Serum Concentrations of Infliximab and IL-6 for Predicting One-Year Discontinuation of Infliximab Treatment Owing to Secondary Non-response in Patients with Rheumatoid Arthritis.

Secondary non-response to infliximab (IFX) occurs in some patients with rheumatoid arthritis (RA). Although therapeutic drug monitoring (TDM) is a useful tool to optimize IFX therapy, it is unclear whether it can help to identify the risk of secondary non-response. This study aimed to explore the utility of serum levels of IFX or other biomarkers to predict IFX discontinuation owing to secondary non-response. A single-center, retrospective study was conducted using the Kyoto University Rheumatoid Arthritis Management Alliance cohort database between 2011 and 2020. Serum IFX levels were measured using liquid chromatography-tandem mass spectrometry. An electrochemiluminescence assay was used to quantify serum levels of tumor necrosis factor-α and interleukin-6 and detect anti-drug antibodies. Eighty-four out of 310 patients were eligible for this study. The cutoff levels of biomarkers were determined by receiver operating characteristic analysis. IFX persistence was similar between groups stratified using IFX levels, tumor necrosis factor-α levels, interleukin-6 levels, and anti-drug antibodies positivity. The group with lower IFX and higher interleukin-6 levels had the worst therapy persistence (p = 0.017) and the most frequent disease worsening (90.0%, p < 0.001). Evaluating both interleukin-6 and IFX levels, not just IFX alone, enabled us to identify patients at risk of discontinuing IFX treatment. These findings support the utility of measuring IFX and interleukin-6 levels for successful maintenance therapy for RA.

Effect of Severe Renal Dysfunction on the Plasma Levels of DNA-Reactive Platinum after Oxaliplatin Administration.

Higher amounts of circulating ultrafilterable platinum (fPt) are found in patients with renal dysfunction receiving a constant dose of oxaliplatin. However, the increased systemic fPt levels do not increase oxaliplatin-induced toxicities. We hypothesized that renal dysfunction has minimal effect on the elimination rate of reactive fPt, and that the DNA-binding capacity is one of the properties of reactive Pt species. This study aimed to quantify DNA-reactive fPt in plasma and to evaluate the impact of severe renal dysfunction on its pharmacokinetics. The pharmacokinetics of oxaliplatin was assessed in rats with bilateral nephrectomy (BNx) and in a hemodialysis patient who received mFOLFOX7 therapy for advanced metastatic gastric cancer. The platinum concentrations were determined using inductively coupled plasma-mass spectrometry. The amount of DNA-reactive fPt in the plasma was evaluated by the reaction between plasma and calf thymus DNA. Compared to the sham group in rats, the BNx group had significantly higher plasma total fPt concentrations at 24 h after drug administration. However, there was no significant difference in the plasma levels of DNA-reactive fPt between the two groups. In a hemodialysis patient, the plasma levels of total fPt decreased to 35.9 and 7.3% at 2 and 14 d after treatment, respectively. The plasma level of DNA-reactive fPt also decreased to 1.9 and 0.6%, respectively, on these days. This study showed that severe renal dysfunction has a limited effect on the plasma levels of DNA-reactive fPt after oxaliplatin administration.

Dynamic Changes in Fluid Temperatures during Laser Irradiation Using Various Laser Modes: A Thermography-Based In Vitro Phantom Study.

The differences in dynamic thermal changes during laser lithotripsy between various laser pulse modes are unclear. We used thermography to evaluate the temporal changes in high-temperature areas during laser activation in order to compare different laser pulse modes. An unroofed artificial kidney model was used for the experiments. The laser fired for 60 s with a laser setting of 0.4 J/60 Hz in the following four different laser pulse modes without saline irrigation: short pulse mode (SPM), long pulse mode (LPM), virtual basket mode (VBM) and Moses mode (MM). Using the first 30 s of moving images, we compared the ratio of a high-temperature area of >43 °C to the total area every 5 seconds. The dynamic changes in fluid temperatures were shown to be different between the laser pulse modes. The extent of the high-temperature areas during the laser activation was large in the LPM and MM compared with the SPM and VBM. While the high-temperature areas expanded in an anterior direction in the early laser irradiation period using the LPM, they spread in a posterior direction in the early laser activation period using the MM. Although only the temperature profile in one specific plane was investigated, these results are considered useful for preventing thermal injuries during retrograde intrarenal surgeries.

Pelvicalyceal anatomy on the accessibility of reusable flexible ureteroscopy to lower pole calyx during retrograde intrarenal surgery.

OBJECTIVE: This study aimed to evaluate the pelvicalyceal anatomy on accessibility of reusable flexible ureteroscopy (fURS) to the lower pole calyx during retrograde intrarenal surgery (RIRS). METHODS: Here, 854 patients with ureteral or kidney stones with access to a renal collecting system using reusable fURS were classified into either the accessible group, in whom the deepest lower pole calyces could be touched; and the inaccessible group, in whom the deepest lower calyces could not be touched. We measured the infundibulopelvic angle (IPA), infundibular width (IW), infundibular length (IL), and calyceal pelvic height (CPH) using retrograde pyelograms and performed intergroup comparisons. RESULTS: The median IPA, IW, IL, and CPH in the accessible and inaccessible group were 60.5° and 45.6° (p < 0.001), 10.8 and 9.4 mm (p < 0.001), 33.2 and 36.4 mm (p < 0.001), and 25.9 and 30.9 mm (p < 0.001), respectively. IPA (OR 0.963, 95% CI 0.952-0.974, p < 0.001) and IW (OR 0.519, 95% CI 0.331-0.816, p = 0.004) were significant risk factors of renal pelvicalyceal anatomy related to the accessibility of the lower pole calyces. The cut-off value for IPA and IW was 45.8°(p < 0.001) and 7.8 mm (p < 0.001), respectively. CONCLUSIONS: IPA < 45.8° and IW <7.8 mm were negative predictors to access the lower pole calyces when using reusable fURS during RIRS.

Preparation and pharmaceutical properties of Hangeshashinto oral ointment and its safety and efficacy in Syrian hamsters with 5-fluorouracil-induced oral mucositis.

Chemotherapy-induced oral mucositis (COM) is a common adverse effect of cancer chemotherapy. Several clinical studies reported that repetitive use of mouthwashes containing 2.5-6.25% Hangeshashinto (HST), a Kampo formula, relieves COM, but the effect is insufficient. To solve this problem, we produced an oral ointment of 12% HST extract (considered quantitatively equivalent to 20% commercially available HST), which will increase the local concentrations of its active ingredients and prolong the contact time with COM. In this study, we evaluated the pharmaceutical properties (spreadability and stability) of HST oral ointment. In addition, its safety (oral mucosal irritation) and therapeutic effects on 5-fluorouracil-induced oral mucositis were evaluated in male Syrian hamsters. The HST ointment showed good spreadability and stability for more than 8 weeks at 4 °C. In the oral mucosal irritation test, topical application of HST ointment (0.2 g) three times per day for 14 days had no adverse effect on the oral mucosa of hamsters. In hamsters treated with 5-fluorouracil (60 mg/kg) twice, COM was induced by a submucosal injection of 5% acetic acid into the cheek pouch. When HST ointment (50 µg) was topically applied to the mucositis area once per day for 12 days, the area and macroscopic score of mucositis were significantly decreased, and the depth of the wound tended to be reduced compared with the lactose ointment-treated control animals. These findings suggest that HST oral ointment shows good properties in spreadability, stability, and safety, and elicits a therapeutic effect in an animal model of COM.

N-terminus of Etanercept is Proteolytically Processed by Dipeptidyl Peptidase-4.

PURPOSE: Biologics are structurally heterogeneous and can undergo biotransformation in the body. Etanercept (ETN) is a fusion protein composed of a soluble tumor necrosis factor (TNF) receptor and the Fc portion of human immunoglobulin G1. The N-terminus of ETN has a putative sequence cleaved by dipeptidyl peptidase-4 (DPP-4). The purpose of this study was to investigate the biotransformation of ETN in humans and mice and evaluate its effects on functional properties. METHODS: An analytical method using liquid chromatography-mass spectrometry (LC-MS/MS) was established. The N-terminal heterogeneity of ETN was assessed in the serum of patients with rheumatoid arthritis or mice receiving ETN. The in vitro N-terminal truncation was explored using recombinant DPP-4. The binding affinity to TNF-α or TNF-ß was investigated using an in-house enzyme-linked immunosorbent assay. RESULTS: In the formulations, about 90% of ETN had an intact N-terminus, while the N-terminal truncated form was most abundant in the serum of the patients with rheumatoid arthritis and mice. Recombinant human DPP-4 cleaved two amino acids from the N-terminus of ETN in vitro. Sitagliptin, a DPP-4 inhibitor, inhibited N-terminal truncation both in vivo and in vitro. However, N-terminal truncation did not affect the binding ability to TNF-α or TNF-ß and the pharmacokinetics of ETN. ETN biosimilars exhibited similar characteristics to the reference product in vivo and in vitro. CONCLUSIONS: ETN undergoes N-terminal truncation in the body, and DPP-4 cleaves exogenous ETN via N-terminal proteolysis. The application of an MS-based assay will detect novel biotransformation of therapeutic proteins.

Infliximab Treatment Persistence among Japanese Patients with Chronic Inflammatory Diseases: A Retrospective Japanese Claims Data Study.

Infliximab (IFX) has contributed to the treatment of several chronic inflammatory diseases, including Crohn's disease (CD), ulcerative colitis (UC), psoriasis (Pso), and rheumatoid arthritis (RA). However, the loss of response in some patients with long-term IFX therapy has been a major problem. Randomized controlled trials (RCTs) are limited in their short duration and lack of generalizability to the real-world population. We aimed to describe the persistence rates of IFX therapy to estimate its long-term effectiveness in clinical practice. Claims data from the Japan Medical Data Center database from January 2005 to June 2017 were used. The study population was identified based on the International Classification of Diseases, 10th Revision and the Anatomical Therapeutic Chemical Classification System. The 5-year persistence rates of IFX therapy were estimated using the Kaplan-Meier method. Overall, 281, 235, 41, and 222 patients with CD, UC, Pso, and RA, respectively, were selected. The 5-year persistence rates for IFX claims were 62.9, 38.9, 22.1, and 28.1% in patients with CD, UC, Pso, and RA, respectively. Patients with CD and UC administered IFX beyond the median dose had higher persistence rates. In patients with RA, female sex and no prior use of other biologics were associated with longer persistence. In conclusion, IFX persistence rates differed across chronic inflammatory diseases, which did not correspond to the results of the major RCTs. Factors associated with longer IFX persistence were identified in each disease group. Our findings may provide useful information to facilitate the proper use of IFX.

Mouse Gastric Epithelial Cells Resist CagA Delivery by the Helicobacter pylori Type IV Secretion System.

The initial step in bacterial infection is adherence of the bacterium to the target cell surface. Helicobacter pylori exploits the interaction of bacterial adhesin protein HopQ with human epithelial CEACAMs (CEACAM1, 5, and 6) to stably adhere to gastric epithelial cells, which is necessary for delivery of the H. pylori CagA oncoprotein into the epithelial cells via a type IV secretion system. In contrast to human CEACAMs, however, HopQ does not interact with Ceacam1 (mouse CEACAM1) in vitro or in CHO cells ectopically expressing Ceacam1. Since the mouse genome lacks Ceacam5 and Ceacam6, no significant HopQ-Ceacam interaction may occur in mouse gastric epithelial cells. Here, we found that the mouse stomach has a much lower expression level of Ceacam1 than the expression level of CEACAM1 in the human stomach. Consistently, mouse gastric epithelial cells resist CagA delivery by cagA-positive H. pylori, and the delivery is restored by ectopic expression of human CEACAM1 or CEACAM5 in mouse gastric epithelial cells. Thus, despite the fact that mice are routinely used for H. pylori infection studies, a low expression level of Ceacam1 in the mouse stomach together with the loss or greatly reduced interaction of HopQ with Ceacams make the mouse an inappropriate model for studying the role of H. pylori-delivered CagA in gastric pathogenesis, including the development of gastric cancer.

Efficiency of novel shielding curtains combined with pulsed irradiation for reducing radiation exposure in an operating room: Human renal collecting system phantom study.

OBJECTIVE: To evaluate the impact of novel shielding curtains combined with pulsed irradiation mode to protect medical radiation workers from radiation exposure during ureteroscopy. METHODS: 0.25 mm Pb equivalent novel shielding curtains were mounted to the caudal and bilateral sides of the operating table in the ureteroscopy setting. C-arm was positioned as per normal in the operating room with the X-ray tube under the patient table. A water-filled anthropomorphic renal collecting system phantom was positioned in the standard position on the operating table that was set at a height of 100 cm. The ionization chambers were also positioned at a height of 100 cm and set in eight positions. We took measurements at distances of 50, 100, 150, and 200 cm from the phantom with the focus directed toward the X-ray tube. We measured the spatial distribution of the scattered radiation dose in four combinations: (1) continuous irradiation mode without novel shielding curtains; (2) pulsed irradiation mode (11 films per second) without novel shielding curtains; (3) continuous irradiation mode with novel shielding curtains; and (4) pulsed irradiation mode with novel shielding curtains. Continuous or pulsed irradiation was activated for 30 s each time. RESULTS: Pulsed irradiation mode with novel shielding curtains was a significantly more efficient method than other combinations to reduce scattered radiation exposure in this study (P < 0.001). There was approximately a 95% reduction in scattered radiation exposure with the pulsed irradiation mode with novel shielding curtains set up as compared with continuous irradiation mode without novel shielding curtains. CONCLUSION: Combining a novel shielding curtain and using a low pulse radiation setting can greatly reduce radiation exposure during ureteroscopic procedures.

Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis.

Infection with CagA-producing Helicobacter pylori plays a causative role in the development of gastric cancer. Upon delivery into gastric epithelial cells, CagA deregulates prooncogenic phosphatase SHP2 while inhibiting polarity-regulating kinase PAR1b through complex formation. Here, we show that CagA/PAR1b interaction subverts nuclear translocation of BRCA1 by inhibiting PAR1b-mediated BRCA1 phosphorylation. It hereby induces BRCAness that promotes DNA double-strand breaks (DSBs) while disabling error-free homologous recombination-mediated DNA repair. The CagA/PAR1b interaction also stimulates Hippo signaling that circumvents apoptosis of DNA-damaged cells, giving cells time to repair DSBs through error-prone mechanisms. The DSB-activated p53-p21Cip1 axis inhibits proliferation of CagA-delivered cells, but the inhibition can be overcome by p53 inactivation. Indeed, sequential pulses of CagA in TP53-mutant cells drove somatic mutation with BRCAness-associated genetic signatures. Expansion of CagA-delivered cells with BRCAness-mediated genome instability, from which CagA-independent cancer-predisposing cells arise, provides a plausible "hit-and-run mechanism" of H. pylori CagA for gastric carcinogenesis.

Cilostazol is an effective causal therapy for preventing paclitaxel-induced peripheral neuropathy by suppression of Schwann cell dedifferentiation.

Chemotherapy-induced peripheral neuropathy (CIPN) can lead to discontinuation of chemotherapy and is consequently a serious impediment to effective cancer treatment. Due to our limited understanding of mechanisms underlying the pathogenesis of CIPN, no causal therapy has been approved for relief of this condition. We previously demonstrated that taxanes (paclitaxel and docetaxel) induce Schwann cell dedifferentiation, characterized by increased expression of p75 and galectin-3, ultimately leading to demyelination. These changes appear to be responsible for CIPN pathogenesis. This study was designed to identify a novel candidate therapeutic for CIPN with the ability to suppress paclitaxel-induced Schwann cell dedifferentiation. Given that elevation of cyclic adenosine monophosphate (cAMP) signaling participates in Schwann cell differentiation, we performed immunocytochemical screening of phosphodiesterase (PDE) inhibitors. We found that the PDE3 inhibitor cilostazol strongly promoted differentiation of primary cultures of rat Schwann cells via a mechanism involving cAMP/exchange protein directly activated by cAMP (Epac) signaling. Co-treatment with cilostazol prevented paclitaxel-induced dedifferentiation of Schwann cell cultures and demyelination in a mixed culture of Schwann cells and dorsal root ganglia neurons. Notably, continuous oral administration of cilostazol suppressed Schwann cell dedifferentiation within the sciatic nerve and the development of mechanical hypersensitivity in a mouse model of paclitaxel-related CIPN. Importantly, cilostazol potentiated, rather than inhibited, the anti-cancer effect of paclitaxel on the human breast cancer cell line MDA-MB-231. These findings highlight the potential utility of cilostazol as a causal therapeutic that avoids the development of paclitaxel-related CIPN without compromising anti-cancer properties.

Pronociceptive Roles of Schwann Cell-Derived Galectin-3 in Taxane-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of taxanes such as paclitaxel and docetaxel. Despite the high medical needs, insufficient understanding of the complex mechanism underlying CIPN pathogenesis precludes any endorsed causal therapy to prevent or relieve CIPN. In this study, we report that elevation of plasma galectin-3 level is a pathologic change common to both patients with taxane-treated breast cancer with CIPN and a mouse model of taxane-related CIPN. Following multiple intraperitoneal injections of paclitaxel in mice, galectin-3 levels were elevated in Schwann cells within the sciatic nerve but not in other peripheral organs or cells expressing galectin-3. Consistent with this, paclitaxel treatment of primary cultures of rat Schwann cells induced upregulation and secretion of galectin-3. In vitro migration assays revealed that recombinant galectin-3 induced a chemotactic response of the murine macrophage cell line RAW 264.7. In addition, perineural administration of galectin-3 to the sciatic nerve of naive mice mimicked paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. By contrast, chemical depletion of macrophages by clodronate liposomes suppressed paclitaxel-induced mechanical hypersensitivity despite the higher level of plasma galectin-3. Deficiency (Galectin-3 -/- mice) or pharmacologic inhibition of galectin-3 inhibited paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. In conclusion, we propose that Schwann cell-derived galectin-3 plays a pronociceptive role via macrophage infiltration in the pathogenesis of taxane-induced peripheral neuropathy. Therapies targeting this phenomenon, which is common to patients with CIPN and mouse models, represent a novel approach to suppress taxane-related CIPN. SIGNIFICANCE: These findings demonstrate that the elevation of plasma galectin-3 is a CIPN-related pathologic change common to humans and mice, and that targeting galectin-3 is a therapeutic option to delay CIPN progression.

[A Case of a Young Patient with Nested Variant of Urothelial Carcinoma of the Bladder].

A 26-year-old man visited our hospital with a complaint of macrohematuria. Cystoscopy revealed a nodular tumor around the right ureteral orifice. Transurethral resection of bladder tumor was performed, and the tumor was pathologically diagnosed as the nested variant of urothelial carcinoma (NVUC). Radical cystectomy and modified Studer orthotopic neobladder reconstruction were performed. The pathological stage was pT2a, pN2. The patient received 2 courses of adjuvant chemotherapy consisting of gemcitabine and cisplatin. The patient is currently free from disease at 31 months after the treatment. To our knowledge, this case report represents the youngest case of NVUC.

Pathological complete response after nivolumab therapy following angiogenesis inhibitors in a patient with metastatic renal cell carcinoma.

INTRODUCTION: Nivolumab is effective for advanced renal cell carcinoma; however, reports are limited wherein nivolumab is combined with sequential therapy of angiogenesis inhibitors and metastasectomy. CASE PRESENTATION: A 65-year-old man was diagnosed with left renal cell carcinoma of cT2aN0M1 with lung metastasis. The patient underwent nephrectomy and sequential therapy with interferon-α and angiogenesis inhibitors. Lung metastasis decreased by angiogenesis inhibitors, but new right adrenal gland metastasis appeared. Nivolumab as the fifth systemic therapy remarkably shrank the metastasis. After discontinuing nivolumab therapy, the metastasis continued to shrink. The patient underwent adrenalectomy, and pathological analysis revealed no remnant cancer cells in the specimen, confirming a pathological complete response. Twenty months postoperatively, he remains in good health without recurrence. CONCLUSION: We report a rare case with renal cell carcinoma of a pathological complete response by nivolumab after angiogenesis inhibitors.

Removal of an encrusted ureteral stent by cutting the stent with a holmium laser using 4.5-Fr semi-rigid and flexible ureteroscopes.

INTRODUCTION: Ureteral stents (double-J stents) are widely used in urology to prevent or relieve ureteral obstruction and have become an integral part of urological practice. We have often experienced cases in which a stent cannot be removed due to encrustation. CASE PRESENTATION: We describe the case of a 54-year-old male, who presented with a severely encrusted ureteral stent, which had only been inserted for one month until second surgery for renal stones. The ureteral stent could not be removed as it had become encrusted with renal stones. The encrusted ureteral stent was successfully removed by cutting it with a Ho:YAG laser using 4.5/6.5-Fr semi-rigid and flexible ureteroscopes retrogradely. The patient subsequently remained stone-free without any complication. CONCLUSION: We experienced a case in which an encrusted ureteral stent was successfully removed retrogradely. Technological advancements in endourology will hopefully make the treatment of such cases safer and less invasive.

Schwann cell-derived CXCL1 contributes to human immunodeficiency virus type 1 gp120-induced neuropathic pain by modulating macrophage infiltration in mice.

The neuroinflammatory responses to human immunodeficiency virus type 1 (HIV-1) coat proteins, such as glycoprotein 120 (gp120), are considered to be responsible for the HIV-associated distal sensory neuropathy. Accumulating evidences suggest that T-cell line tropic X4 gp120 increases macrophage infiltration into the peripheral nerves, and thereby induces neuroinflammation leading to pain. However, the mechanisms underlying X4 gp120-induced macrophage recruitment to the peripheral nervous systems remain unclear. Here, we demonstrated that perineural application of X4 gp120 from HIV-1 strains IIIB and MN elicited mechanical hypersensitivity and spontaneous pain-like behaviors in mice. Furthermore, flow cytometry and immunohistochemical studies revealed increased infiltration of bone marrow-derived macrophages into the parenchyma of sciatic nerves and dorsal root ganglia (DRG) 7 days after gp120 IIIB or MN application. Chemical deletion of circulating macrophages using clodronate liposomes markedly suppressed gp120 IIIB-induced pain-like behaviors. In in vitro cell infiltration analysis, RAW 264.7 cell (a murine macrophage cell line) was chemoattracted to conditioned medium from gp120 IIIB- or MN-treated cultured Schwann cells, but not to conditioned medium from these gp120-treated DRG neurons, suggesting possible involvement of Schwann cell-derived soluble factors in macrophage infiltration. We identified using a gene expression array that CXCL1, a chemoattractant of macrophages and neutrophils, was increased in gp120 IIIB-treated cultured Schwann cells. Similar to gp120 IIIB or MN, perineural application of recombinant CXCL1 elicited pain-like behaviors accompanied by macrophage infiltration to the peripheral nerves. Furthermore, the repeated injection of CXCR2 (receptor for CXCL1) antagonist or CXCL1 neutralizing antibody prevented both pain-like behaviors and macrophage infiltration in gp120 IIIB-treated mice. Thus, the present study newly defines that Schwann cell-derived CXCL1, secreted in response to X4 gp120 exposure, is responsible for macrophage infiltration into peripheral nerves, and is thereby associated with pain-like behaviors in mice. We propose herein that communication between Schwann cells and macrophages may play a prominent role in the induction of X4 HIV-1-associated pain.

Improvement of peripheral vascular impairment by a phosphodiesterase type 5 inhibitor tadalafil prevents oxaliplatin-induced peripheral neuropathy in mice.

Oxaliplatin, a platinum-based chemotherapeutic drug, frequently induces peripheral neuropathy. Accumulating evidences suggest a possible relationship between peripheral vascular impairment and peripheral neuropathy. In this study, we investigated the effects of vasodilators on cumulative peripheral neuropathy induced by repeated injections of oxaliplatin (10 mg/kg) once a week for 8 weeks in mice. Single injections of vasodilators, including a phosphodiesterase type 5 inhibitor tadalafil acutely alleviated oxaliplatin-induced cold hypersensitivity, while tadalafil had no effect on the mechanical hypersensitivity. By contrast, long-term administration of tadalafil (0.1% in chow diets) during the oxaliplatin injection period reduced the oxaliplatin-induced decreases in skin temperature and blood flow without affecting platinum concentrations in blood, sciatic nerves, and dorsal root ganglion. The long-term administration significantly suppressed cold, mechanical, and electrical current hypersensitivities as well as thermal hypoesthesia. Furthermore, it prevented the decreases in sensory nerve conductance velocity and the number of endoneurial microvessels, and axon degeneration in the sciatic nerves. In vitro studies confirmed that tadalafil does not interfere with the cytotoxicity of oxaliplatin against human cancer cell lines. Altogether, these results suggest that improvement of peripheral vascular impairment by tadalafil could alleviate and prevent oxaliplatin-induced peripheral neuropathy.

[Identification of biomarkers and new therapies for taxane-induced peripheral neuropathy].

Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect frequently caused by taxanes. Because the mechanisms underlying CIPN pathogenesis remain to be fully elucidated, there is no indicator for objective diagnosis like a biomarker. In addition, treatment options for CIPN is still unsatisfactory. We have previously demonstrated that paclitaxel preferentially impair myelin-forming Schwann cells, and consequently induce dedifferentiation and demyelination of Schwann cells. Recently, in a paclitaxel CIPN model mouse, we found that an inflammatory factor is released from dedifferentiated Schwann cells in the mouse sciatic nerve into the blood, highly correlated with the on-set of mechanical hypersensitivity. On the other hand, considering our previous findings, it seems that some drugs, which supply newly formed mature Schwann cells at the sites of demyelinated lesions, may be a new beneficial therapy for taxane-induced peripheral neuropathy. In this review, we will introduce our findings about new therapeutic drug candidate for taxane-related CIPN based on this concept, and plasma biomarker to detect CIPN on-set and progression.

Concentration and Glycoform of Rituximab in Plasma of Patients with B Cell Non-Hodgkin's Lymphoma.

PURPOSE: Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. METHODS: Twenty B cell non-Hodgkin's lymphoma patients who were treated with rituximab for the first time or after more than one year's abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. RESULTS: Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. CONCLUSION: Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.