 24 weeks after resection may be an independent prognostic factor for survival in patients with resected PC.

Disparities in the Diagnosis and Treatment of Gastric Cancer in Relation to Disabilities.

INTRODUCTION: We investigated potential disparities in the diagnosis, treatment, and survival of gastric cancer (GC) patients with and without disabilities. METHODS: We linked Korean National Disability Registry data with the Korean National Health Insurance database and Korean Central Cancer Registry data. This study included a total of 16,849 people with disabilities and 58,872 age- and sex-matched control subjects in whom GC had been diagnosed. RESULTS: When compared to GC patients without disabilities, patients with disabilities tended to be diagnosed at a later stage (localized stage 53.7% vs 59.0% or stage unknown 10.7% vs 6.9%), especially those with severe disabilities (P < 0.001). This was more evident in patients with mental impairment (localized stage 41.7% and stage unknown 15.2%). In addition, not receiving treatment was more common in patients with disabilities than those without disabilities (29.3% vs 27.2%, P < 0.001), and this disparity was more evident in those with severe disabilities (35.4%) and in those with communication (36.9%) and mental (32.3%) impairment. Patients with disabilities were at slightly higher risk of overall mortality as well as GC-specific mortality compared to people without disabilities (adjusted hazard ratio [aHR] = 1.18, 95% confidence interval: 1.14-1.21 and aHR = 1.12, 95% confidence interval: 1.09-1.16, respectively), and these disparities were more pronounced in those with severe disabilities (aHR = 1.62 and 1.51, respectively). DISCUSSION: Patients with disabilities, especially severe disabilities, were diagnosed with GC at a later stage, received less staging evaluation and treatment, and their overall survival rate was slightly worse compared to those without disabilities.

Field-plate engineering for high breakdown voltage ß-Ga2O3 nanolayer field-effect transistors.

The narrow voltage swing of a nanoelectronic device limits its implementations in electronic circuits. Nanolayer ß-Ga2O3 has a superior breakdown field of approximately 8 MV cm-1, making it an ideal candidate for a next-generation power device nanomaterial. In this study, a field modulating plate was introduced into a ß-Ga2O3 nano-field-effect transistor (nanoFET) to engineer the distribution of electric fields, wherein the off-state three-terminal breakdown voltage was reported to be 314 V. ß-Ga2O3 flakes were separated from a single-crystal bulk substrate using a mechanical exfoliation method. The layout of the field modulating plate was optimized through a device simulation to effectively distribute the peak electric fields. The field-plated ß-Ga2O3 nanoFETs exhibited n-type behaviors with a high output current saturation, exhibiting excellent switching characteristics with a threshold voltage of -3.8 V, a subthreshold swing of 101.3 mV dec-1, and an on/off ratio greater than 107. The ß-Ga2O3 nanoFETs with a high breakdown voltage of over 300 V could pave a way for downsizing power electronic devices, enabling the economization of power systems.

Clinical outcomes of FOLFIRINOX in locally advanced pancreatic cancer: A single center experience.

Systemic chemotherapy or chemoradiotherapy is the initial primary option for patients with locally advanced pancreatic cancer (LAPC). This study analyzed the effect of FOLFIRINOX and assessed the factors influencing conversion to surgical resectability for LAPC.Sixty-four patients with LAPC who received FOLFIRINOX as initial chemotherapy were enrolled retrospectively. Demographic characteristics, tumor status, interval/dosage/cumulative relative dose intensity (cRDI) of FOLFIRINOX, conversion to resection, and clinical outcomes were reviewed and factors associated with conversion to resectability after FOLFIRINOX were analyzed.After administration of FOLFIRINOX (median 9 cycles, 70% of cRDI), the median patient overall survival (OS) was 17.0 months. Fifteen of 64 patients underwent surgery and R0 resection was achieved in 11 patients. During a median follow-up time of 9.4 months after resection, cumulative recurrence rate was 28.5% at 18 months after resection. The estimated median OS was significantly longer for the resected group (>40 months vs 13 months). There were no statistical differences between the resected and non-resected groups in terms of baseline characteristics, tumor status and hematologic adverse effects. The patients who received standard dose of FOLFIRINOX had higher probability of subsequent resection compared with patients who received reduced dose, although cRDIs did not differ between groups.FOLFIRINOX is an active regimen in patients with LAPC, given acceptable resection rates and promising R0 resection rates. Additionally, our data demonstrate it is advantageous for obtaining resectability to administer FOLFIRINOX without dose reduction.

Peripheral GABAA receptor-mediated signaling facilitates persistent inflammatory hypersensitivity.

Unlike in the central nervous system (CNS), in the adult peripheral nervous system (PNS), activation of GABAA receptors (GABAAR) is excitatory because of the relatively high concentration of intracellular chloride in these neurons. Indeed, exogenous GABA and muscimol, a GABAAR agonist, exacerbate acute inflammatory hypersensitivity in rodents. However, it remains unclear whether peripheral GABAAR and the endogenous GABA play an important role in persistent inflammatory hypersensitivity. In this study, we thus investigated how peripheral GABAAR affects pain hypersensitivity by using the complete Freund's adjuvant (CFA)-induced persistent inflammatory pain mouse model. We found that intraplantar (i.pl.) administration of GABAAR antagonists, picrotoxin, and 1(S),9(R)-(-)-bicuculline methiodide significantly inhibited both spontaneous nociceptive (paw licking and flinching) behavior and mechanical hypersensitivity in CFA-injected mice at day 3 (D3), but not in naïve mice. Interestingly, CFA-induced mechanical hypersensitivity was significantly reversed by anti-GABA antibody (anti-GABA, i.pl.). In addition, RT-qPCR revealed that glutamate decarboxylase Gad1 (GAD 67) and Gad2 (GAD 65) mRNA expression was also upregulated in the ipsilateral hind paw of CFA-injected mice at D3. Finally, 5α-pregnan-3α-ol-20-one (3α,5α-THP), a selective positive allosteric modulator of GABAAR, produced mechanical hypersensitivity in naïve mice in a dose-dependent manner. Taken together, our results indicate that peripheral GABAAR and endogenous GABA, possibly produced by the inflamed tissue, potentiate CFA-induced persistent inflammatory hypersensitivity, suggesting that they can be used as a therapeutic target for alleviating inflammatory pain.