Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse events.

Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged, but not young, mice, antiprogrammed death receptor (PD)-1 therapy elicited irAE-like multiorgan dysfunctions with ectopic accumulation of T and B cells in damaged organs. In this preclinical model, the organ toxicities were mediated by immunoglobulin G (IgG) deposition because administration of IG from ICB-treated aged mice induced the pathogenicity specifically in naïve aged hosts. Mechanistically, CD4 T-cell-derived interleukin (IL)-21 upregulated B-cell-homing chemokine, CXCL13, preferentially in irAE organs from aged mice treated with anti-PD-1 therapy. The ICB-induced pathogenicity was alleviated by B-cell depletion or by blockade of IL-21 or CXCL13 activity. These results suggest that age-associated immune regulatory milieu contributes to the formation of tertiary lymphoid structure-like lymphocytic aggregates in irAE organs and irAE-related toxicity employing IL-21-CXCL13-auto-antibody axis. Supporting this, a systemic increase in CXCL13 and Il21 expression in CD4 T cells correlated with irAE incidence in ICB-treated patients. These findings provide rationale for therapeutic usefulness of CXCL13 in irAE management.

Outcome of surgical parathyroidectomy for tertiary hyperparathyroidism in kidney transplant recipients: tertiary hyperparathyroidism should not be ignored, for the sake of precious allografts.

Tertiary hyperparathyroidism is a complication of kidney transplantation. This complicated condition carries over from the dialysis period and varies according to the function of the transplanted allograft. Treatments include pharmacotherapy (mainly using calcimimetics) and parathyroidectomy, but calcimimetics are currently not covered by the national insurance system in Japan. Two types of parathyroidectomy can be performed: subtotal parathyroidectomy; and total parathyroidectomy with partial autograft. Both types can be expected to improve hypercalcemia. Concerns about the postoperative deterioration of allograft function are influenced by preoperative allograft function, which is even more likely to be affected by early surgery after kidney transplantation. In general, transient deterioration of allograft function after surgery is not expected to affect graft survival rate in the medium to long term. Tertiary hyperparathyroidism in kidney transplant recipients negatively impacts allograft and patient survival rates, and parathyroidectomy can be expected to improve prognosis in both kidney recipients and dialysis patients. However, studies offering high levels of evidence remain lacking.

[Case of a Patient with Cancer of Unknown Primary in the Poor Prognosis Group Who Had a Experienced a Beneficial Treatment Course].

A 47-year-old woman with general malaise and abdominal pain presented with multiple liver tumors and lymph node metastasis. She was diagnosed with small cell carcinoma on the basis of a lymph node biopsy; however, the primary lesion was not identified. Finally, we diagnosed her with cancer of unknown primary lesion and placed her in the poor prognosis group. Although her general condition was poor, she experienced a relatively good response to treatment for small cell carcinoma.

Syntheses and Structures of Arenethiolato Cobalt(II) Complexes Containing Acylamino Groups: Steric Effects of Bulky Ligands on Coordination and Geometry.

Bulky thiolato ligands have been developed for creating biomimetic model complexes of active sites in metalloenzymes. Herein, we report a series of di-ortho-substituted arenethiolato ligands containing bulky acylamino groups (RCONH; R = t-Bu-, (4-t-BuC6H4)3C-,{3,5-(Me2CH)2C6H3}3C-, and {3,5-(Me3Si)2C6H3}3C-) that were developed for biomimetics. Bulky hydrophobic substituents generate a hydrophobic space around the coordinating sulfur atom through the NHCO bond. This steric environment induces the formation of low-coordinate mononuclear thiolato Co(II) complexes. The well-positioned NHCO moieties in the hydrophobic space coordinate to the vacant sites of the cobalt center with different coordination modes, viz., the S,O-chelate of the carbonyl C═O or the S,N-chelate of the acylamido CON-. The solid (crystalline) and solution structures of the complexes were investigated in detail using single-crystal X-ray crystallography, 1H NMR, and absorption spectroscopic analyses. The spontaneous deprotonation of NHCO, which is commonly observed in metalloenzymes but requires a strong base in artificial systems, was simulated by forming a hydrophobic space in the ligand. This new ligand design strategy is advantageous for creating model complexes that have never been constructed artificially.

Clinical factors associated with acute abdominal symptoms induced by gastric anisakiasis: a multicenter retrospective cohort study.

BACKGROUND: Gastric anisakiasis typically causes severe abdominal symptoms; however, we incidentally detected asymptomatic gastric anisakiasis cases during esophagogastroduodenoscopy. The factors associated with developing acute abdominal symptoms induced by gastric anisakiasis remain unclear. Therefore, this study aimed to investigate the clinical factors associated with abdominal symptoms of gastric anisakiasis by comparing symptomatic and asymptomatic cases. METHODS: This was a retrospective cohort study involving 264 patients diagnosed with gastric anisakiasis at nine hospitals in Japan between October 2015 and October 2021. We analyzed patients' medical records and endoscopic images and compared the clinical factors between the symptomatic and asymptomatic groups. RESULTS: One hundred sixty-five patients (77.8%) were diagnosed with abdominal symptoms, whereas 47 (22.2%) were asymptomatic. Older age, male sex, diabetes mellitus, gastric mucosal atrophy, and gastric mucosal atrophy of the Anisakis penetrating area were significantly more common in the asymptomatic group than in the symptomatic group. Multivariate analysis revealed that age (p = 0.007), sex (p = 0.017), and presence or absence of mucosal atrophy (p = 0.033) were independent factors for the occurrence of acute abdominal symptoms. In addition, cases that were Helicobacter pylori naïve, with an elevation of white blood cells, or without an elevation of eosinophils were more common in the symptomatic group than in the asymptomatic group. CONCLUSIONS: Age, sex, and presence or absence of gastric mucosal atrophy were the clinical factors associated with the occurrence of acute abdominal symptoms. Older and male patients and those with gastric mucosal atrophy were less likely to show abdominal symptoms. The mechanisms of the occurrence of symptoms induced by gastric anisakiasis remain unclear; however, our results will help clarify this issue in the future.

The usefulness of a newly developed full-core biopsy needle in liver biopsy.

AIM: To evaluate the usefulness and safety of a newly developed full-core biopsy needle. METHODS: We selected 149 patients who underwent percutaneous liver biopsy at our institution from February 2019 to April 2021. We excluded 35 patients with hepatic fibrosis stage F3 or higher, which made it histopathologically difficult to measure the number of complete portal triads. The patients were divided into two groups as follows: 62 cases with the 18-G conventional automated needle (TruCore needle: T needle), and 52 cases with the 18-G full-core needle (CorVocet needle: C needle). We measured the number of complete portal triads in the liver tissue specimens, and the sum of the length and width of the collected tissues. Moreover, we compared the number of session counts, fragmentations, and complications. RESULTS: The sum of the length and the width was 12.8 mm (11.2-14.3) and 15.9 mm (13.1-17.3; p < 0.001), and 0.68 mm (0.63-0.74) and 0.82 mm (0.78-0.90; p < 0.001) for the T needle and C needle, respectively. The number of complete portal triads and fragmentation was six (3-8) and 10 (6-13; p < 0.001), and one (1-10) and one (1-3; p < 0.001), for the T needle and C needle, respectively. There was one session count (1-2) in both groups; however, there were significantly higher cases of two sessions with the T needle than that with the C needle (p = 0.018). There were no serious adverse events. CONCLUSIONS: Compared with the conventional needles, the newly developed full-core needles enabled the acquisition of a larger amount of tissue sample in liver biopsy.

Tumor steatosis and glutamine synthetase expression in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy.

AIM: The anti-programmed death-ligand 1 antibody atezolizumab and vascular endothelial growth factor-neutralizing antibody bevacizumab in combination (Atezo + Bev) have become the first-line therapy in advanced hepatocellular carcinoma (HCC). Distinct types of tumor immune microenvironment (TIME) and their associations with specific molecular subclasses and driver gene mutations have been identified in HCC; however, these insights are mainly based on surgically resected early-stage tumors. The current study aimed to reveal the biology and TIME of advanced HCC and their significance in predicting clinical outcomes of Atezo + Bev therapy. METHODS: Thirty-three patients with advanced HCC who were scheduled for treatment with Atezo + Bev therapy were included in this study. Pretreatment tumor biopsy, pre- and posttreatment diffusion-weighted magnetic resonance imaging (MRI) with nine b values (0-1500 s/mm2 ), and other clinicopathologic factors were analyzed. RESULTS: Compared with resectable HCC, advanced HCC was characterized by higher proliferative activity, a higher frequency of Wnt/ß-catenin-activated HCC, and lower lymphocytic infiltration. Prognostically, two metabolism-related factors, histopathologically determined tumor steatosis and/or glutamine synthetase (GS) expression, and MRI-determined tumor steatosis, were the most significant prognostic indicators for progression-free survival (PFS) and overall survival after Atezo + Bev therapy. Furthermore, changes in the pre- and posttreatment true diffusion coefficients on MRI, which might reflect changes in TIME after treatment, were significantly associated with better PFS. CONCLUSIONS: The biology and TIME of HCC were strikingly different in advanced HCC compared with those of surgically resected HCC. Two metabolism-related factors, pathologically determined tumor steatosis and/or GS expression, and MRI-determined tumor steatosis, were found to be the most significant prognostic indicators for Atezo + Bev therapy in advanced HCC.

A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M.

Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. RNA-sequencing analysis revealed that the differentially expressed genes in H3.3K27M tumors were non-overlapping between Olig2;PDGF-B, Olig2;PDGF-A, and Nestin;PDGF-A models. GSEA analysis of PDGFA tumors confirmed that the transcriptomal effects of H3.3K27M are cell-of-origin dependent with H3.3K27M promoting epithelial-to-mesenchymal transition (EMT) and angiogenesis when Olig2 marks the cell-of-origin and inhibiting EMT and angiogenesis when Nestin marks the cell-of-origin. We did observe some overlap with H3.3K27M promoting negative enrichment of TNFA_Signaling_Via_NFKB in both models. Our study suggests that the tumorigenic effects of H3.3K27M are cell-of-origin dependent, with H3.3K27M being more oncogenic in Nestin+ cells than Olig2+ cells.

The utility of DNA methylation analysis in elderly patients with pilocytic astrocytoma morphology.

PURPOSE: Pilocytic astrocytoma (PA) is a circumscribed low-grade astrocytic glioma, generally considered to be associated with a good prognosis. However, a subset of PA patients shows unfavorable outcomes. In this study, we retrospectively reviewed PA patients and performed further molecular analysis, such as DNA methylation profiling, to identify prognostic factors. METHODS: We analyzed 29 histologically-confirmed PA patients from a single center from 2002 to 2021 and conducted integrated molecular analyses among elderly PA patients since age was an independent prognostic factor for poor outcomes. RESULTS: The median age at diagnosis was 14 years (range 3-82 years) and 4 patients (14%) were elderly (patients ≥ 60 years old). Age over 60 was associated with poor progression-free survival and overall survival. We performed DNA methylation analysis on 2 of the 4 elderly patients. Both cases were histologically diagnosed as PA, but DNA methylation profiling revealed one as high-grade astrocytoma with piloid features (all methylation class scores were below 0.3 in both v11b4 and v12.5) and the other as glioblastoma, IDH-wildtype (score was over 0.5 in both v11b4 and v12.5), using the German Cancer Research Center methylation profiling classifiers and t-SNE analysis. CONCLUSIONS: Elderly patients with PA morphology showed unfavorable outcomes in this cohort. In those patients, further molecular analysis and DNA methylation profiling revealed the possibility of high-grade astrocytic tumors, including newly defined entities.

Comparison of modified CEUS LI-RADS with sonazoid and CT/MRI LI-RADS for diagnosis of hepatocellular carcinoma.

AIM: To compare the diagnostic performance based on the modified CEUS Liver Imaging Reporting and Data System (LI-RADS), which includes Kupffer-phase findings as a major imaging feature, with that of CT and MRI (CT/MRI) LI-RADS for liver nodules in patients at high risk of HCC. METHODS: A total of 120 patients with 120 nodules were included in this retrospective study. The median size of the lesions was 20.0 mm (interquartile range, 14.0-30.8 mm). Of these lesions, 90.0% (108 of 120) were confirmed as HCCs, 6.7% (8 of 120) were intrahepatic cholangiocarcinomas, 1.7% (2 of 120) were metastases, and 1.7% (2 of 120) were dysplastic nodules. All nodules were diagnosed histopathologically. Each nodule was categorized according to the modified CEUS LI-RADS and CT/MRI LI-RADS version 2018. The diagnostic performance and inter-modality agreement of each criterion was compared. RESULTS: The inter-modality agreement for the modified CEUS LI-RADS and CT/MRI LI-RADS was slight agreement (kappa = 0.139, p = 0.015). The diagnostic accuracies of HCCs for the modified CEUS LR-5 and CT/MRI LR-5 were 70.0% (95% confidence interval [CI]: 61.0%, 78.0%) versus 70.8% (95% CI: 61.8%, 78.8%) (p = 0.876), respectively. The diagnostic accuracies of non-HCC malignancies for the modified CEUS LR-M and CT/MRI LR-M were 84.2% (95% CI: 76.4%, 90.2%) versus 96.7% (95% CI: 91.7%, 99.1%) (p = 0.002), respectively. CONCLUSIONS: The diagnostic performance for HCCs on the modified CEUS LR-5 and CT/MRI LR-5 are comparable. In contrast, CT/MRI LR-M has better diagnostic performance for non-HCC malignancy than that of the modified CEUS LR-M.

Clinical impact of cerebral infarction in patients with non-small cell lung cancer.

BACKGROUND: Lung cancer patients have a high risk of cerebral infarction, but the clinical significance of cerebral infarction in advanced non-small cell lung cancer (NSCLC) remains unclear. This study aimed to comprehensively investigate the incidence, prognostic impact, and risk factors of cerebral infarction in patients with NSCLC. METHODS: We retrospectively examined 710 consecutive patients with advanced or post-operative recurrent NSCLC treated between January 2010 and July 2020 at Kumamoto University Hospital. Cerebral infarction was diagnosed according to the detection of high-intensity lesions on diffusion-weighted magnetic resonance imaging regardless of the presence of neurological symptoms during the entire course from 3 months before NSCLC diagnosis. The prognostic impact and risk factors of cerebral infarction were evaluated based on propensity score matching (PSM) and multivariate logistic regression analysis. RESULTS: Cerebral infarction occurred in 36 patients (5%). Of them, 21 (58%) and 15 (42%) patients developed asymptomatic and symptomatic cerebral infarction, respectively. PSM analysis for survival showed that cerebral infarction was an independent prognostic factor (hazards ratio: 2.45, 95% confidence interval (CI): 1.24-4.85, P = 0.010). On multivariate logistic regression analysis, D-dimer (odds ratio [OR]: 1.09, 95% CI 1.05-1.14, P < 0.001) and C-reactive protein (OR: 1.10, 95% CI 1.01-1.19, P = 0.023) levels were independent risk factors. CONCLUSION: Cerebral infarction occurred in 5% of NSCLC patients, and asymptomatic cerebral infarction was more frequent. Cerebral infarction was a negative prognostic factor and was associated with hyper-coagulation and inflammation. The high frequency of asymptomatic cerebral infarction and its risk in NSCLC patients with these conditions should be recognized.

Clinical Implications and Molecular Characterization of Drebrin-Positive, Tumor-Infiltrating Exhausted T Cells in Lung Cancer.

T cells express an actin-binding protein, drebrin, which is recruited to the contact site between the T cells and antigen-presenting cells during the formation of immunological synapses. However, little is known about the clinical implications of drebrin-expressing, tumor-infiltrating lymphocytes (TILs). To address this issue, we evaluated 34 surgical specimens of pathological stage I-IIIA squamous cell lung cancer. The immune context of primary tumors was investigated using fluorescent multiplex immunohistochemistry. The high-speed scanning of whole-slide images was performed, and the tissue localization of TILs in the tumor cell nest and surrounding stroma was automatically profiled and quantified. Drebrin-expressing T cells were characterized using drebrin+ T cells induced in vitro and publicly available single-cell RNA sequence (scRNA-seq) database. Survival analysis using the propensity scores revealed that a high infiltration of drebrin+ TILs within the tumor cell nest was independently associated with short relapse-free survival and overall survival. Drebrin+ T cells induced in vitro co-expressed multiple exhaustion-associated molecules. The scRNA-seq analyses confirmed that the exhausted tumor-infiltrating CD8+ T cells specifically expressed drebrin. Our study suggests that drebrin-expressing T cells present an exhausted phenotype and that tumor-infiltrating drebrin+ T cells affect clinical outcomes in patients with resectable squamous cell lung cancer.

Multiparametric US for Identifying Patients with High-Risk NASH: A Derivation and Validation Study.

Background Nonalcoholic fatty liver disease (NAFLD) is common in the general population but identifying patients with high-risk nonalcoholic steatohepatitis (NASH) who are candidates for pharmacologic therapy remains a challenge. Purpose To develop a score to identify patients with high-risk NASH, defined as NASH with an NAFLD activity score (NAS) of 4 or greater and clinically significant fibrosis (stage 2 [F2] or higher). Materials and Methods This was a cross-sectional secondary analysis of data prospectively collected between April 2017 and March 2019 for a group of patients with NAFLD in Japan (Japan NAFLD, the derivation data set) with contemporaneous two-dimensional shear-wave elastography and biopsy-proven NAFLD (age range, 20-89 years). Three US markers (liver stiffness [LS, measured in kilopascals], attenuation coefficient [AC, measured in decibels per centimeter per megahertz], and dispersion slope [DS, measured in meters per second per kilohertz]) were determined, together with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and the AST-to-ALT ratio. The best-fit multivariate logistic regression model for identifying patients with high-risk NASH was determined. Diagnostic performance was assessed by using the area under the receiver operating characteristic curve (AUC). The findings were validated in an independent data set (Korea NAFLD; age range, 20-78 years). Results The Japan NAFLD data set included 111 patients (mean age, 53 years ± 18 [standard deviation]; 57 men), 84 (76%) with NASH. The Korea NAFLD data set included 102 patients (mean age, 48 years ± 18; 43 men), 55 (36%) with NASH. The most predictive model (LAD NASH score) combined LS, AC, and DS. Performance was satisfactory in both the derivation sample (AUC, 0.86; 95% CI: 0.79, 0.93) and the validation sample (AUC, 0.88; 95% CI: 0.80, 0.95). The LAD NASH score showed a positive predictive value of 86.5% and a negative predictive value of 87.5% for high-risk NASH in the derivation sample. Conclusion A score combining three US markers may be useful for noninvasive identification of patients with high-risk nonalcoholic steatohepatitis for inclusion in clinical trials and pharmacologic therapy. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lockhart in this issue.

Does second-look endoscopy reduce the bleeding after gastric endoscopic submucosal dissection for patients receiving antithrombotic therapy?

BACKGROUND: In patients with average risk of bleeding, second-look endoscopy does not reportedly reduce bleeding after gastric endoscopic submucosal dissection. However, effectiveness of second-look endoscopy for patients with a high risk of bleeding, such as those who are taking antithrombotic agents, is unclear. Hence, this study aims to clarify the effectiveness of second-look endoscopy for patients with antithrombotic therapy. METHODS: We studied 142 consecutive patients with 173 gastric epithelial neoplasms who were routinely taking antithrombotic agents and were treated by endoscopic submucosal dissection at Tonan Hospital between November 2013 and December 2019. They were classified into two groups: those with second-look endoscopy (SLE group, 69 patients with 85 lesions) and those without second-look endoscopy (non-SLE group, 73 patients with 88 lesions). The incidence of post-endoscopic submucosal dissection bleeding was compared between the SLE and non-SLE groups. RESULTS: There were no statistical differences in the rate of patients undergoing single antiplatelet therapy, single anticoagulant therapy, and multiple therapy between the SLE and non-SLE groups (SLE group vs. non-SLE group; 32 [46.4%], 16 [23.2%], and 21 [30.4%] patients vs. 37 [50.7%], 20 [27.4%], and 16 [21.9%] patients, respectively; p = 0.50). Post-endoscopic submucosal dissection bleeding incidence was 21.7% (15/69) and 21.9% (16/73) in the SLE and non-SLE groups, respectively, and did not significantly differ between the two groups (p = 0.98). CONCLUSIONS: For patients taking antithrombotic agents, the incidence of post-endoscopic submucosal dissection bleeding was not reduced by second-look endoscopy.

Comparison of clinicopathological features and long-term prognosis between mixed predominantly differentiated-type and pure differentiated-type early gastric cancer.

BACKGROUND: Recent studies have shown that mixed predominantly differentiated-type (MD) early gastric cancer (EGC) might have more malignant potential than pure differentiated-type (PD) EGC. However, no study has analyzed all differentiated-type EGC cases treated endoscopically and surgically. This study aimed to compare the differences in clinicopathological features and long-term prognosis between MD- and PD-EGC. METHODS: We evaluated all patients with differentiated-type EGCs who were treated endoscopically and surgically in our hospital between January 2010 and October 2014. The clinicopathological features and long-term prognosis of MD-EGC were compared with those of PD-EGC. RESULTS: A total of 459 patients with 459 lesions were evaluated in this study; of them, 409 (89.1%) and 50 (10.9%) were classified into the PD and MD groups, respectively. Submucosal invasion was found in 96 (23.5%) patients of the PD group and in 33 (66.0%) patients of the MD group (p < 0.01). The rates of positive lymphatic and vascular invasion and ulceration were significantly higher in the MD group than in the PD group (p < 0.01). The proportion of patients with lymph node metastasis was also significantly higher in the MD group than in the PD group (5 (10%) vs 6 (1.5%), p < 0.01). The 5-year overall and EGC-specific survival rates in the PD group were 88.3 and 99.5%, respectively, while they were 94.0 and 98.0% in the MD group, respectively. CONCLUSIONS: MD-EGC has more malignant potential than PD-EGC. However, the long-term prognosis of MD-EGC is good and is not significantly different from that of PD-EGC when treated appropriately.

Cabozantinib plus docetaxel and prednisone in metastatic castration-resistant prostate cancer.

OBJECTIVE: To evaluate the safety and efficacy of cabozantinib combined with docetaxel. PATIENTS AND METHODS: This was a phase 1/2 multicentre study in patients with metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (75 mg/m2 every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone. RESULTS: A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose-limiting toxicities were neutropenic fever and palmar-plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively). CONCLUSION: Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.

Airway Pseudomonas aeruginosa density in mechanically ventilated patients: clinical impact and relation to therapeutic efficacy of antibiotics.

BACKGROUND: The bacterial density of Pseudomonas aeruginosa is closely related to its pathogenicity. We evaluated the effect of airway P. aeruginosa density on the clinical course of mechanically ventilated patients and the therapeutic efficacy of antibiotics. METHODS: We retrospectively analyzed data of mechanically ventilated ICU patients with P. aeruginosa isolated from endotracheal aspirates. Patients were divided into three groups according to the peak P. aeruginosa density during ICU stay: low (≤ 104 cfu/mL), moderate (105‒106 cfu/mL), and high (≥ 107 cfu/mL) peak density groups. The relationship between peak P. aeruginosa density and weaning from mechanical ventilation, risk factors for isolation of high peak density of P. aeruginosa, and antibiotic efficacy were investigated using multivariate and propensity score-matched analyses. RESULTS: Four-hundred-and-sixty-one patients were enrolled. Patients with high peak density of P. aeruginosa had higher inflammation and developed more severe respiratory infections. High peak density of P. aeruginosa was independently associated with few ventilator-free days on day 28 (P < 0.01) and increased ICU mortality (P = 0.047). Risk factors for high peak density of P. aeruginosa were prolonged mechanical ventilation (odd ratio [OR] 3.07 95% confidence interval [CI] 1.35‒6.97), non-antipseudomonal cephalosporins (OR 2.17, 95% CI 1.35‒3.49), hyperglycemia (OR 2.01, 95% CI 1.26‒3.22) during ICU stay, and respiratory diseases (OR 1.9, 95% CI 1.12‒3.23). Isolation of commensal colonizer was associated with lower risks of high peak density of P. aeruginosa (OR 0.43, 95% CI 0.26‒0.73). Propensity score-matched analysis revealed that antibiotic therapy for patients with ventilator-associated tracheobronchitis improved weaning from mechanical ventilation only in the high peak P. aeruginosa group. CONCLUSIONS: Patients with high peak density of P. aeruginosa had worse ventilator outcome and ICU mortality. In patients with ventilator-associated tracheobronchitis, antibiotic therapy was associated with favorable ventilator weaning only in the high peak P. aeruginosa density group, and bacterial density could be a good therapeutic indicator for ventilator-associated tracheobronchitis due to P. aeruginosa.

Clinical outcomes and predictive value of programmed cell death-ligand 1 expression in response to anti-programmed cell death 1/ligand 1 antibodies in non-small cell lung cancer patients with performance status 2 or greater.

BACKGROUND: Anti-programmed cell death protein-1/ligand-1 (anti-PD-1/PD-L1) therapy is promising for patients with non-small-cell lung cancer (NSCLC); however, clinical trials have focused on patients with a performance status (PS) 0 or 1. This study aimed to evaluate the clinical outcomes and correlation between PD-L1 expression status and tumor response to anti-PD-1/PD-L1 therapy among NSCLC patients with poor PS (i.e., PS ≥ 2). METHODS: In total, 130 patients with NSCLC and PS ≥ 2 treated with anti-PD-1/PD-L1 monotherapy at 12 institutions between January 2016 and August 2019 were retrospectively reviewed. PD-L1 expression status was divided into four groups: < 1%, 1-49%, ≥ 50%, and unknown. RESULTS: The objective response rate and PS improvement rate were 23 and 21% and were higher in the PD-L1 ≥ 50% group than in other groups (P < 0.01). Median progression-free survival (PFS) was 62 days and was longer in the PD-L1 ≥ 50% group than in other groups (P = 0.03). Multivariate analyses revealed that PD-L1 expression is significantly associated with prolonged PFS (PD-L1 < 1%; reference; 1-49%, hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.04-0.99, P = 0.05; ≥ 50%, HR 0.12, 95% CI 0.02-0.71, P = 0.02; unknown, HR 0.30, 95% CI 0.08-1.22, P = 0.09). CONCLUSIONS: NSCLC patients with poor PS and PD-L1 ≥ 50% are expected to benefit from anti-PD-1/PD-L1 therapy, despite a modest overall response among NSCLC patients with poor PS. Accordingly, PD-L1 expression provides useful information regarding decision-making for anti-PD-1/PD-L1 therapy even in these populations.

Pyogenic Ventriculitis After Anterior Skull Base Surgery Treated With Endoscopic Ventricular Irrigation And Reconstruction Using a Vascularized Flap.

Ventriculitis is a rare, serious complication of neurosurgery. A 59-year-old man who had undergone a craniotomy for a paranasal adenocarcinoma, developed a right frontal cystic lesion. We performed a bifrontal craniotomy to remove the lesion. The dura was repaired with non-vascularized free fascia lata in watertight fashion. Ventriculitis occurred 3 days postoperatively. Ventricular drainage, craniectomy, and endoscopic irrigation were undertaken to remove an abscess. The dura and the resection cavity were reconstructed using a vascularized anterolateral thigh adipofascial flap. His symptoms disappeared, indicating that endoscopic irrigation and reconstruction can effectively address ventriculitis even in patients in critical clinical condition.

[A case of endoscopic injection sclerotherapy for duodenal varices].

A 67-year-old man with a history of esophageal and gastric varices that were treated endoscopically was treated for Budd-Chiari syndrome and immunoglobulin G4-related sclerosing cholangitis in our facility. Varices in the second portion of the duodenum were revealed in follow-up upper endoscopy. The draining vein formed a venous plexus that was detected on computed tomography. Treatment with interventional radiology was difficult;therefore, endoscopic injection sclerotherapy (EIS) was performed instead. No recurrence has been observed to date. Thus, in this case, EIS for duodenal varices was effective.