Event-free survival at 36 months is a suitable endpoint for diffuse large B-cell lymphoma patients treated with immunochemotherapy: real-world evidence from the North Japan Hematology Study Group.

Information regarding follow-up duration after treatment for newly diagnosed diffuse large B-cell lymphoma (DLBCL) is important. However, a clear endpoint has yet to be established. We totally enrolled 2182 patients newly diagnosed with DLBCL between 2008 and 2018. The median age of the patients was 71 years. All patients were treated with rituximab- and anthracycline-based chemotherapies. Each overall survival (OS) was compared with the age- and sex-matched Japanese general population (GP) data. At a median follow-up of 3.4 years, 985 patients experienced an event and 657 patients died. Patients who achieved an event-free survival (EFS) at 36 months (EFS36) had an OS equivalent to that of the matched GP (standard mortality ratio [SMR], 1.17; P=0.1324), whereas those who achieved an EFS24 did not have an OS comparable to that of the matched GP (SMR, 1.26; P=0.0095). Subgroup analysis revealed that relatively old patients (>60 years), male patients, those with limited-stage disease, those with a good performance status, and those with low levels of soluble interleukin 2 receptor already had a comparable life expectancy to the matched GP at an EFS24. In contrast, relatively young patients had a shorter life expectancy than matched GP, even with an EFS36. In conclusion, an EFS36 was shown to be a more suitable endpoint for newly diagnosed DLBCL patients than an EFS24. Of note, younger patients require a longer EFS period than older patients in order to obtain an equivalent life expectancy to the matched GP.

Association between smoking and central sensitization pain: a web-based cross-sectional study.

PURPOSE: This study aimed to investigate whether smoking is an independent risk factor for central sensitization syndrome (CSS) in individuals with pain as measured by the Central Sensitization Inventory (CSI). METHODS: In 2020, we conducted an Internet survey targeting 2000 ordinary residents of Japan (aged 20-69 years) who had pain symptoms from October to November 2020. A multiple regression analysis was performed on the association between smoking status (nonsmokers and current smokers; Brinkman index) and CSI values. Moreover, compared to nonsmokers, the relative risk (RR) of the CSI cut-off score of 40 points or higher among current smokers was calculated using a modified Poisson regression model. Covariates included age, sex, body mass index, marital status, equivalized income, exercise habits, history of hypertension, history of hyperlipidemia, history of diabetes, pain chronicity, and Pain Catastrophizing Scale score. RESULTS: This study analyzed 1,822 individuals (1,041 men and 781 women). Among those experiencing pain, current smoking was associated with the increase in CSI values (ß = 0.07). The Brinkman index was also significantly associated with the increase in CSI values (ß = 0.06). Current smoking also increased the risk of being over the CSI cut-off score, with a relative risk (RR) of 1.29 (95% confidence intervals, 1.04-1.60). Younger age, being women, experiencing chronic pain, and higher pain catastrophizing thinking were also significantly associated with increased CSS severity, independent of smoking status. CONCLUSION: Smoking is an independent risk factor for CSS. This indicates that smoking may be an important factor in the management of central pain disorders.

Characterization of the Second Apoptosis Inhibitor Encoded by Guinea Pig Cytomegalovirus.

Despite the usefulness of guinea pig cytomegalovirus (GPCMV) for studies on congenital CMV infection, its viral mechanisms for the evasion of host defense strategies have not been fully elucidated. We reported previously that GPCMV gp38.1 functions as a viral mitochondria-localized inhibitor of apoptosis-like function, and its weak activity suggested the presence of an additional inhibitory molecule(s). Here, we identified gp38.3-2, a 42-amino-acid (aa) reading frame embedded within the gp38.3 gene that encodes a positional homolog of murine CMV (MCMV) m41. Characterization of gp38.3-2 resulted in the following findings: (i) the aa sequence of gp38.3-2 shows some similarity to that of MCMV m41.1, a viral inhibitor of oligomerization of a member of Bcl-2 family protein BAK, but there is no correspondence in their predicted secondary structures; (ii) gp38.3-2, but not gp38.3, showed inhibitory activities against staurosporine-induced apoptosis; (iii) three-dimensional protein complex prediction suggests that the N-terminal α-helix of gp38.3-2 interacts with residues in the BH3 and BH1 motifs of BAK, and analysis of gp38.3-2 and BAK mutants supported this model; (iv) guinea pig fibroblast cells infected with gp38.3-2-deficient GPCMV strain Δ38.3-2 died earlier than cells infected with rescued strain r38.3-2, resulting in lower yields of Δ38.3-2; (v) Δ38.3-2 exhibited a partial but significant decrease in monocyte and macrophage infection in comparison with r38.3-2; and, however, (vi) little difference in the viral infection of guinea pigs was observed between these two strains. Therefore, we hypothesize that gp38.3-2 contributes little to the evasion of host defense mechanisms under the experimental conditions used. IMPORTANCE Although GPCMV provides a useful animal model for studies on the pathogenesis of congenital CMV infection and the development of CMV vaccine strategies, our understanding of the viral mechanisms by which it evades apoptosis of infected cells has been limited in comparison with those of murine and human CMVs. Here, we report a second GPCMV apoptosis inhibitor (42 amino acids in length) that interacts with BAK, a Bcl-2 family proapoptotic protein. Three-dimensional structural prediction indicated a unique BAK recognition by gp38.3-2 via the BH3 and BH1 motif sequences. Our findings suggest the potential development of BH3 mimetics that can regulate inhibition or induction of apoptosis based on short ~40-amino-acid peptide molecules as with GPCMV.

Therapeutic Potential of Orally Administered Rubiscolin-6.

Rubiscolins are naturally occurring opioid peptides derived from the enzymatic digestion of the ribulose bisphosphate carboxylase/oxygenase protein in spinach leaves. They are classified into two subtypes based on amino acid sequence, namely rubiscolin-5 and rubiscolin-6. In vitro studies have determined rubiscolins as G protein-biased delta-opioid receptor agonists, and in vivo studies have demonstrated that they exert several beneficial effects via the central nervous system. The most unique and attractive advantage of rubiscolin-6 over other oligopeptides is its oral availability. Therefore, it can be considered a promising candidate for the development of a novel and safe drug. In this review, we show the therapeutic potential of rubiscolin-6, mainly focusing on its effects when orally administered based on available evidence. Additionally, we present a hypothesis for the pharmacokinetics of rubiscolin-6, focusing on its absorption in the intestinal tract and ability to cross the blood-brain barrier.

Distinct Profiles of Desensitization of µ-Opioid Receptors Caused by Remifentanil or Fentanyl: In Vitro Assay with Cells and Three-Dimensional Structural Analyses.

Remifentanil (REM) and fentanyl (FEN) are commonly used analgesics that act by activating a µ-opioid receptor (MOR). Although optimal concentrations of REM can be easily maintained during surgery, it is sometimes switched to FEN for optimal pain regulation. However, standards for this switching protocol remain unclear. Opioid anesthetic efficacy is decided in part by MOR desensitization; thus, in this study, we investigated the desensitization profiles of REM and FEN to MOR. The efficacy and potency during the 1st administration of REM or FEN in activating the MOR were almost equal. Similarly, in ß arrestin recruitment, which determines desensitization processes, they showed no significant differences. In contrast, the 2nd administration of FEN resulted in a stronger MOR desensitization potency than that of REM, whereas REM showed a higher internalization potency than FEN. These results suggest that different ß arrestin-mediated signaling caused by FEN or REM led to their distinct desensitization and internalization processes. Our three-dimensional analysis, with in silico binding of REM and FEN to MOR models, highlighted that REM and FEN bound to similar but distinct sites of MOR and led to distinct ß arrestin-mediated profiles, suggesting that distinct binding profiles to MOR may alter ß arrestin activity, which accounts for MOR desensitization and internalization.

Single-Nucleotide Polymorphisms of the PAR2 and IL-17A Genes Are Significantly Associated with Chronic Pain.

Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case-control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine.

Novel Opioid Analgesics for the Development of Transdermal Opioid Patches That Possess Morphine-Like Pharmacological Profiles Rather Than Fentanyl: Possible Opioid Switching Alternatives Among Patch Formula.

BACKGROUND: Transdermal fentanyl is widely used in the treatment of severe pain because of convenience, safety, and stable blood concentrations. Nevertheless, patients often develop tolerance to fentanyl, necessitating the use of other opioids; transdermal buprenorphine patch is widely used as an analgesic agent, though available formulation does not provide comparable analgesic effect as transdermal fentanyl patch. Opioids bind to the opioid receptor (OR) to activate both G protein-mediated and ß-arrestin-mediated pathways. We synthesized morphine-related compounds with high transdermal absorbability (N1 and N2) and evaluated their OR activities pharmacologically in comparison with fentanyl and morphine. METHODS: In cells stably expressing µ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), G protein-mediated pathways were assessed using the CellKey and an intracellular cyclic adenosine monophosphate (cAMP) assay, while ß-arrestin-mediated pathways were analyzed with ß-arrestin recruitment and receptor internalization assays. Furthermore, analgesic effects were evaluated using a tail-flick test in mice, and the analgesic effect on fentanyl-tolerant mice was evaluated. RESULTS: In the CellKey and cAMP assays, both N1 and N2 showed the highest affinity for MOR and acted as full agonists as well as partial agonists for DOR and KOR. In the ß-arrestin and internalization assays, only fentanyl acted as a full agonist; N1 and N2 acted as partial agonists of MOR. In the mouse tail-flick test, N1 and N2 showed analgesic effects equivalent to those of fentanyl and morphine. In fentanyl-tolerant mice, fentanyl showed a diminished analgesic effect, whereas N1 and N2 as well as morphine retained their analgesic effects. CONCLUSIONS: While N1 and N2 have higher transdermal absorbability than fentanyl, they also have analgesic effects comparable to those of morphine, suggesting that they may be attractive compounds for the development of novel opioid patches for transitioning from fentanyl patches.

Anti-Inflammatory Action of Dexmedetomidine on Human Microglial Cells.

Neuroinflammation, where inflammatory cytokines are produced in excess, contributes to the pathogenesis of delirium. Microglial cells play a central role in neuroinflammation by producing and releasing inflammatory cytokines in response to infection, tissue damage and neurodegeneration. Dexmedetomidine (DEX) is a sedative, which reduces the incidence of delirium. Thus, we hypothesized that DEX may alleviate delirium by exhibiting anti-inflammatory action on microglia. In the present study, we investigated the anti-inflammatory action of DEX on human microglial HMC3 cells. The results indicated that DEX partially suppressed the IL-6 and IL-8 production by lipopolysaccharide (LPS)-stimulated HMC3 cells as well as the phosphorylation of p38 MAPK and IκB and the translocation of NF-κB. Furthermore, DEX substantially suppressed IL-6 and IL-8 production by unstimulated HMC3 cells as wells as the phosphorylation of p38 MAPK and IκB and the translocation of NF-κB. These observations suggest that DEX exhibits anti-inflammatory action on not only LPS-stimulated but also unstimulated microglial cells via the suppression of inflammatory signaling and cytokine production.

Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and ß-Arrestin-Mediated Pathways.

Opioid receptors (ORs) are classified into three types (µ, δ, and κ), and opioid analgesics are mainly mediated by µOR activation; however, their use is sometimes restricted by unfavorable effects. The selective κOR agonist nalfurafine was initially developed as an analgesic, but its indication was changed because of the narrow safety margin. The activation of ORs mainly induces two intracellular signaling pathways: a G-protein-mediated pathway and a ß-arrestin-mediated pathway. Recently, the expectations for κOR analgesics that selectively activate these pathways have increased; however, the structural properties required for the selectivity of nalfurafine are still unknown. Therefore, we evaluated the partial structures of nalfurafine that are necessary for the selectivity of these two pathways. We assayed the properties of nalfurafine and six nalfurafine analogs (SYKs) using cells stably expressing κORs. The SYKs activated κORs in a concentration-dependent manner with higher EC50 values than nalfurafine. Upon bias factor assessment, only SYK-309 (possessing the 3S-hydroxy group) showed higher selectivity of G-protein-mediated signaling activities than nalfurafine, suggesting the direction of the 3S-hydroxy group may affect the ß-arrestin-mediated pathway. In conclusion, nalfurafine analogs having a 3S-hydroxy group, such as SYK-309, could be considered G-protein-biased κOR agonists.

Successful management of segmental zoster paresis on the upper arm with temporally burst spinal cord stimulation.

Segmental zoster paresis (SZP) of the limbs is characterized by a focal, asymmetric neurogenic weakness that may occur in an extremity affected by herpes zoster (HZ). In this case report, we describe the case of a patient with SZP who presented with these problems and responded well to temporary spinal cord stimulation (SCS) and systematic rehabilitation. A 62-year-old female patient was referred for right upper limb pain, weakness, and insomnia due to pain. After completing the 14-day trial stimulation, the pain numerical rating scale of the patient in the right upper extremity decreased from 8/10 to 2/10. The Athens insomnia scale score decreased from 15/24 to 10/24. Furthermore, the grip strength of the right hands increased from 6.7 to 16.8 kg at discharge. We induced temporal SCS and rehabilitation of the right upper limb SZP and successfully reduced the pain. An in-depth understanding of the neurological complications secondary to HZ should be emphasized, with temporal SCS and rehabilitation expected to play a crucial role in the motor recovery of patients with SZP.

Paths of thoracic epidural catheters in children undergoing the Nuss procedure for pectus excavatum repair.

PURPOSE: To investigate the paths of thoracic epidural catheters in children, this retrospective study was performed. METHODS: We investigated 73 children aged 4 to 12 (mean ± SD 7.8 ± 2.3) years, who underwent the Nuss procedure for pectus excavatum repair under combined general and epidural anesthesia over a 5-year period at Tokyo Metropolitan Police Hospital. Following induction of general anesthesia, we inserted a radiopaque epidural catheter via the T5/6 or T6/7 interspace and advanced for 5 cm cephalad in the thoracic epidural space. We evaluated the paths of the epidural catheters on plain chest radiographs after surgery. RESULTS: The median level for the catheter tip location was T3 (range C6-T7), while the median number of vertebrae crossed by the catheter tips was 2.5. In most children, the catheters advanced straight for the first 2-3 cm (1-1.5 vertebrae) in the thoracic epidural space. However, they continued to advance straight in only 25 children, while they exhibited curved or coiled paths in the remaining 48. The catheter tips were located at higher levels in children with straight epidural catheter paths [median (range) T2 (C6-T4)] than in those with curved or coiled paths after the initial 2-3 cm [median (range) T4 (T2-T7)] (p < 0.0001). CONCLUSIONS: Our findings indicate that the course of epidural catheters in children is unpredictable after the first 2-3 cm in the thoracic epidural space. Clinicians should be aware of such findings, although further studies are required for confirmation.

Continuing versus withholding angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) combination tablets during perioperative periods in patients undergoing minor surgery: a single-blinded randomized controlled trial.

PURPOSE: This trial was conducted to compare effects of continuing versus withholding single-pill combination tablets consisting of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) on perioperative hemodynamics and clinical outcomes. METHODS: Patients undergoing minor abdominal or urological surgery (n = 106) were randomly assigned to Group C, in which ARB/CCB combination tablets were continued until surgery, or Group W, in which they were withheld within 24 h of surgery. Perioperative hemodynamics and clinical outcomes were compared between the Groups. RESULTS: The incidence of hypotension during anesthesia requiring repeated treatment with vasoconstrictors was higher in Group C than Group W (p = 0.0052). Blood pressure during anesthesia was generally lower in Group C than Group W (p < 0.05) despite significantly more doses of ephedrine and phenylephrine administrated in Group C (p = 0.0246 and p = 0.0327, respectively). The incidence of postoperative hypertension did not differ between Groups (p = 0.3793). Estimated glomerular filtration rate (eGFR) on the preoperative day did not differ between Groups (p = 0.7045), while eGFR was slightly lower in Group C than Group W on the first and third postoperative days (p = 0.0400 and p = 0.0088, respectively), although clinically relevant acute kidney injury did not develop. CONCLUSIONS: Continuing ARB/CCB combination tablets preoperatively in patients undergoing minor surgery increased the incidence of hypotension during anesthesia, increased requirements of vasoconstrictors to treat hypotension, and might deteriorate postoperative renal function, albeit slightly. These results suggest that withholding ARB/CCB tablets preoperatively is preferable to continuing them. CLINICAL TRIAL REGISTRATION: This trial is registered with the Japan Registry of Clinical Trials (jRCT) at Japanese Ministry of Health, Labour, and Welfare (Trial ID: jRCT1031190027).

In Vitro Analyses of Spinach-Derived Opioid Peptides, Rubiscolins: Receptor Selectivity and Intracellular Activities through G Protein- and ß-Arrestin-Mediated Pathways.

Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the ß-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are selective δ opioid receptor agonists, and their p.o. administration exhibits antinociceptive effects. Although the potency and effect of rubiscolins as G-protein-biased molecules are partially confirmed, their in vitro profiles remain unclear. We, therefore, evaluated the properties of rubiscolins, in detail, through several analyses, including the CellKeyTM assay, cADDis® cAMP assay, and PathHunter® ß-arrestin recruitment assay, using cells stably expressing µ, δ, κ, or µ/δ heteromer opioid receptors. In the CellKeyTM assay, rubiscolins showed selective agonistic effects for δ opioid receptor and little agonistic or antagonistic effects for µ and κ opioid receptors. Furthermore, rubiscolins were found to be G-protein-biased δ opioid receptor agonists based on the results obtained in cADDis® cAMP and PathHunter® ß-arrestin recruitment assays. Finally, we found, for the first time, that they are also partially agonistic for the µ/δ dimers. In conclusion, rubiscolins could serve as attractive seeds, as δ opioid receptor-specific agonists, for the development of novel opioid analgesics with reduced side effects.

Cerebrospinal fluid leak presented with the C1-C2 sign caused by spinal canal stenosis: a case report.

BACKGROUND: Intracranial hypotension is a disorder characterized by low cerebrospinal fluid (CSF) pressure typically caused by loss of CSF. Although some mechanisms account for the CSF leakage have been elucidated, spinal canal stenosis has never been reported as a pathological cause of intracranial hypotension. C1-C2 sign is a characteristic imaging feature, which indicates CSF collection between the spinous processes of C1 and C2, occasionally observed on magnetic resonance imaging (MRI) in patients with intracranial hypotension. CASE PRESENTATION: A 58-year-old man was presented to our institute with complaints of posterior cervical pain persisting for 3 months, along with numbness and muscle weakness of extremities. A fat suppression T2-weighted image of MRI illustrated fluid collection in the retrospinal region at C1-C2 level, and an 111In-DTPA cisternoscintigram clearly revealed the presence of CSF leakage into the same region. The MRI also showed stenosis in spinal canal at C3/4 level, and a computed tomography (CT) myelogram suggested a blockage at the same level. We gave a diagnosis as intracranial hypotension due to the CSF leakage, which might be caused by the spinal canal stenosis at C3/4 level. Despite 72 h of conservative therapy, a brain CT showed the development of bilateral subdural hematomas. We, therefore, performed burr-hole drainage of the subdural hematoma, blood-patch therapy at C1/2 level, and laminoplasty at C3-4 at the same time. Improvement of symptoms and imaging features which suggested the CSF leak and subdural hematoma were obtained post-operatively. CONCLUSION: The present case suggested the mechanism where the CSF leakage was revealed as fluid collection in the retrospinal region at C1-C2 level. Increased intradural pressure due to the spinal canal stenosis resulted in dural tear. CSF leaked into the epidural space and subsequently to the retrospinal region at C1-C2 level, due to the presence of spinal canal stenosis caudally as well as the vulnerability of the tissue structure in the retrospinal region at C1-C2 level. Thus, our theory supports the mechanisms of previously reported CSF dynamics associated to C1-C2 sign, and also, we suggest spinal canal stenosis as a novel etiology of intracranial hypotension.

[Refractory Erdheim-Chester disease with central nervous system lesion complicated by central diabetes insipidus].

We report a case of Erdheim-Chester disease (ECD) complicated with central diabetes insipidus that was refractory to several treatments. A 58-year-old female suffered from fatigue, fever, thirst, polyuria, leg pain, xanthoma of her upper eyelids, and disturbance of consciousness. Computed tomography (CT) imaging showed infiltration of perivascular soft tissue surrounding the aorta, hydronephrosis, and sclerotic lesions of the femurs and tibias. Magnetic resonance imaging showed the enhancement of expansile pachymeningeal lesions. A water deprivation test revealed the presence of central diabetes insipidus. The results of skin and bone marrow biopsies were consistent with ECD. The patient was treated with prednisone (30 mg daily) and interferon-α (6 mIU three times/week). The perivascular soft tissue showed a slight improvement, but she experienced cerebral hemorrhage 4 and 8 months later. Subsequently, she was treated biweekly with IV tocilizumab (8 mg/kg). Although her clinical symptoms improved, enlargement of the meningeal tumor and hydrocephalus led to disturbance of consciousness 6 months later. After the surgical debulking of the intracranial lesion, she was treated with two cycles of IV cladribine (0.12 mg/kg for 5 d). She had a transient clinical improvement but developed central nervous system disease marked by progressive neurological symptoms.

Association between treatment-related early changes in psychological factors and development of postherpetic neuralgia.

PURPOSE: To examine the association between catastrophizing and pain intensity with acute herpes zoster, and the association of treatment-related early changes in depressive symptoms, anxiety, and catastrophizing with postherpetic neuralgia (PHN) development, independent of acute pain intensity. METHODS: We analyzed 44 outpatient participants with acute herpes zoster who completed a 6-month follow-up. Participants completed a self-reported questionnaire with a Visual Analog Scale (VAS), the Pain Catastrophizing Scale (PCS), and the Hospital Anxiety and Depression Scale (HADS) at first visit, and 3 and 6 months, thereafter. We assessed associations between acute pain intensity and analyzed factors using univariate regression analyses. Univariate and bivariate logistic regression models were constructed to assess associations of variables at the first visit and early changes in psychological factors with PHN development. RESULTS: Sex, severe skin rash at first visit, PCS, and HADS depression were associated with acute pain intensity {standardized regression coefficient, 0.46 [95% confidence interval (CI) 0.12-0.74], 0.36 (95% CI 0.07-0.65), 0.33 (95% CI 0.03-0.62), 0.47 (95% CI 0.19-0.74), respectively}. Acute pain intensity and early change in pain intensity were associated with PHN development [odds ratio (OR) 1.08 (95% CI 1.02-1.14) OR 2.38 (95% CI 1.10-5.16), respectively]. Decreased PCS was associated with decreased risk of PHN development, independent of acute pain intensity [OR 0.31 (95% CI: 0.12-0.80)]. CONCLUSION: Catastrophizing was associated with acute pain intensity, and lower pain-related catastrophizing among patients with acute herpes zoster was associated with less risk of PHN development, independent of acute pain intensity.

Prevalence of chronic postsurgical pain after thoracotomy and total knee arthroplasty: a retrospective multicenter study in Japan (Japanese Study Group of Subacute Postoperative Pain).

We performed a multicenter observational study to assess the prevalence and risk factors of persistent pain after lung cancer surgery and total knee arthroplasty (TKA) in the Japanese population. After receiving Ethics Committee approval, a retrospective chart review was performed for patients who underwent surgery at seven university hospitals in Japan in 2013. A total of 511 patients who underwent lung cancer surgery and 298 patients who underwent TKA were included. The prevalence of chronic postsurgical pain (CPSP) at 3 and 6 months was 18 and 12% after lung surgery and 49 and 33% after TKA, respectively. The prevalence of analgesic use at 3 and 6 months was 16 and 9% after lung surgery and 34 and 22% after TKA, respectively. In both groups, preoperative analgesic use was associated with CPSP. Anesthetic methods or techniques during both types of surgery did not significantly affect the prevalence of CPSP. This is the first study in which the prevalence of CPSP after lung surgery and TKA in Japanese population was extensively evaluated in a multicenter trial. Further prospective studies are needed to confirm the prevalence of CPSP in the Japanese population and to identify risk factors and prevention methods.

Effects of dexmedetomidine on hemodynamics and respiration in intubated, spontaneously breathing patients after endoscopic submucosal dissection for cervical esophageal or pharyngeal cancer.

PURPOSE: We evaluated the hemodynamic and respiratory effects of dexmedetomidine in intubated, spontaneously breathing patients after endoscopic submucosal dissection (ESD) for cervical esophageal or pharyngeal cancer. METHODS: This retrospective study included 129 patients aged 66.5 ± 8.3 years, who underwent ESD under general anesthesia, and who were kept intubated overnight to prevent airway obstruction, receiving sedation with dexmedetomidine. Constant dexmedetomidine infusion at 0.51 ± 0.16 µg/kg/h was started intraoperatively (n = 109) or postoperatively (n = 20), following (n = 29) or not following (n = 100) loading doses, and continued until extubation. Hemodynamic and respiratory variables, and Richmond Agitation-Sedation Scale (RASS) score, were recorded. RESULTS: Postoperatively, 129 patients remained intubated while breathing spontaneously for 16.4 ± 3.3 h, and 124 patients could be sedated solely with dexmedetomidine, whereas 5 required rescue sedatives. During infusion, blood pressure decreased progressively until 12 h, whereas heart rate decreased only at 3 h. Hemodynamic alterations during dexmedetomidine infusion greatly depended not only on its hemodynamic effects but also on baseline hemodynamics before anesthesia. No serious adverse effect was noted. CONCLUSION: Dexmedetomidine in intubated, spontaneously breathing patients after ESD was safe and effective. Patient baseline hemodynamics could significantly affect hemodynamics during drug infusion. Without loading doses, plasma drug concentrations were expected to increase progressively. A progressive decrease in blood pressure and unchanged heart rate after an initial decrease suggested that hemodynamic effects of dexmedetomidine in our patients might differ from those reported in young volunteers, although further studies are required to elucidate these points.

[With the Characteristics of Chronic Pain Patients, Can the Therapeutic Effect of Antidepressant Duloxetine be Predicted?].

BACKGROUND: Duloxetine, an antidepressant, is used for treatment of pain, but the factors related to its effectiveness are not well known, and therefore we have performed a retrospective study. METHODS: Over a 22-month period from June 2012 patients with pain lasting for 3 months or more, with an NRS of 4 or higher, and given duloxetine within 3 months from their first diagnosis, were extracted from the medical records. These patients were compared and studied regarding their scores of the HADS (hos- pital anxiety and depression scale) at the time of first visit, duration of the disease, type of patient, and treat- ment effect after 1 month. RESULTS: The subjects were 61 patients, and they were categorized based on the presence of anxiety, the presence of dysphoria whether from organic or inor- ganic condition, and the duration of the disease, and no significant difference in the effectiveness of duloxetine was found. CONCLUSIONS: Duloxetine had an overall effectiveness of 50.8%, regardless of the presence of anxiety or depression, the duration of the disease and the type of diseases.

Usefulness of stroke volume index obtained with the FloTrac/ Vigileo system for the prediction of acute kidney injury after radical esophagectomy.

PURPOSE: To assess the impact of stroke volume index (SVI) at the end of esophagectomy upon postoperative renal function. METHODS: We reviewed medical records of 128 patients undergoing esophagectomy. Intraoperative hemodynamics were monitored with the FloTrac sensor/Vigileo monitor system in addition to standard monitors. Patients were divided into two groups according to SVI at the end of surgery: the normal SVI group (n = 76), with SVI ≥ 35 ml/m2, and the low SVI group (n = 52), with SVI<35 ml/m2. We compared postoperative renal function, indicated by serum creatinine and estimated glomerular filtration rate, on post-operative days 0 through 3. We also compared numbers of patients who developed postoperative acute kidney injury (AKI). RESULTS: Although there were no intergroup differences in preoperative renal function or other intraoperative hemodynamic variables, including arterial pressure, central venous pressure, stroke volume variation, a volume of infusion, urine output, and the total intraoperative in-out balance, estimated glomerular filtration rate was significantly lower and serum creatinine was significantly higher in the low SVI group than in the normal SVI group on postoperative days 1 and 2 (P<0.05). In addition, more patients developed postoperative AKI in the low SVI group than in the normal SVI group (12 of 52 vs. 5 of 76, P = 0.015). CONCLUSIONS: Low SVI at the end of esophagectomy may represent a risk factor for AKI in the early postoperative period. Further studies are required to examine whether maintaining SVI above 35 ml/m2 reduces the incidence of AKI after esophagectomy.