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Treatment of non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) is limited because of the risk of its acute exacerbation (AE). Furthermore, the efficacy and safety of second-line chemotherapy for these patients is unclear.To investigate the efficacy and safety of second-line chemotherapy for NSCLC patients with ILD, we retrospectively reviewed patients who were treated at our institute between April 2010 and December 2018.Thirty-five patients received two or more regimens. Thirty-four patients were male and the median age at the initiation of second-line chemotherapy was 70 years. Almost all patients had a smoking history. Fourteen patients had adenocarcinoma and 15 had squamous cell carcinoma histology. Stages III and IV were observed in 20 and 11 patients, respectively. With respect to the type of ILD, 12 patients had usual interstitial pneumonia (UIP). The overall response rate and disease control rate were 11.4 and 68.6%, respectively. The median progression-free and median overall survival were 4.1 and 6.4 months, respectively. The AE of ILD was observed in eight patients, five of whom died. UIP and low percentage vital capacity were detected as significant risk factors for the AE of ILD.Second-line chemotherapy among patients with NSCLC complicated by ILD showed a certain effectiveness, but some patients experienced the AE of ILD, which may lead to death. The risk of the AE of ILD must be considered especially for patients with UIP and low percentage VC.

Background Nivolumab is used for the treatment of malignant pleural mesothelioma (MPM). However, immune-related adverse events (irAEs) occur in patients treated with nivolumab. Several studies have reported the correlation between irAEs and therapeutic effects of immune checkpoint inhibitor, but none have reported the correlation in MPM. Here we report a retrospective study which shows the correlation between irAEs and therapeutic effects of nivolumab in patients with MPM. Methods This study included patients treated with nivolumab at Tokushima University Hospital from February 2009 to September 2021. We retrospectively reviewed the medical records to evaluate the several clinical factors, such as the presence or absence of irAEs, their severities, progression-free survival (PFS), overall survival (OS) or objective response to the treatment. Results Eleven patients received treatment with nivolumab. Objective response rate was 18.2% and the disease control rate was 90.9%. Median PFS was 6.8 months (95% confidence interval, 1.3 to 11.9 months) and median OS was 15.2 months (95% confidence interval, 8.9 to 21.5 months). IrAEs occurred in eight patients (72.7%), and grade ≥ 2 irAEs occurred in six patients (54.5%). PFS and OS were significantly longer in the grade ≥ 2 irAEs group than in grade p = 0.0093; median OS not reached vs. 8.6 months, p = 0.0108). Conclusions This is the first study to report the correlation between irAEs and therapeutic effects in patients with MPM. Because the presence of irAEs may be associated with a favorable clinical outcome, early detection and appropriate management of irAEs will increase the therapeutic benefits to patients.

Immune checkpoint inhibitor (ICI) programmed death (PD)‐1/PD‐ligand 1 (PD‐L1) blockade has been approved for various cancers. However, the underlying antitumor mechanisms mediated by ICIs and the predictive biomarkers remain unclear. We report the effects of anti‐PD‐L1/PD‐1 Ab in tumor angiogenesis. In syngeneic mouse models, anti‐PD‐L1 Ab inhibited tumor angiogenesis and induces net‐like hypoxia only in ICI‐sensitive cell lines. In tumor tissue and serum of ICI‐sensitive cell line‐bearing mice, interferon‐γ (IFN‐γ) inducible angiostatic chemokines CXCL10/11 were upregulated by PD‐L1 blockade. In vitro, CXCL10/11 gene upregulation by IFN‐γ stimulation in tumor cell lines correlated with the sensitivity of PD‐L1 blockade. The CXCL10/11 receptor CXCR3‐neutralizing Ab or CXCL11 silencing in tumor cells inhibited the antiangiogenic effect of PD‐L1 blockade in vivo. In pretreatment serum of lung carcinoma patients receiving anti‐PD‐1 Ab, the concentration of CXCL10/11 significantly correlated with the clinical outcome. Our results indicate the antiangiogenic function of PD‐1/PD‐L1 blockade and identify tumor‐derived CXCL10/11 as a potential circulating biomarker of therapeutic sensitivity., Our results show the novel antiangiogenic function of PD‐1/PD‐L1 blockade and identify tumor‐derived angiostatic chemokines CXCL10/11 as a potent circulating biomarker of therapeutic sensitivity. These findings contribute to the further understanding of antitumor mechanisms mediated by immune checkpoint inhibitors and provide a major advance in personalized immunotherapy.

Objectives The clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remain unclear. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of S-1 in combination with carboplatin (CBDCA) in NSCLC patients with ILD. Materials and methods A total of 33 advanced or recurrent NSCLC patients with ILD were prospectively enrolled in this multicenter, open-label, phase II study. Every 4 weeks, CBDCA at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m2 daily for 14 days were administered. The primary endpoint was the investigator-assessed objective response rate. Results The median age at initiating chemotherapy was 70. Sixteen patients (48.5%) had squamous cell carcinoma histology. With respect to the types of ILD, the usual interstitial pneumonia pattern was dominant (66.7%). The median number of cycles administered was 3, and the overall response rate and disease control rate were 33.3% and 78.8%, respectively. The median progression-free survival, the median survival time and the 1-year survival rate were 4.8 months, 12.8 months and 51.4%, respectively. Acute exacerbation of ILD caused by chemotherapy was noted in 2 patients (6.1%). Conclusion This is the first prospective study designed to evaluate the efficacy of a specific chemotherapeutic regimen as the primary endpoint in patients with advanced NSCLC with ILD. The combination of S-1 with CBDCA may be a treatment option for advanced NSCLC patients with ILD (The clinical trial registration number: UMIN000011046).

Fibrocytes, a distinct population of collagen-producing, monocyte-derived cells, are involved in wound healing as well as fibrotic diseases. Recently, fibrocytes have been revealed to play a role in the tumor microenvironment, particularly under antiangiogenic therapy. In addition, combination cancer immunotherapy with immune checkpoint inhibitor and antiangiogenic agents have been developed for various cancers in the clinical setting, although the immunological background is not clear. In the current study, we aimed to determine the function of fibrocytes in tumor immunity induced by immune checkpoint inhibitor therapy. Human and murine fibrocytes were generated from PBMCs and lungs, respectively. The expression of costimulatory and inhibitory molecules on fibrocytes was examined by flow cytometry. The stimulation of CD8+ T cells by fibrocytes was examined in MLRs with a 3H-thymidine incorporation assay. Fibrocytes expressed CD80low and CD86high as a costimulatory molecule, and expressed PD-L1high, but not PD-L2, as a coinhibitory molecule. Without any stimulation, fibrocytes strongly enhanced the proliferation of CD8+ T cells in mice and humans. Treatment with anti-CD86 and -CD54 Abs inhibited the growth of CD8+ T cells induced by fibrocytes. Anti–PD-L1 Ab further enhanced the proliferation of CD8+ T cells, even in the OVA-specific MLR with OT-1Rag−/− mice. Importantly, fibrocytes derived from PBMCs of patients with lung adenocarcinoma or murine MC38 tumors augmented the proliferation of CD8+ T cells with PD-L1 blockade. These results suggest that fibrocytes infiltrating tumor sites may play a role in the antitumor immunity mediated by CD8+ T cells when the activity is further enhanced by PD-L1/PD-1 blockade.

(Objectives) Transurethral Ureterolithotripsy (TUL) has become an increasingly more common treatment for ureteric stones since the reduction in ureteroscope diameter and other device improvements. At the same time, TUL sometimes shows postoperative febrile urinary tract infection (fUTI) with severe complications. Therefore we investigated the occurrence and risk factors of fUTI in our hospital, and assessed the effect of antibiotic prophylaxis prior to TUL. (Materials and methods) The subjects were 260 patients who underwent TUL in our department during the period from January 2011 to October 2014. We retrospectively reviewed the data of those who developed postoperative fUTI and identified the risk factors of postoperative fUTI. From November 2014 to August 2016, we enrolled 110 patients undergoing TUL with one or more risk factors in a prospective clinical trial of prophylactic oral levofloxacin (500 mg) for 1 week before TUL. The chi-squared test, Mann-Whitney U-test, and logistic regression analysis were used for data analysis (significance level of 0.05). (Results) Postoperative fUTI occurred in 43 (16.5%) of 260 patients. The risk factors of postoperative fUTI included preoperative pyelonephritis (P=0.02), preoperative ureteral stent placement (P=0.017), and operative time90 min (P=0.005). Operative time was correlated with and could be substituted for pre-TUL stone size (P0.0001). Chemopreventive therapy before TUL in patients with preoperative pyelonephritis, preoperative ureteral stent placement, or stones of20 mm significantly reduced their risk of fUTI (P=0.012). (Conclusions) The use of antibiotic prophylaxis significantly reduces the risk of postoperative fUTI in patients with preoperative pyelonephritis, preoperative ureteral stent placement, or stones of20 mm.

The low-density lipoprotein receptor-related protein 4 (LRP4) and the muscle-specific receptor tyrosine kinase (MuSK) form a tetrameric protein complex on the postsynaptic membrane at the neuromuscular junction (NMJ). Binding of agrin to LRP4 triggers phosphorylation of MuSK. Activated MuSK drives clustering of acetylcholine receptor (AChR). Wnt ligands also directly bind to MuSK to induce AChR clustering. MuSK anchors the acetylcholinesterase (AChE)/collagen Q (ColQ) complex to the synaptic basal lamina. In addition, an extracellular proteoglycan, biglycan, binds to MuSK. Anti-MuSK autoantibodies (MuSK-IgG) are observed in 5–15% of autoimmune myasthenia gravis (MG) patients. MuSK-IgG blocks both ColQ-MuSK and LRP4-MuSK interactions. MuSK-IgG, LRP4, ColQ, and biglycan bind to the immunoglobulin-like domains 1 and 4 of MuSK. Lack of the effects of cholinesterase inhibitors in MuSK-MG patients is likely due to hindrance of ColQ-MuSK interaction by MuSK-IgG and subsequent deficiency of AChE observed in model mice, which, however, has not been proven in MuSK-MG patients. As ColQ enhances expression of membrane-bound MuSK, inhibition of ColQ-MuSK interaction by MuSK-IgG may account for lack of AChR clusters in MuSK-MG. We thus made passive transfer models using Colq+/+ and Colq−/− mice to dissect the effect of ColQ on AChR clustering in MuSK-MG. We found that MuSK-IgG-mediated suppression of LRP4-MuSK interaction, not of ColQ-MuSK interaction, caused defective AChR clustering. We also unexpectedly observed that both MuSK-IgG and ColQ suppressed agrin/LRP4/MuSK signaling in dose-dependent manners. Quantitative comparison revealed that MuSK-IgG blocked agrin-LRP4-MuSK signaling more than ColQ. We propose that attenuation of AChR clustering in MuSK-MG is due to hindrance of LRP4-MuSK interaction in the presence of agrin by MuSK-IgG.

Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin mAb, NZ-1, and a rat-human chimeric anti-human podoplanin antibody, NZ-8, derived from NZ-1, which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against podoplanin-positive MPM cell lines. In this study, we showed the antitumor effect of NZ-1, NZ-8, and NZ-12, a novel rat-human chimeric anti-human podoplanin antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a(+) ) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human natural killer (NK) (CD56(+) ) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ-12 induced potent ADCC mediated by human MNC, compared with either NZ-1 or NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56(+) ) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ-12 mediated by human NK (CD56(+) ) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin-targeting immunotherapy using both NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM.

Background Older patients with lung cancer have increased over the past decades. Several standard treatments for older patients were established, but their clinical features in real world clinics remain unknown. Thus, we performed a retrospective study to clarify the clinical features of them. Methods The patients with lung cancer who were admitted to our hospital between April 1, 2012 and March 31, 2015 were retrospectively analyzed. Patients older than 75 years were defined as older patients. Standard treatments were based on the guidelines. Results In total, 333 patients were analyzed. The older patients had a poor performance status (PS), more comorbidities, and fewer opportunities to receive standard treatments. The prognosis of the older patients who received standard treatments was superior to that of those who did not. The therapeutic efficacy of standard treatments for older patients with stages I and II diseases was similar to their younger counterparts. However, the prognosis of older patients with advanced stage, especially stage III disease, was poor. The tolerability of first-line chemotherapy by older patients was comparable with their younger counterparts, but the older patients had fewer opportunities to receive several chemotherapy regimens, even second line chemotherapy. Conclusions We should positively consider standard treatments for older patients. However, not only their shorter life expectancy but also their poor PS and multiple comorbidities that sometimes render patients unable to receive standard treatments and several chemotherapy regimens, make their prognosis poor. The standard treatments for older patients, especially in locally advanced stages, require modification.

We clinicaliye valuated 355 patients with urinarytract infections (UTI), suspected of having urosepsis at Tane General Hospital, and determined the usefulness of the biomarker procalcitonin (PCT) as an aid in predicting urosepsis. Clinical and microbiological data were collected. The logistic regression analysis was used to determine the risk factors of urosepsis. Of 355 patients, 169 patients (47.6%) were diagnosed with urosepsis. C-reactive protein (CRP) (OR 2. 633, p＜0. 001), PCT (OR 2. 153, p＝0. 003) and clinical diagnosis (calculous pyelonephritis OR 1. 886, p＝0. 019, acute prostatitis OR 3. 614, p＜0. 001) were established as the independent risk factors of urosepsis. Of 169 patients with urosepsis, 43 patients (25.4%) were diagnosed with severe urosepsis. In the severe urosepsis group, 2 patients with a PCT value ＜2.0 ng/ml were included. The mortalityrate in patients with severe urosepsis was 4.65% (2/43) in this study. We concluded that the PCT level could be a reliable marker suggestive of urosepsis. However, patients very early in the onset of infection mayhave a normal PCT value. It is essential to use all available clinical information when interpreting the results of a PCT measurement.

Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is mostly composed of an asymmetric form in which three tetramers of catalytic AChE subunits are linked to a triple helical collagen Q (ColQ). Mutations in COLQ cause endplate AChE deficiency. We report three patients with endplate AChE deficiency with five recessive COLQ mutations. Sedimentation profiles showed that p.Val322Asp and p.Arg227X, but not p.Cys444Tyr, p.Asp447His, or p.Arg452Cys, inhibit formation of triple helical ColQ. In vitro overlay of mutant ColQ-tailed AChE on muscle sections of Colq(-/-) mice revealed that p.Cys444Tyr, p.Asp447His, and p.Arg452Cys in the C-terminal domain (CTD) abrogate anchoring ColQ-tailed AChE to the NMJ. In vitro plate-binding assay similarly demonstrated that the three mutants inhibit binding of ColQ-tailed AChE to MuSK. We also confirmed the pathogenicity of p.Asp447His by treating Colq(-/-) mice with adeno-associated virus serotype 8 carrying mutant COLQ-p.Asp447His. The treated mice showed no improvement in motor functions and no anchoring of ColQ-tailed AChE at the NMJ. Electroporation of mutant COLQ harboring p.Cys444Tyr, p.Asp447His, and p.Arg452Cys into anterior tibial muscles of Colq(-/-) mice similarly failed to anchor ColQ-tailed AChE at the NMJ. We proved that the missense mutations in ColQ-CTD cause endplate AChE deficiency by compromising ColQ-MuSK interaction at the NMJ.

Background : Small-cell lung cancer (SCLC) presents aggressive clinical behavior, and its prognosis is still poor. Previously, performance status (PS), or the existence of brain, bone, or liver metastasis were reported to be unfavorable prognostic factors. Given the recent progress of treatment modalities such as radiotherapy techniques and bone modifying agents, the prognostic factors might be different from previous findings. Therefore, we analyzed the prognostic factors of extensive disease SCLC (ED-SCLC) in recent years. Methods : ED-SCLC patients treated in Tokushima University Hospital between 2010 and 2016 were analyzed. Log-rank test and the Cox proportional hazards regression model was used in univariate and multivariate analysis, respectively. Results : Totally, 79 patients were analyzed. In the univariate analysis, age, PS, interstitial pneumonia (IP), liver metastasis, pleural dissemination, neutrophil counts, hypoalbuminemia, hypercalcemia and several liver and biliary enzymes were identified as poor prognostic factors. In the multivariate analysis, age, PS, IP, and liver and biliary enzymes were identified. Moreover, the PS in patients with liver metastasis was significantly worsened. Conclusions : In this study, we newly demonstrated that IP was a significant poor prognostic factor of ED-SCLC. Although liver metastasis was not extracted in multivariate analysis, it may have an impact on the prognosis of ED-SCLC.

A 68-year-old man presented with the chief complaint of swelling of the penis. A pencil had been inserted into his urethra by a commercial sex worker for sexual stimulation. On a computed tomography (CT) scan, a foreign object was visible throughout the urethra and in the urinary bladder. Cystoscopy performed under spinal anesthesia showed a pencil in the urethra. We attempted removing the object endoscopically by using a Holmium laser. However, the endoscopic procedure failed and finally, we removed the object by transvesical open surgery. At the same time, suprapubic cystostomy was performed for the disorder of the urethra. An anterior urethrocutaneous fistula was formed 5 days after the operation. After removal of the urethral catheter, he was managed with only suprapubic cystostomy. Conservative management of the urethrocutaneous fistula was effective. The fistula was completely closed 26 days after the operation. He was discharged 33 days after the operation.

Background Interstitial lung disease (ILD) is commonly concomitant with lung cancer, and its acute exacerbation (AE) is the most serious complication in patients receiving treatment for lung cancer. Methods To investigate the incidence and characteristic features of AE of ILD, we conducted a retrospective study of 665 consecutive patients with lung cancer who were treated at our institute between 2008 and 2014. Results Among the 665 patients, 74 (11.1%) had preexisting ILD, and 64 of them received chemotherapy. Four of the 64 patients (6.3%) had experienced AE of ILD, and two (3.1%) died of respiratory failure during first-line chemotherapy. The use of a combination of carboplatin with tegafur-gimeracil-oteracil potassium (S-1) or paclitaxel as a first-line chemotherapy for non-small cell lung cancer led to a lower frequency of AE, at 8.3% (1/12) and 9.1% (1/11), respectively. The incidence of AE rose to 12.8% (5/39) during second-line treatment, and 14 (total: 15 times) of the 64 patients (21.9%) experienced AE from the time of diagnosis to the end of treatment. The incidence of AE was 17.7% (6/34), 15.8% (3/19), 5.0% (2/40), and 4.2% (1/24) in the paclitaxel-, vinorelbine-, etoposide-, and S-1-containing regimens, respectively. No difference in clinical features and laboratory data was detected between the AE and non-AE groups. Conclusions Although this was a small retrospective study, its findings showed that S-1 and etoposide may be relatively safe options for the treatment of patients with lung cancer and concomitant ILD.

Background The aim of this study is to investigate the prognostic relevance of the best objective response of metastatic target lesions during sunitinib treatment in patients with metastatic renal cell carcinoma. Methods Radiographic analysis of the best objective response according to the Response Evaluation Criteria in Solid Tumors was assessed in 50 patients. Clinicopathological characteristics including the Heng risk classification and sunitinib-related adverse reactions were compared among four patient subgroups [complete response or partial response (CR/PR), stable disease (SD), progressive disease (PD), and those without treatment evaluation (NE)]. Kaplan–Meier and Cox proportional regression analyses of progression-free survival and overall survival were performed to identify prognostic variables. Results The best objective response was CR/PR in 12 (24 %) patients, SD in 22 (44 %), PD in 6 (12 %), and NE in 10 (20 %). The incidence of hypertension and hypothyroidism was associated with a better objective response. Progression-free survival was 15.0, 9.2, 6.8, and 2.2 months in the CR/PR, SD, PD, and NE groups, respectively (P = 0.0004, log-rank test), while the corresponding median overall survival was 59.7, 24.2, 17.1, and 18.1 months, respectively (P = 0.007). Multivariate analysis revealed that hazard ratios for risk of death of the SD, PD, and NE groups were 4.51 (P = 0.06), 7.93 (P = 0.02), and 4.88 (P = 0.04), respectively, as compared to the CR/PR group. Conclusions Our findings suggested that the best objective response of target lesions was a prognostic marker for both progression-free survival and overall survival in sunitinib treatment. Furthermore, the incidence of sunitinib-induced hypertension was associated with a longer progression-free survival.

Persistent mullerian duct syndrome describes a group of patients with a 46 XY karyotype and normal male external genitalia, but internal mullerian structures. A 7-month-old boy presented with a left inguinal hernia, a left undescended testis and a right impalpable testis. Inguinal herniorrhaphy was performed and laparoscopy was done for search of a right impalpable testis and internal genitalia simultaneously. Laparoscopic examination revealed the structure like a mullerian duct remnant along the left spermatic duct in rectovesical fossa and right intra-abdominal testis. The structure like a mullerian duct remnant was not removed to preserve the left spermatic duct. Left orchiopexy and right laparoscopic staged Fowler- Stephens orchiopexy were performed. Chromosomal analysis was 46 XY karyotype and we diagnosed this case as persistent mullerian duct syndrome.