Poor performance status is a risk factor for higher detection of Gram positive coccus in stone-related pyelonephritis.

INTRODUCTION: We aimed to investigate the detection rate of causative organisms in stone-related pyelonephritis and to compare their distribution according to patient backgrounds. METHODS: We retrospectively identified patients with stone-related pyelonephritis. Clinical data were collected between November 2012 and August 2020 at Wakayama Medical University Hospital, including on patient backgrounds and causative organisms. Patients were categorized by Eastern Cooperative Oncology Group performance status (PS) as the good PS group (0, 1) and the poor PS group (2-4). Bacteria were divided into Gram-positive cocci (GPC) or non-GPC groups and logistic regression analysis was used to examine factors that predict detection of GPC. RESULTS: Seventy-nine patients had stone-related pyelonephritis, 54 (68.4 %) in the good PS group and 25 (31.6 %) in the poor PS group. In the good PS group, Escherichia coli (67 %) was followed by Klebsiella species (9 %), while in the poor PS group, Escherichia coli (20 %) was followed by Enterococci and Staphylococci (12 %). GPC detection rate was significantly higher in the poor PS group than in the good PS group (40.0 % vs 14.8 %, p = 0.016), and multivariate logistic regression analysis showed that poor PS was an independent factor predicting detection of GPC (OR = 6.54, p = 0.02). CONCLUSIONS: The distribution of the causative organisms in stone pyelonephritis was similar to that in common complicated urinary tract infections. Poor PS may be an independent predictor of GPC detection in patients with stone pyelonephritis.

Three cases of open surgical procedures on ileal conduits for the repair of benign ureteroenteric anastomotic strictures after total pelvic exenteration of rectal tumors.

Ureteroenteric anastomotic strictures (UEAS) are typical complications after creating an ileal conduit for total pelvic exenteration (TPE) of rectal tumors. We report the ileal conduit for reconstruction in three patients, in the age-range of 47-73 years. Case 1 was when a left-sided UEAS had sufficient length of ureter for anastomosis, Case 2 was a right-sided UEAS with sufficient length of ureter for anastomosis, and Case 3 was a left-sided UEAS with insufficient length of ureter for anastomosis. There were no complications after operation and no recurrence of UEAS. It is important to learn the open surgical procedures for repair of a benign UEAS after TPE of rectal cancers. This has fewer complications and is safe in the long term.

How many times can patients tolerate reoperation for the local recurrence of colorectal cancer in terms of complications?

The frequency of resection for the recurrence of colorectal cancer has not been investigated in previous studies. Likewise, the related postoperative complications and the limit for indicating surgical resection has not been reported. Herein, we reported the complications of a highly frequent surgical approach for rectal cancer recurrence, i.e., exceeding three reoperations, based on our clinical experience. We included 15 cases exceeding two operations for the local recurrence of colorectal cancer from 2014 to 2019. We examined the postoperative complications classified as Clavien?Dindo IIIb. The positive rates of the complications were 0 (0.0%), 0 (0.0%), 2 (13.3%), 3 (37.5%), and 0 (0.0%) for the primary, 1st recurrent, 2nd recurrent, 3rd recurrent, and 4th recurrent operation group (p=0.027), respectively. It is important to exercise caution in handling cases exceeding two reoperations (exceeding three reoperations including the primary operation). J. Med. Invest. 70 : 369-376, August, 2023.

Autopsy case of a patient with rapidly progressive combined small-cell lung carcinoma with spindle-shaped cell tumor.

A 69-year-old Japanese man visited our hospital because of worsening shortness of breath. His chest computed tomography (CT) showed a giant left lung mass with a massive left pleural effusion. He could not be treated with chemotherapy and eventually died from a rapidly progressive tumor. He was diagnosed with combined small cell lung carcinoma (C-SCLC) with spindle-shaped cell tumor at autopsy. C-SCLC is characterized by pathologically concurrent SCLC and adenocarcinoma or squamous cell carcinoma, or rarely, spindle-shaped cell tumor. The clinical course of C-SCLC with spindle-shaped cell tumor has not previously been determined. Our patient's tumor increased by 2.59-fold in 20 days. The combination of C-SCLC with spindle-shaped cell tumor suggested rapid progression and a poor prognosis.

Suppressive effects of Ixodes persulcatus sialostatin L2 against Borrelia miyamotoi-stimulated immunity.

Borrelia miyamotoi infection is an emerging tick-borne disease that causes hard tick-borne relapsing fever. B. miyamotoi is transmitted through the bite of ticks, including Ixodes persulcatus. Although accumulating evidence suggests that tick salivary proteins enhance the infectivity of other tick-borne pathogens, the association of B. miyamotoi with tick-derived proteins remains unknown. In this study, the effect of I. persulcatus sialostatin L2 (Ip-sL2), a tick-derived cystatin, on specific immunity to B. miyamotoi was preliminarily investigated in vitro. Mice were immunized with heat-killed B. miyamotoi and in vitro analyses of the splenocytes of the immunized mice indicated that the expression levels of the activation markers of CD11c+ and CD3+ cells were significantly upregulated by B. miyamotoi stimulation. Spleen cells from B. miyamotoi-immunized mice were used to determine whether Ip-sL2 regulates murine immune responses against B. miyamotoi. Treatment with Ip-sL2 in vitro inhibited the activation of CD11c+ and CD3+ cells as well as inflammatory cytokine production by cultured splenocytes. These findings show that Ip-sL2 has modulatory effects on murine immune responses to B. miyamotoi. Therefore, it is necessary to clarify in the future whether Ip-sL2 is involved in the enhanced infectivity of B. miyamotoi.

A Defucosylated Mouse Anti-CD10 Monoclonal Antibody (31-mG2a-f) Exerts Antitumor Activity in a Mouse Xenograft Model of CD10-Overexpressed Tumors.

CD10 is a glycosylated transmembrane protein and is known as a membrane endopeptidase. It is expressed on predifferentiated lymphocyte progenitor, epithelial, stromal, and tumor cells. Therefore, antibodies against CD10 are used for diagnosing follicular lymphoma and solid tumors, including renal carcinomas. In this study, we developed an anti-human CD10 monoclonal antibody, clone C10Mab-31 (IgG1, kappa), which detects CD10 by flow cytometry and shows high affinity for CD10-overexpressed CHO-K1 (CHO/CD10) cells. Furthermore, the defucosylated mouse IgG2a version of C10Mab-31 (31-mG2a-f) exhibits antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antitumor activities in mouse xenografts of CHO/CD10 cells. These results indicate that 31-mG2a-f exerts antitumor effects against CD10-expressing tumors and could be valuable as part of an antibody treatment regimen for them.

A Defucosylated Mouse Anti-CD10 Monoclonal Antibody (31-mG2a-f) Exerts Antitumor Activity in a Mouse Xenograft Model of Renal Cell Cancers.

CD10 is a cell surface metalloendopeptidase that cleaves and degrades many secreted physiologically active peptides by its enzymatic activity. Although CD10 expression has been found in various types of cells, its expression is increased in several cancers, including renal cancer. In this study, the antitumor activity of a novel anti-human CD10 monoclonal antibody (mAb) was investigated. A defucosylated mouse IgG2a version of C10Mab-31 (31-mG2a-f) was created from an anti-CD10 mAb, C10Mab-31 (IgG1, kappa). Both C10Mab-31 and 31-mG2a-f specifically reacted with endogenous CD10 in renal cancer cells, VMRC-RCW, with the dissociation constant (KD) values of 6.3 × 10-9 M and 1.1 × 10-9 M, respectively, indicating high binding affinity. To further examine the anti-CD10 mAb-mediated effector functions, the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) were examined. The 31-mG2a-f significantly exhibited ADCC and CDC against VMRC-RCW cells in vitro. Furthermore, 31-mG2a-f exhibited antitumor activities in mouse xenografts of VMRC-RCW cells. These results suggest that 31-mG2a-f exerts antitumor activities against CD10-expressing renal cancers and could be a valuable therapeutic candidate for treating them.

Epitope Mapping of an Anti-CD10 Monoclonal Antibody (MME/1870) Using Enzyme-Linked Immunosorbent Assay.

CD10 is a glycosylated transmembrane protein and is known as a membrane endopeptidase. CD10 is expressed on predifferentiated lymphocyte progenitor, epithelial, stromal, and tumor cells. Antibodies against CD10 are used for the diagnosis of follicular lymphoma. Anti-human CD10 monoclonal antibody (clone MME/1870) can be used for Western blotting and immunohistochemical analyses. This study examined the critical epitope of MME/1870 using enzyme-linked immunosorbent assay (ELISA) with synthesized peptides. First, we performed ELISA with deletion mutants, and MME/1870 reacted to the 501-520 amino acid sequence of CD10. Next, we analyzed the reaction to 20 point mutants, and MME/1870 did not recognize the alanine-substituted peptides of Y507A, I511A, I512A, and L515A. These results indicate that the binding epitope of MME/1870 includes Tyr507, Ile511, Ile512, and Leu515 of CD10.

An Autopsy Case of An Acute Exacerbation of Idiopathic Pulmonary Fibrosis Triggered by the Inhalation of a Waterproofing Spray.

An 82-year-old Japanese man with idiopathic pulmonary fibrosis (IPF) experienced dyspnea after using a waterproofing spray in a closed room. He presented with hypoxemia and his chest computed tomography showed additive bilateral diffuse ground-glass attenuation on fibrosis, which was diagnostic of an acute exacerbation of IPF (AE-IPF). Combined treatment with high-dose corticosteroids and immunosuppressants were ineffective, and he later died of respiratory failure. Autopsy findings showed diffuse alveolar damage with honeycombing. His medical history and autopsy histopathology suggested AE-IPF caused by the inhalation of a waterproofing spray.

Myosteatosis as a novel predictor of urinary incontinence after robot-assisted radical prostatectomy.

OBJECTIVES: To evaluate the impact of sarcopenia and myosteatosis on urinary incontinence after prostatectomy. METHODS: We retrospectively reviewed consecutive patients who underwent robot-assisted radical prostatectomy without nerve sparing between December 2012 and March 2019. Psoas muscle index and average total psoas density, which were measured on preoperative computed tomography images at level L3, were used to evaluate sarcopenia and myosteatosis, respectively. In addition, several magnetic resonance imaging variables associated with pelvic muscles, the urethra and the prostate were measured. Urinary continence was defined as non-use or use of just one incontinence pad per day. Logistic regression analyses aimed to identify the predictors of urinary incontinence 3 and 12 months after surgery. RESULTS: Overall, 121 patients were included in the analysis. The incidence rates of urinary incontinence 3 and 12 months after surgery were 42% (51/121 cases) and 16% (19/121 cases), respectively. Logistic multivariable analysis showed that low average total psoas density was the only significant independent predictor of urinary incontinence 3 months after surgery (P < 0.01), and low obturator internus muscle thickness (P = 0.01), short membranous urethral length (P = 0.01) and low average total psoas density (P < 0.01) were significant independent predictors of urinary incontinence 12 months after surgery. By contrast, psoas muscle index was not statistically associated with urinary incontinence after surgery. CONCLUSIONS: Myosteatosis (low average total psoas density) could be a novel predictor of urinary incontinence after robot-assisted radical prostatectomy.

Combined detection of lymphocyte clonality and MALT1 translocations in bronchoalveolar lavage fluid for diagnosing pulmonary lymphomas.

Diagnosis of pulmonary lymphoma using small tissue samples is difficult and often requires surgical procedures; thus, a less invasive sampling method is desirable. We previously showed that pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma can be diagnosed by detecting MALT lymphoma translocation gene 1 (MALT1) translocations in bronchoalveolar lavage fluid (BALF) cells. Analysis of B-cell clonality based on immunoglobulin heavy chain (IGH) gene rearrangements was also reportedly useful for diagnosing pulmonary lymphoma. The aim of this prospective multicenter study was to evaluate the yet unknown diagnostic potential of combined detection of MALT1 translocations and clonality using BALF. We analyzed B- and T-cell clonality based on IGH and T-cell receptor (TCR) rearrangements together with MALT1 translocations using BALF of patients with clinically suspected pulmonary lymphomas. In total, 39 patients were evaluated and categorized into three groups: B-cell lymphoma, lymphoproliferative disorders, and other diseases. IGH rearrangement detection for B-cell lymphoma diagnosis exhibited sensitivity and specificity of 88.9% and 90.0%, respectively. TCR rearrangements were not observed in patients with B-cell lymphomas. The presence of IGH rearrangements together with the absence of TCR rearrangements indicated 96.0% specificity for the diagnosis of B-cell lymphoma. The sensitivity and specificity of MALT1 translocations for diagnosing MALT lymphoma were 28.6% and 100%, respectively. The combined detection of lymphocyte clonality and MALT1 translocations using BALF is suitable for screening and diagnosis of B-cell lymphomas. Analysis of specific genes such as MALT1 should improve the precision of B-cell lymphoma diagnosis.

Immune checkpoint inhibitors-induced eosinophilic pneumonia: A case report.

A 78-year-old male with renal cell carcinoma was treated with combined immunotherapy of nivolumab and ipilimumab. After four courses of the treatment, a chest computed tomography (CT) revealed newly formed ground-glass opacities (GGOs) in both the lower lung lobes; drug-induced pneumonia was speculated. Eosinophil counts were elevated in both peripheral blood and bronchoalveolar lavage fluid. Both the immune checkpoint inhibitors (ICIs) were discontinued, following which the chest CT findings improved. Based on these findings, a diagnosis of ICI-induced eosinophilic pneumonia was made. Hence, clinicians should be wary of the risk of eosinophilic pneumonia during ICI-anticancer therapy.

Natural History of Asymptomatic Pseudoaneurysm Soon After Robot-assisted Partial Nephrectomy: Single-center Prospective Study.

OBJECTIVE: To prospectively investigate the natural history of asymptomatic pseudoaneurysm after robotic-assisted partial nephrectomy. METHODS: Robotic-assisted partial nephrectomy was undertaken for 67 patients between July 2014 and July 2018. Patients who could not undergo enhanced CT were excluded, so 60 patients were finally included in the present study. We prospectively investigated the presence of pseudoaneurysm based on early enhanced CT scan on postoperative day 7. According to our treatment policy, patients with symptomatic pseudoaneurysm underwent selective transarterial embolization. Meanwhile, patients with asymptomatic pseudoaneurysm were observed with follow-up CT imaging, regardless of the size of the aneurysm. RESULTS: Overall incidence of pseudoaneurysm on postoperative day 7 was 18% (11/60 cases). The median size of the pseudoaneurysm was 9 mm (quartile: 6-12 mm). Two patients with symptomatic pseudoaneurysm underwent selective transarterial embolization. Nine patients had asymptomatic pseudoaneurysm; in 8 of these it disappeared without therapeutic intervention. The median period from surgery to confirmed disappearance of the aneurysm was 19 days (quartile 14-32 days). In the remaining 1 patient, small asymptomatic pseudoaneurysm (2 mm) could still be observed even 1 year after surgery. CONCLUSION: Our study showed high incidence of pseudoaneurysm 1 week after robotic-assisted partial nephrectomy that mostly disappeared without therapeutic intervention. Routine enhanced CT screening and pre-emptive embolization may not be necessary for asymptomatic renal artery pseudoaneurysm.

Phylogenies from mitochondrial genomes of 120 species of ticks: Insights into the evolution of the families of ticks and of the genus Amblyomma.

The evolution and phylogenetic relationships of the ticks at both the family and genus levels are contested. The genus Amblyomma and its subgenera are in a state of flux; moreover, the relationships among the three tick families are controversial due to conflicting phylogenetic support for different arrangements of the three families of living ticks. With 18 newly sequenced mitochondrial (mt) genomes of ticks included, we executed the largest mt genome phylogenetic study of ticks so far. Phylogenetic trees were inferred from one sea spider mt genome, one horseshoe crab, five mite mt genomes and 146 tick mt genomes from 120 species: 153 mt genomes in total. Sixteen phylogenetic trees were inferred from 10 datasets using both maximum likelihood and Bayesian inference methods. We describe the first novel mt gene-arrangement for the metastriate Ixodidae in Amblyomma (Africaniella) transversale. Also, three unusual partial 16S rRNA gene inserts were found in the mt genome of Haemaphysalis (Alloceraea) kitaokai: we consider the possible role of past genome translocation events in the formation of these inserts. Our phylogenies revealed evidence that: (i) the genus Amblyomma is polyphyletic with respect to Amblyomma (Africaniella) transversale; (ii) the subgenus Aponomma is apparently embedded in the genus Amblyomma; (iii) Haemaphysalis (Segalia) parva and Haemaphysalis (Alloceraea) kitaokai form a clade to the exclusion of other Haemaphysalis species; and (iv) the phylogenetic position of the family Nuttalliellidae is unstable among phylogenies from different datasets.

Immunosuppressive effects of sialostatin L1 and L2 isolated from the taiga tick Ixodes persulcatus Schulze.

Tick saliva contains immunosuppressants which are important to obtain a blood meal and enhance the infectivity of tick-borne pathogens. In Japan, Ixodes persulcatus is a major vector for Lyme borreliosis pathogens, such as Borrelia garinii, as well as for those causing relapsing fever, such as B. miyamotoi. To date, little information is available on bioactive salivary molecules, produced by this tick. Thus, in this study, we identified two proteins, I. persulcatus derived sialostatin L1 (Ip-sL1) and sL2 (Ip-sL2), as orthologs of I. scapularis derived sL1 and sL2. cDNA clones of Ip-sL1 and Ip-sL2 shared a high identity with sequences of sL1 and sL2 isolated from the salivary glands of I. scapularis. Semi-quantitative PCR revealed that Ip-sL1 and Ip-sL2 were expressed in the salivary glands throughout the life of the tick. In addition, Ip-sL1 and Ip-sL2 were expressed even before the ticks started feeding, and their expression continued during blood feeding. Recombinant Ip-sL1 and Ip-sL2 were developed to characterize the proteins via biological and immunological analyses. These analyses revealed that both Ip-sL1 and Ip-sL2 had inhibitory effects on cathepsins L and S. Ip-sL1 and Ip-sL2 inhibited the production of IP-10, TNFα, and IL-6 by LPS-stimulated bone-marrow-derived dendritic cells (BMDCs). Additionally, Ip-sL1 significantly impaired BMDC maturation. Taken together, these results suggest that Ip-sL1 and Ip-sL2 confer immunosuppressive functions and appear to be involved in the transmission of pathogens by suppressing host immune responses, such as cytokine production and dendritic cell maturation. Therefore, further studies are warranted to investigate the immunosuppressive functions of Ip-sL1 and Ip-sL2 in detail to clarify their involvement in pathogen transmission via I. persulcatus.

[Evaluation of the Influence of the Experience and Training of EBUS-TBNA on Diagnostic Rate and Safety].

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely used in Japan. The guidelines of the American College of Chest Physicians has recommended that EBUS-TBNA should be performed by well-trained operators who can perform highly accurate procedures, but the indicators of the degree of experience and training are unclear. In our department, physicians who do not have enough experience perform EBUS-TBNA under the supervision of bronchoscopic instructors who have EBUS-TBNA techniques (Board Certified Member of the Japan Society for Respiratory Endoscopy) after guidance and training in EBUS-TBNA using a simulator as an operator and helper. In order to evaluate the influence of the experience and training of EBUS-TBNA on diagnostic accuracy and safety, we retrospectively compared the diagnostic accuracy and safety of EBUS-TBNA performed by physicians within one year of experience of EBUS-TBNA and those performed by physicians with more than one year of experience. A total of 111 cases (148 lesions) who were eventually diagnosed as having primary lung cancer and underwent EBUS-TBNA in our department between April 2014 and January 2016 were divided into two groups. Group A (43 cases, 57 lesions) was examined by third-year doctors within one year of experience of EBUS-TBNA, and group B (68 cases, 91 lesions) was examined by doctors with four or more years of experience and with more than one year of experience of EBUS-TBNA. Diagnostic rate, examination time, and complications were evaluated. There were no significant differences between the two groups in the diagnostic rate (A, 89.5% vs. B, 90.1%, P = 1.0) or examination time (A, 27 min vs. B, 23 min, P = 0.149), and no complications were observed in either group. This study suggests that even less-experienced physicians may safely perform EBUS-TBNA as well as moderately-experienced physicians with more than 1 year experience of EBUS-TBNA with similar diagnostic rates when proper training and supervision are supplied.

Peripheral pulmonary carcinoid tumor diagnosed by endobronchial-ultrasound-guided bronchoscopy.

A 45-year-old Japanese woman complained of uncontrolled hypertension and face swelling. She was diagnosed with Cushing's syndrome with secretion of adrenocorticotropic hormone. Fluorodeoxyglucose positron emission tomography-computed tomography revealed a 2 × 2 cm mass in her left lung, with high standardized maximum uptake value. She underwent bronchoscopy with endobronchial ultrasound via a guide-sheath. Surgical resection of her left upper lung was performed, and pathological examination showed a typical carcinoid tumor. After lung resection, she recovered from her subjective symptoms. Diagnosis of peripheral carcinoid tumor of the lung is generally difficult. Here, we introduce a case of peripheral pulmonary carcinoid tumor diagnosed by endobronchial-ultrasound-guided bronchoscopy.

TLR3 activation augments matrix metalloproteinase production through reactive nitrogen species generation in human lung fibroblasts.

Viral infection often triggers asthma exacerbation and contributes to airway remodeling. Cell signaling in viral infection is mainly mediated through TLR3. Many mediators are involved in airway remodeling, but matrix metalloproteinases (MMPs) are key players in this process in asthma. However, the role of TLR3 activation in production of MMPs is unknown. In this study, we examined the effects of polyinosinic-polycytidylic acid [poly(I:C)], a ligand for TLR3, on production of MMPs in human lung fibroblasts, with a focus on nitrosative stress in TLR3 modulation of MMP production. After lung fibroblasts were treated with poly(I:C), production of MMP-1, -2, and -9 and inducible NO synthase (iNOS) was assessed. The roles of NF-κB and IFN regulatory factor-3 (IRF-3) in the poly(I:C)-mediated production of MMPs and the responsiveness to poly(I:C) of normal lung fibroblasts and asthmatic lung fibroblasts were also investigated. Poly(I:C) augmented production of MMPs and iNOS in fibroblasts, and an iNOS inhibitor diminished this production of MMPs. Poly(I:C) stimulated translocation of NF-κB and IRF-3 into the nucleus in fibroblasts and inhibition of NF-κB or IRF-3 abrogated the poly(I:C)-induced increase in both iNOS expression and release of MMPs. Poly(I:C)-induced production of iNOS and MMPs was greater in asthmatic fibroblasts than in normal fibroblasts. We conclude that viral infection may induce nitrosative stress and subsequent MMP production via NF-κB- and IRF-3-dependent pathways, thus potentiating viral-induced airway remodeling in asthmatic airways.