Aggregated eosinophils and neutrophils characterize the properties of mucus in chronic rhinosinusitis.

BACKGROUND: Airway obstruction caused by viscous mucus is an important pathophysiologic characteristic of persistent inflammation, which can result in organ damage. OBJECTIVE: We investigated the hypothesis that the biophysical characteristics of accumulating granulocytes affect the clinical properties of mucus. METHODS: Surgically acquired nasal mucus samples from patients with eosinophilic chronic rhinosinusitis and neutrophil-dominant, noneosinophilic chronic rhinosinusitis were evaluated in terms of computed tomography density, viscosity, water content, wettability, and protein composition. Isolated human eosinophils and neutrophils were stimulated to induce the formation of extracellular traps, followed by the formation of aggregates. The biophysical properties of the aggregated cells were also examined. RESULTS: Mucus from patients with eosinophilic chronic rhinosinusitis had significantly higher computed tomography density, viscosity, dry weight, and hydrophobicity compared to mucus from patients with noneosinophilic chronic rhinosinusitis. The levels of eosinophil-specific proteins in mucus correlated with its physical properties. Eosinophil and neutrophil aggregates showed physical and pathologic characteristics resembling those of mucus. Cotreatment with deoxyribonuclease and heparin, which slenderizes the structure of eosinophil extracellular traps, efficiently induced reductions in the viscosity and hydrophobicity of both eosinophil aggregates and eosinophilic mucus. CONCLUSIONS: The present study elucidated the pathogenesis of mucus stasis in infiltrated granulocyte aggregates from a novel perspective. These findings may contribute to the development of treatment strategies for eosinophilic airway diseases.

Artificial intelligence-based analysis of the spatial distribution of abnormal computed tomography patterns in SARS-CoV-2 pneumonia: association with disease severity.

BACKGROUND: The substantial heterogeneity of clinical presentations in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia still requires robust chest computed tomography analysis to identify high-risk patients. While extension of ground-glass opacity and consolidation from peripheral to central lung fields on chest computed tomography (CT) might be associated with severely ill conditions, quantification of the central-peripheral distribution of ground glass opacity and consolidation in assessments of SARS-CoV-2 pneumonia remains unestablished. This study aimed to examine whether the central-peripheral distributions of ground glass opacity and consolidation were associated with severe outcomes in patients with SARS-CoV-2 pneumonia independent of the whole-lung extents of these abnormal shadows. METHODS: This multicenter retrospective cohort included hospitalized patients with SARS-CoV-2 pneumonia between January 2020 and August 2021. An artificial intelligence-based image analysis technology was used to segment abnormal shadows, including ground glass opacity and consolidation. The area ratio of ground glass opacity and consolidation to the whole lung (GGO%, CON%) and the ratio of ground glass opacity and consolidation areas in the central lungs to those in the peripheral lungs (GGO(C/P)) and (CON(C/P)) were automatically calculated. Severe outcome was defined as in-hospital death or requirement for endotracheal intubation. RESULTS: Of 512 enrolled patients, the severe outcome was observed in 77 patients. GGO% and CON% were higher in patients with severe outcomes than in those without. Multivariable logistic models showed that GGO(C/P), but not CON(C/P), was associated with the severe outcome independent of age, sex, comorbidities, GGO%, and CON%. CONCLUSION: In addition to GGO% and CON% in the whole lung, the higher the ratio of ground glass opacity in the central regions to that in the peripheral regions was, the more severe the outcomes in patients with SARS-CoV-2 pneumonia were. The proposed method might be useful to reproducibly quantify the extension of ground glass opacity from peripheral to central lungs and to estimate prognosis.

Computed tomography mucus plugs and airway tree structure in patients with chronic obstructive pulmonary disease: Associations with airflow limitation, health-related independence and mortality.

BACKGROUND AND OBJECTIVE: Mucus plugs and underlying airway tree structure can affect airflow limitation and prognosis in patients with chronic obstructive pulmonary disease (COPD), but their relative roles are unclear. This study used two COPD cohorts to examine whether mucus plugs on computed tomography (CT) were associated with airflow limitation and clinical outcomes independent of other airway structural changes and emphysema. METHODS: Based on visual CT assessment, patients with mucus plugs in 0, 1-2 and ≥3 lung segments were assigned to no-, low- and high-mucus groups. Loss of health-related independence and mortality were prospectively recorded for 3 and 10 years in the Kyoto-Himeji and Hokkaido cohorts, respectively. The percentages of the wall area of the central airways (WA%), total airway count (TAC) and emphysema were quantified on CT. RESULTS: Of 199 and 96 patients in the Kyoto-Himeji and Hokkaido cohorts, 34% and 30%, respectively, had high mucus scores. In both cohorts, TAC was lower in the high-mucus group than in the no-mucus group, whereas their emphysema severity did not differ. High mucus score and low TAC were independently associated with airflow limitation after adjustment for WA% and emphysema. In multivariable models adjusted for WA% and emphysema, TAC, rather than mucus score, was associated with a greater rate of loss of independence, whereas high mucus score, rather than TAC, was associated with increased mortality. CONCLUSION: Mucus plugs and lower airway branch count on CT had distinct roles in airflow limitation, health-related independence and mortality in patients with COPD.

Longitudinal assessment of interstitial lung abnormalities on CT in patients with COPD using artificial intelligence-based segmentation: a prospective observational study.

BACKGROUND: Interstitial lung abnormalities (ILAs) on CT may affect the clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), but their quantification remains unestablished. This study examined whether artificial intelligence (AI)-based segmentation could be applied to identify ILAs using two COPD cohorts. METHODS: ILAs were diagnosed visually based on the Fleischner Society definition. Using an AI-based method, ground-glass opacities, reticulations, and honeycombing were segmented, and their volumes were summed to obtain the percentage ratio of interstitial lung disease-associated volume to total lung volume (ILDvol%). The optimal ILDvol% threshold for ILA detection was determined in cross-sectional data of the discovery and validation cohorts. The 5-year longitudinal changes in ILDvol% were calculated in discovery cohort patients who underwent baseline and follow-up CT scans. RESULTS: ILAs were found in 32 (14%) and 15 (10%) patients with COPD in the discovery (n = 234) and validation (n = 153) cohorts, respectively. ILDvol% was higher in patients with ILAs than in those without ILA in both cohorts. The optimal ILDvol% threshold in the discovery cohort was 1.203%, and good sensitivity and specificity (93.3% and 76.3%) were confirmed in the validation cohort. 124 patients took follow-up CT scan during 5 ± 1 years. 8 out of 124 patients (7%) developed ILAs. In a multivariable model, an increase in ILDvol% was associated with ILA development after adjusting for age, sex, BMI, and smoking exposure. CONCLUSION: AI-based CT quantification of ILDvol% may be a reproducible method for identifying and monitoring ILAs in patients with COPD.

[A Case of Metastatic Renal Cancer Responding to Sunitinib as the Eighth Line Therapy].

A 62-year-old male presenting with gross hematuria and right renal mass was referred to our Urology Department. Computed tomography revealed a right renal mass, with multiple pulmonary lesions. He underwent right nephrectomy for highly suspected renal cell carcinoma with pulmonary metastases (cT3aN0M1). The pathological diagnosis was clear cell renal cell carcinoma, pT1b. Following surgery, he was treated with multiple regimens of chemotherapy, ranging from interferon alpha, multiple tyrosine kinase inhibitors such as sorafenib, axitinib, pazopanib and cabozantinib, everolimus, and nivolumab, all of which were discontinued after its induction, either due to adverse events or progressive disease. He was finally administered Sunitinib as the 8th line "last-ditch" treatment, which resulted in significant tumor shrinkage. No disease progression has been observed 25 months after initiating sunitinib administration.

N-(3,4-dimethoxyphenethyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine inhibits bladder cancer progression by suppressing YAP1/TAZ.

Bladder cancer (BlC) is the fourth most common cancer in males worldwide, but few systemic chemotherapy options for its effective treatment exist. The development of new molecularly-targeted agents against BlC is therefore an urgent issue. The Hippo signaling pathway, with its upstream LATS kinases and downstream transcriptional co-activators YAP1 and TAZ, plays a pivotal role in diverse cell functions, including cell proliferation. Recent studies have shown that overexpression of YAP1 occurs in advanced BlCs and is associated with poor patient prognosis. Accessing data from our previous screening of a chemical library of compounds targeting the Hippo pathway, we identified DMPCA (N-(3,4-dimethoxyphenethyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine) as an agent able to induce the phosphorylation of LATS1 and YAP1/TAZ in BlC cells, thereby suppressing their viability both in vitro and in mouse xenografts. Our data indicate that DMPCA has a potent anti-tumor effect, and raise the possibility that this agent may represent a new and effective therapeutic option for BlC.

Clinical utilization of artificial intelligence-based COVID-19 pneumonia quantification using chest computed tomography - a multicenter retrospective cohort study in Japan.

BACKGROUND: Computed tomography (CT) imaging and artificial intelligence (AI)-based analyses have aided in the diagnosis and prediction of the severity of COVID-19. However, the potential of AI-based CT quantification of pneumonia in assessing patients with COVID-19 has not yet been fully explored. This study aimed to investigate the potential of AI-based CT quantification of COVID-19 pneumonia to predict the critical outcomes and clinical characteristics of patients with residual lung lesions. METHODS: This retrospective cohort study included 1,200 hospitalized patients with COVID-19 from four hospitals. The incidence of critical outcomes (requiring the support of high-flow oxygen or invasive mechanical ventilation or death) and complications during hospitalization (bacterial infection, renal failure, heart failure, thromboembolism, and liver dysfunction) was compared between the groups of pneumonia with high/low-percentage lung lesions, based on AI-based CT quantification. Additionally, 198 patients underwent CT scans 3 months after admission to analyze prognostic factors for residual lung lesions. RESULTS: The pneumonia group with a high percentage of lung lesions (N = 400) had a higher incidence of critical outcomes and complications during hospitalization than the low percentage group (N = 800). Multivariable analysis demonstrated that AI-based CT quantification of pneumonia was independently associated with critical outcomes (adjusted odds ratio [aOR] 10.5, 95% confidence interval [CI] 5.59-19.7), as well as with oxygen requirement (aOR 6.35, 95% CI 4.60-8.76), IMV requirement (aOR 7.73, 95% CI 2.52-23.7), and mortality rate (aOR 6.46, 95% CI 1.87-22.3). Among patients with follow-up CT scans (N = 198), the multivariable analysis revealed that the pneumonia group with a high percentage of lung lesions on admission (aOR 4.74, 95% CI 2.36-9.52), older age (aOR 2.53, 95% CI 1.16-5.51), female sex (aOR 2.41, 95% CI 1.13-5.11), and medical history of hypertension (aOR 2.22, 95% CI 1.09-4.50) independently predicted persistent residual lung lesions. CONCLUSIONS: AI-based CT quantification of pneumonia provides valuable information beyond qualitative evaluation by physicians, enabling the prediction of critical outcomes and residual lung lesions in patients with COVID-19.

Centrilobular Emphysema Is Associated with Pectoralis Muscle Reduction in Current Smokers without Airflow Limitation.

BACKGROUND: Physiological and prognostic associations of centrilobular emphysema (CLE) and paraseptal emphysema (PSE) in smokers with and without chronic obstructive pulmonary disease (COPD) have been increasingly recognized, but the associations with extrapulmonary abnormalities, such as muscle wasting, osteoporosis, and cardiovascular diseases, remain unestablished. OBJECTIVES: The aim of the study was to investigate whether CLE was associated with extrapulmonary abnormalities independent of concomitant PSE in smokers without airflow limitation. METHODS: This retrospective study consecutively enrolled current smokers without airflow limitation who underwent lung cancer screening with computed tomography and spirometry. CLE and PSE were visually identified based on the Fleischner Society classification system. Cross-sectional areas of pectoralis muscles (PM) and adjacent subcutaneous adipose tissue (SAT), bone mineral density (BMD), and coronary artery calcification (CAC) were evaluated. RESULTS: Of 310 current smokers without airflow limitation, 83 (26.8%) had CLE. The PSE prevalence was higher (67.5% vs. 23.3%), and PM area, SAT area, and BMD were lower in smokers with CLE than in those without (PM area (mean), 34.5 versus 38.6 cm2; SAT area (mean), 29.3 versus 36.8 cm2; BMD (mean), 158.3 versus 178.4 Hounsfield unit), while CAC presence did not differ. In multivariable models, CLE was associated with lower PM area but not with SAT area or BMD, after adjusting for PSE presence, demographics, and forced expiratory volume in 1 s. CONCLUSIONS: The observed association between CLE and lower PM area suggests that susceptibility to skeletal muscle loss could be high in smokers with CLE even without COPD.

Impact of cytoreductive nephrectomy prior to combination therapy of ipilimumab plus nivolumab in metastatic renal cell carcinoma.

OBJECTIVES: The efficacy of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs) has been suggested in the real-world setting. We retrospectively examined the efficacy of CN prior to nivolumab plus ipilimumab systemic therapy for synchronous mRCC. METHODS: Synchronous mRCC patients who received nivolumab plus ipilimumab at Kobe University Hospital or five affiliated hospitals between October 2018 and December 2021 were included in this study. We compared the outcomes of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) between patients with CN prior to systemic therapy and without CN. In addition, patients were 1:1 matched by propensity scores accounting for factors associated with treatment assignment. RESULTS: Twenty-one patients received CN prior to nivolumab plus ipilimumab (Prior CN) and 33 received nivolumab plus ipilimumab alone (Without CN). PFS of the Prior CN group was 10.8 months (95%CI 5.5-NR) and 3.4 months (95%CI 2.0-5.9) for the Without CN group (p = 0.0158). OS of Prior CN was 38.4 months (95%CI NR-NR) and 12.6 months (95%CI 4.2-30.8) for Without CN (p = 0.0024). Univariate and multivariate analyses identified prior CN as a significant prognostic indicator for PFS and OS. Moreover, propensity score matching analysis showed significant improvements in PFS and OS in Prior CN. CONCLUSIONS: Patients who underwent CN prior to nivolumab plus ipilimumab systemic therapy for synchronous mRCC had a better prognosis than patients treated with nivolumab plus ipilimumab alone. These results suggest the efficacy of prior CN for synchronous mRCC with ICI combination therapy.

[Intraoperative Evaluation of Ureteral Blood Flow Using Indocyanine Green Fluorescence imaging on Living-Donor Kidney Transplantation].

Ureteral stenosis occurs in 2-10% after kidney transplantation. Most are caused by ischemia of the distal ureter and are difficult to manage. There is no standard method for evaluating ureteral blood flow during surgery, and it is left to the judgement of the operator. Indocyanine green (ICG) is used not only for a liver or cardiac function test but also for an assessment of tissue perfusion. We evaluated the intraoperative ureteral blood flow under a surgical light and by ICG fluorescence imaging in 10 living-donor kidney transplant patients between April 2021 and March 2022. No ureteral ischemia was detected under the surgical light, but ICG fluorescence imaging revealed/decreased blood flow in 4 of the 10 patients (40%). Further resection was performed in these 4 patients to increase the blood flow, and the median resection length was 1.0cm (0.3-2.0). The postoperative course was uneventful in all 10 patients, and no ureter-related complications were observed. ICG fluorescence imaging is a useful method for evaluating ureteral blood flow and is expected to help reduce complications caused by ureteral ischemia.

[Risk Factors of Antiresorptive Agent-Related Osteonecrosis of the Jaw in Prostate Cancer Patients with Bone Metastases].

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a severe adverse event associated with use of bone resorption inhibitors (BRIs), such as zoledronic acid and denosumab. Based on the results of phase 3 clinical trials for BRIs, the frequency of ARONJ is reported to be 1 to 2%, but the actual frequency could be higher. We investigated 173 patients with prostate cancer with bone metastases who were treated either with zoledronic acid or denosumab at our hospital between July 2006 and June 2020. ARONJ occurred in 13 patients (8%); i.e., ten out of 159 patients (6%) who were treated with zoledronic acid, and three out of 14 patients (21%) who were treated with denosumab. Multivariate analysis showed that longer duration of BRI exposure and dental treatment before the initiation of BRI are associated with risk of ARONJ. ARONJ is associated with decreased mortality but the association is not significant. Generally, the occurrence of ARONJ may be underestimated; therefore, further studies are warranted to determine the actual frequency of ARONJ.

[Challenging Case of Primary Renal Castleman's Disease Accompanied with Bacterial Pyelonephritis].

Castleman's disease is a rare lymphoproliferative disease, mostly found in the mediastinum. The number of Castleman's disease cases involving the kidneys is still limited. We report a case of primary renal Castleman's disease sporadically detected during a regular health check-up as pyelonephritis with ureteral stones. In addition, computed tomography showed renal pelvic and ureteral wall thickening with paraaortic lymphadenopathy. A lymph node biopsy was performed, but it did not confirm either malignancy or Castleman's disease. The patient underwent open nephroureterectomy for diagnostic and therapeutic purposes. The pathological diagnosis was renal and retroperitoneal lymph node Castleman's disease with pyelonephritis.

[The Effect of Naldemedine Tosylate on the Postoperative Course of Robot-Assisted Radical Cystectomy].

Radical cystectomy is an invasive procedure frequently followed by postoperative complications. Although the protocol of enhanced recovery after surgery (ERAS) is used in the postoperative course, several components of the ERAS protocol may increase the workload of medical workers. In this study, we added naldemedine tosylate only to routine postoperative management instead of using the ERAS protocol and evaluated the effect on the postoperative course of robot-assisted radical cystectomy (RARC). We retrospectively investigated 58 patients who underwent RARC from May 2015 to February 2022 at our hospital and evaluated the postoperative complications, such as ileus and urinary tract infections, and, length of hospital stay (LOS). We used naldemedine tosylate for the patients who underwent RARC after November 2019. As a result, naldemedine tosylate reduced 26.8% of postoperative complications within 30 days after the operation (p＝0.041) and shortened LOS 8 days (p＝0.018). Naldemesine tosylate improved the postoperative course of RARC.

Clinical practice pattern in patients with advanced urothelial cancer who had progressed on pembrolizumab in the pre-enfortumab vedotin era.

OBJECTIVES: Pembrolizumab, an anti-PD-1 monoclonal antibody, revolutionized the treatment for advanced urothelial carcinoma. However, the standard treatment for patients after disease progression with pembrolizumab had not been established until the recent approval of enfortumab vedotin. We analyzed the treatment of these patients in the real world, and the patient background and outcomes. METHODS: We extracted data from 543 patients who experienced progressive disease after pembrolizumab initiation from a Japanese nation-wide cohort of platinum-refractory, metastatic urothelial carcinoma. RESULTS: The median overall survival of the 543 patients was 3.5 months (95% confidence interval 3.0-4.1). Of these, only 20.6% (n = 112) received chemotherapy as a subsequent systemic treatment after progressive disease. The regimen of chemotherapy was very diverse. The median overall survival was 11.9 months (95% confidence interval 9.2-14.7) for patients who received chemotherapy, compared to 2.4 months for those who did not receive chemotherapy (95% confidence interval 2.1-2.9; P < 0.0001). Patients who received subsequent chemotherapy were more likely to have better performance status, neutrophil-to-lymphocyte ratio <3, hemoglobin >11 mg/dL, and history of a single chemotherapeutic regimen at pembrolizumab initiation. CONCLUSIONS: This report highlights the real-world practice of the management after pembrolizumab treatment failure in the pre-enfortumab vedotin era, characterized by infrequent use of subsequent anticancer therapy comprising various regimens, reflecting the lack of a standard treatment. Clinical introduction of enfortumab vedotin is expected to improve treatment outcomes in this setting. The present study will provide important baseline data for evaluating the influence of enfortumab vedotin on clinical practices and outcomes.

[Efficacy of Combination Chemotherapy of Gemcitabine and Nedaplatin for Squamous Cell Carcinoma of the Urinary Tract : Experience of Four Cases].

We report the use of combination chemotherapy of gemcitabine (800 mg/m² on day1 and 8) and nedaplatin (60 mg/m² on day 1), including neoadjuvant therapy in four cases of squamous cell carcinoma of the urinary tract. In each case, the dose was reduced after assessing the performance status and renal function of the patient. Among the four cases, the best overall outcome was complete response in one case, partial response in two cases, and stable disease in one case. The main adverse event observed was thrombocytopenia; however, no serious adverse events were observed, and this regimen was safely administered. Therefore, we believe that this regimen could be an effective treatment option for progressive squamous cell carcinoma originating from the urinary tract.

A comparison of nephrotoxicity between patients with a solitary-functioning kidney and those with bilateral-functioning kidneys in cisplatin-based chemotherapy for advanced urothelial carcinoma: a Japanese retrospective multi-institutional study.

BACKGROUND: To compare the prevalence of nephrotoxicity between patients with a solitary-functioning kidney versus those with bilateral-functioning kidneys during the administration of cisplatin-based chemotherapy for advanced urothelial carcinoma. METHODS: We retrospectively analyzed 244 advanced urothelial carcinoma patients treated with cisplatin-based chemotherapy between 2004 and 2010 at 17 institutes in Japan. The 24 h creatinine clearance, Cockcroft-Gault formula, and estimated glomerular filtration rate equation (eGFR), were compared before all chemotherapies. The urinary tract function status was determined based on the data of nephroureterectomy, hydronephrosis, and relief of upper urinary tract obstruction. A total of 244 patients were divided into four groups according to their urinary tract functioning status and eGFR results, including bilateral-functioning kidneys with pretreatment eGFR ≥60 mL/min/1.73 m2 group (n = 83, 34.0%); a solitary-functioning kidney with pretreatment eGFR ≥60 mL/min/1.73 m2 group (n = 36, 14.8%); bilateral-functioning kidneys with pretreatment eGFR < 60 mL/min/1.73 m2 group (n = 45, 18.4%); and a solitary-functioning kidney with pretreatment eGFR < 60 mL/min/1.73 m2 group (n = 80, 32.8%). RESULTS: The prevalence of nephrotoxicity with impaired eGFR of > 10% and 30% from baseline in the post-third-course of chemotherapy was significantly higher in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney, among patients with pretreatment eGFR < 60 mL/min/1.73 m2 (p = 0.023 and p = 0.026). During all courses of chemotherapy, the prevalence of nephrotoxicity with impaired eGFR of > 20% from baseline were significantly higher in patients with bilateral-functioning kidneys than those with a solitary-functioning kidney among patients with pretreatment eGFR < 60 mL/min/1.73 m2 (p = 0.034), whereas no significant difference was observed among patients with pretreatment eGFR ≥60 mL/min/1.73 m2. CONCLUSIONS: The results suggest that cisplatin-based chemotherapy may have more nephrotoxicity in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney.

Impact of acute kidney injury defined by CTCAE v4.0 during first course of cisplatin-based chemotherapy on treatment outcomes in advanced urothelial cancer patients.

BACKGROUND: The Kidney Disease: Improving Global Outcomes group (KDIGO) defined acute kidney injury (AKI) as an elevation of serum creatinine (sCR) exceeding 0.3 mg/dl within 48 h. The widely used adverse events criteria for chemotherapy, Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAE v4.0), also defined AKI as sCR exceeding 0.3 mg/dl, but with no provision of a time course. Here, we attempted to clarify the impact of AKI (CTCAE v4.0) during cisplatin-based chemotherapy on clinical outcome of patients with advanced urothelial cancer (UC). METHODS: This multicenter retrospective study included 230 UC patients who received cisplatin-based chemotherapy. RESULTS: During the first chemotherapy course, AKI (CTCAE v4.0) episodes were observed in 61 patients (26.5 %), whereas only four patients (1.5 %) experienced AKI (KDIGO) episodes. Both the pretreatment estimated glomerular filtration rate (eGFR) and creatinine clearance by Cockcroft-Gault formula were not efficient predictors for the development of AKI (CTCAE v4.0). AKI (CTCAE v4.0) impacted renal function: at the start of second-course chemotherapy, the average eGFR of the patients with AKI (CTCAE v4.0) was 54.1 ml/min/1.73 m2, significantly lower than that of patients without AKI (CTCAE v4.0) (63.4 ml/min/1.73 m2). As a result, only 57.4 % of patients with AKI (CTCAE v4.0) received the planned treatment at the second course. The survival of the patients who developed AKI (CTCAE v4.0) was significantly worse than that of the patients who did not. The 3-year OSs were 10.3 and 21.4 %, respectively (P = 0.02). CONCLUSION: The present study demonstrated that AKI (CTCAE v4.0) during chemotherapy had a negative impact on both the intensity of subsequent chemotherapy and oncological outcomes.

Current status of systemic chemotherapy for octogenarians with advanced urothelial cancer in Japan: a Japanese multi-institutional study (CURE study).

BACKGROUND: The standard regimen of systemic chemotherapy for patients with advanced urothelial cancer (UC) changed from methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) to gemcitabine and cisplatin (GC) in 2008 when the use of gemcitabine for UC began to be reimbursed by public health insurance in Japan. We examined its influence on the chemotherapy trend in elderly patients aged ≥80 years. METHODS: Among 345 patients included in our previous multicenter retrospective cohort study (chemotherapy for urothelial carcinoma: renal function and efficacy study; CURE study), the outcome of 30 patients aged ≥80 years was reviewed before and after 2008 and compared with 315 young patients. RESULTS: There were only 7 (4.6 %) elderly individuals among all registered patients before 2008, whereas the number increased to 23 (12 %) after 2008. Before 2008, only one elderly patient received MVAC, while GC (whose rate was similar to the rate in young patients) was administered to 13 patients (56.5 %) after 2008. The chemotherapeutic effect and overall survival (OS) rate was not significantly different between young and elderly patients. In the elderly treated with the GC regimen, the renal impairment rate after the first cycle was significantly higher, and the presence of distant metastases and renal impairment were independent prognostic factors in a multivariate analysis. CONCLUSION: Since GC was approved as the standard regimen for first-line chemotherapy in UC, selected elderly patients have been able to safely receive systemic chemotherapy like young patients. The clinical response rate and OS rate were similar to the young, but we need to monitor changes in renal function more closely in the elderly treated with GC.

[Therapy-Related Acute Myeloid Leukemia Following Etoposide Based Chemotherapy in Germ Cell Tumor].

A 27-year-old man visited our hospital with painless swelling of the left scrotum. Hematologic studies showed the following levels of lactate dehydrogenase, 3,171 IU/l ; alpha-fetoprotein, 2.2 ng/ml ; and ß- human chorionic gonadotropin, 0.4 ng/ml, and abdominal computed tomography revealed a mass of 10×8 ×4 cm in the left testis, and that of 3.5×3.0×5.0 cm in the left renal hilar lymph node, without any other metastasis. Left high inguinal orchiectomy was performed, and histopathological examination revealed mixed form with seminoma and teratoma. He was diagnosed to have a left germ cell tumor with left renal hilar lymph node metastases, pT1, N3, M0, stage II C, indicating poor prognosis with IGCCC. The patient received four cycles of chemotherapy, COMPE regimen (CDDP, VCR, MTX, PEP, VP-16 [etoposide]). After lactate dehydrogenase, alpha-fetoprotein, and ß -human chorionic gonadotropin all normalized, retroperitoneal lymph node dissection was performed. Histopathological examination revealed only a mature teratoma. Two and half years later, hematologic studies showed blast transformation. Bone marrow biopsy revealed acute myeloblastic lymphoma (M2). The patient received one cycle of AraC and daunorubicin, one cycle of high dose AraC, and three cycles of AraC and mitoxantrone. After chemotherapy, he has maintained a disease-free status for 11 years. In this case, etoposide, a topoisomerase II inhibitor, was the presumed cause of therapy-related acute myeloid leukemia. After administering chemotherapeutic agents especially etoposide, it is important to check blood count periodically for a long time.

CLINICAL OUTCOMES OF EXTERNAL-BEAM RADIOTHERAPY COMBINED WITH NEOADJUVANT ANDROGEN DEPRIVATION THERAPY FOR HIGH-RISK PROSTATE CANCER.

(Purpose) We investigated the outcome of external-beam radiotherapy (EBRT) with neoadjuvant androgen deprivation therapy (NeoADT) for high-risk prostate cancer defined by National Comprehensive Cancer Network (NCCN) guideline. (Patients and method) From 2002 to 2013, 70 patients with high-risk prostate cancer (PSA ≥20 ng/ml or clinical T stage ≥T3a, Gleason score ≥8) were treated with NeoADT and EBRT. EBRT consisted of three-dimensional conformal or intensity modulated radiotherapy with or without whole-pelvic radiation. Biochemical failure was defined according to the Phoenix definition. Biochemical progression-free survival (bPFS) and overall survival (OS) were calculated by Kaplan-Meier method, and prognostic factors for bPFS were analyzed by using the Cox proportional hazard model. (Result) The median age and initial prostate-specific antigen (PSA) level were 72 years old and 25.2 ng/ml, respectively. 43 patients had PSA level ≥20 ng/ml, 51 patients had clinical stage ≥T3a, 27 patients had Gleason score ≥8. The number of risk factors patients possessed was 1 (RiskN-1) in 31 patients, 2 (RiskN-2) in 27 patients and 3 (RiskN-3) in 12 patients. Median EBRT dose and duration of Neo ADT were 74 Gy and13.0 months, respectively. Whole-pelvic radiation was administered in 7 patients. After median follow-up of 4.8 years, biochemical and clinical failure occurred in 23 and 2 patients, respectively. No patients died of cancer. Five-year/8-year bPFS and OS were 63%/54% and 100%/91%, respectively. In multivariate analysis, three high-risk factor of NCCN guideline (PSA, clinical stage, Gleason score) did not predict outcome after EBRT independently, but RiskN (-1 vs -2, 3, HR 35.35, 95%CI 2.51-498.05, p<0.01) and pre-EBRT PSA (continuous, hazard ratio 1.31, 95%CI 1.01-1.71, p<0.05) were the significant predictors of bPFS. Five-year/8-year bPFS in RiskN-1 group and RiskN-2 or -3 group were 89%/79% and 47%/39%, respectively. Grade 3/4 adverse events (CTCAE ver4.0-JCOG) occurred in 2 patients. (Conclusion) Median dose of 74 Gy EBRT with intermediate-term NeoADT was safe and beneficial for high-risk prostate cancer. The number of risk factors and pre-EBRT PSA level were the independent prognostic factors for biochemical progression-free survival.