Ramucirumab for advanced hepatocellular carcinoma in the current real world: a Japanese single-arm study post-REACH-2 (The R-evolution study).

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

Derivation of pancreatic acinar cell carcinoma cell line HS-1 as a patient-derived tumor organoid.

Acinar cell carcinoma (ACC) of the pancreas is a malignant tumor of the exocrine cell lineage with a poor prognosis. Due to its rare incidence and technical difficulties, few authentic human cell lines are currently available, hampering detailed investigations of ACC. Therefore, we applied the organoid culture technique to various types of specimens, such as bile, biopsy, and resected tumor, obtained from a single ACC patient. Despite the initial propagation, none of these organoids achieved long-term proliferation or tolerated cryopreservation, confirming the challenging nature of establishing ACC cell lines. Nevertheless, the biopsy-derived early passage organoid developed subcutaneous tumors in immunodeficient mice. The xenograft tumor histologically resembled the original tumor and gave rise to infinitely propagating organoids with solid features and high levels of trypsin secretion. Moreover, the organoid stained positive for carboxylic ester hydrolase, a specific ACC marker, but negative for the duct cell marker CD133 and the endocrine lineage marker synaptophysin. Hence, we concluded the derivation of a novel ACC cell line of the pure exocrine lineage, designated HS-1. Genomic analysis revealed extensive copy number alterations and mutations in EP400 in the original tumor, which were enriched in primary organoids. HS-1 displayed homozygous deletion of CDKN2A, which might underlie xenograft formation from organoids. Although resistant to standard cytotoxic agents, the cell line was highly sensitive to the proteasome inhibitor bortezomib, as revealed by an in vitro drug screen and in vivo validation. In summary, we document a novel ACC cell line, which could be useful for ACC studies in the future.

Outcomes and risk factors for mortality in Pneumocystis pneumonia patients with rheumatoid arthritis: A multicentre retrospective cohort study.

OBJECTIVES: The aim is to evaluate outcomes and risk factors for death in patients with rheumatoid arthritis (RA) who developed Pneumocystis pneumonia (PCP). METHODS: We included RA patients who were diagnosed with PCP at seven participating community hospitals between July 2005 and October 2020. Clinical features were compared between survivors and non-survivors. Disease-modifying antirheumatic drugs (DMARDs) before PCP onset and after PCP recovery were also examined. RESULTS: Seventy RA patients developed PCP, and among them, 60 (85.7%) received methotrexate (MTX) monotherapy (40%) or MTX combination therapy with other DMARDs (45.7%). PCP was more likely to occur after 12 months of MTX monotherapy and within 3 months of MTX combination therapy. Thirteen patients (18.6%) died despite PCP treatment. Multivariable logistic regression analysis revealed that coexisting RA-associated interstitial lung disease (odds ratio, 6.18; 95% confidence interval, 1.17-32.63) and delayed PCP treatment with anti-Pneumocystis drugs (odds ratio, 15.29; 95% confidence interval, 1.50-156.15) are significant risk factors for PCP mortality in RA patients. Most survivors successfully resumed DMARD therapy without PCP prophylaxis; one recurrent PCP case was observed during follow-up (median, 4.1 years). CONCLUSIONS: To avoid a treatment delay, RA patients should be followed up for signs and symptoms of PCP development, especially those with RA-associated interstitial lung disease.

Treatment strategies and outcomes in a long-term registry study of patients with high-risk metastatic hormone-naïve prostate cancer in Japan: An interim analysis of the J-ROCK study.

OBJECTIVE: The prognosis of high-risk metastatic hormone-naïve prostate cancer is poor, and real-world evidence of therapeutic options and sequences is lacking. The J-ROCK study aimed to evaluate the outcomes in a real-world setting in Japan. METHODS: Patients with high-risk metastatic hormone-naïve prostate cancer diagnosed after May 2019 were eligible. Based on their treatment within 3 months after diagnosis, patients were allocated to either cohort 1 (androgen deprivation therapy alone or combined androgen blockade with bicalutamide) or cohort 2 (androgen deprivation therapy with abiraterone acetate+prednisolone, docetaxel, enzalutamide, or apalutamide). RESULTS: In this first interim analysis (cut-off January 2021), 410 patients were enrolled, including 163 patients in cohort 1 and 247 in cohort 2. The median follow-up period was 7.6 (range 0.1-20.5) months. A higher proportion of patients in cohort 2 (42.5%) achieved nadir prostate-specific antigen levels ≤0.2 ng/ml within a year, compared with cohort 1 (22.1%). Prostate-specific antigen-progression-free survival was also more favorable in cohort 2 (adjusted hazard ratio 0.629 [95% confidence interval 0.345-1.147]). CONCLUSIONS: The higher proportion of cohort 2 suggest a paradigm shift has occurred in the real-world treatment of high-risk metastatic hormone-naïve prostate cancer in Japan. Some factors including prostate-specific antigen may affect treatment selection but need further observation. Most patients in cohort 2 received abiraterone acetate+prednisolone. The proportion of patients in cohort 1 receiving combined androgen blockade was lower than previously reported in Japan. This analysis suggest that more intensive therapy tends to prolong prostate-specific antigen-progression-free survival in patients with high-risk metastatic hormone-naïve prostate cancer.

Adrenalectomy in Japanese patients with subclinical Cushing syndrome: 1-mg dexamethasone suppression test to predict the surgical benefit.

OBJECTIVES: To investigate whether the result of the 1-mg dexamethasone suppression test can predict the improvement of comorbidities after adrenalectomy in patients with subclinical Cushing syndrome. METHODS: This retrospective study included 117 subclinical Cushing syndrome patients who underwent adrenalectomy. The numbers of prescribed drugs for metabolic comorbidities and the clinical variables at diagnosis were compared with those at the follow up. Patients were classified into subgroups according to the result of the 1-mg dexamethasone suppression test. RESULTS: Significant improvements in blood pressure, serum cholesterol and body mass index were observed. Furthermore, a significant improvement in glycated hemoglobin was observed in patients with diabetes mellitus. These improvements led to a discontinuation or reduction of prescribed drugs after surgery. In addition, the greatest reduction of prescribed drugs was observed in patients whose serum cortisol levels were between 1.8 and 3.0 µg/dL after the 1-mg dexamethasone suppression test. CONCLUSIONS: The result of the 1-mg dexamethasone suppression test can be a useful factor predicting the improvement of comorbidities after adrenalectomy. Current data might give us a new insight into the decision-making for the treatment of subclinical Cushing syndrome.

Validation of a breath-holding test as a screening test for exercise-induced hypoxemia in chronic respiratory diseases.

The detection of exercise-induced hypoxemia is important for evaluating disease status in patients with chronic respiratory diseases. The 6-min walk test (6MWT) is useful for detecting exercise-induced hypoxemia. This pilot study aimed to validate the breath-holding test (BHT) as a screening for exercise-induced hypoxemia and compare its utility with that of the 6MWT in patients with chronic respiratory diseases. Fifty-nine patients with chronic respiratory diseases underwent BHTs lasting 10, 15, and 20 s. Percutaneous oxygen saturation (SpO2), pulse rate, and severity of dyspnoea were measured. The participants also underwent a 6MWT, a pulmonary function test, and analysis of arterial blood gas at rest. Multivariate linear regression analysis was performed to identify significant predictors of desaturation in the 6MWT. The minimum SpO2 during the BHT (all durations) and 6MWT were significantly correlated. Receiver operating characteristic analysis revealed the optimal cut-off for predicting SpO2 < 90% during the 6MWT as a minimum SpO2 ≤ 94% during the 15-s BHT. Perceived dyspnoea and maximum pulse rate were significantly lower during the 15-s BHT than during the 6MWT. In the multivariate linear regression analysis, the minimum SpO2 during the 15-s BHT (ß, 0.565, p < 0.001) and %DLco (ß, 0.255, p < 0.028) were independent predictors of desaturation in the 6MWT. The minimum SpO2 during the 15-s BHT may be a useful measure for screening for exercise-induced hypoxemia in patients with chronic respiratory diseases. The BHT is easier to perform, more readily available, and better tolerated than the 6MWT.

Prognostic value of an inflammatory index for patients with metastatic castration-resistant prostate cancer.

BACKGROUND: The inflammatory process has been reported to be involved in the formation and progression of various types of cancer. Recently, a peripheral inflammatory index, combining the derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and the lactate dehydrogenase (LDH) level, was proposed as a useful prognostic marker in advanced nonsmall cell lung cancer. The prognostic value of inflammatory markers in prostate cancer has not been established. We aimed to validate the prognostic significance of this peripheral inflammatory index in metastatic castration-resistant prostate cancer (mCRPC). METHODS: Clinical data of 196 mCRPC patients were retrospectively collected from multiple institutions. Clinical factors and inflammatory markers at the development of CRPC, including white blood cell count, absolute neutrophil count, dNLR, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, C-reactive protein (CRP), and LDH levels, were evaluated. The patients were classified into three groups based on the inflammatory index: Good (low dNLR and LDH), Intermediate (high dNLR or LDH), and Poor (high dNLR and LDH). Overall survival (OS) and cancer-specific survival after CRPC were analyzed using Cox proportional hazard models and Kaplan-Meier methods. RESULTS: The median age and baseline prostate-specific antigen level were 75 years and 397.15 ng/mL, respectively. On multivariate analysis, dNLR (≥1.51; hazard ratio [HR] = 1.624; P = .0173), LDH (≥upper limit of normal; HR = 2.065; P = .0004), alkaline phosphatase (≥310 U/L; HR = 2.546; P < .0001), and positive N stage (HR = 1.621; P = .048) were associated with poor OS after CRPC, whereas other inflammatory markers including the NLR were not. The Good inflammatory index group showed significantly longer OS after CRPC compared to the Intermediate and Poor groups, with median survivals of 46.2, 28.9, and 16.6 months, respectively. CONCLUSIONS: The novel inflammatory index combining dNLR and LDH was a useful prognostic parameter in patients with mCRPC. Our analysis suggested that dNLR emerged as a more valuable prognostic marker than NLR.

How many bone metastases may be defined as high-volume metastatic prostate cancer in Asians: A retrospective multicenter cohort study.

BACKGROUND: Recent landmark randomized trials (CHAARTED and LATITUDE studies) have highlighted potent upfront therapy for "high-volume" and "high-risk" metastatic castration-naïve prostate cancer (mCNPC). However, treatment response shows racial differences. We aimed to propose a novel definition for "high-volume" prostate cancer in Asians. METHODS: We retrospectively pursued 426 patients with de novo mCNPC from multiple institutions between 1999 and 2017. All patients received androgen deprivation therapy alone as initial treatment. We evaluated the number of bone metastases at diagnosis to clarify the clinical significance for progression-free survival and overall survival (OS). Statistical analyses were conducted using the Mann-Whitney U test, Cox proportional hazard models, and Kaplan-Meier methods. RESULTS: Median age and prostate-specific antigen level were 73 years and 266.2 ng/ml, respectively. Median OS was 55.5 months in patients who met the CHAARTED high criteria (vs 33.1 months in the trial). We evaluated 5 thresholds in the number of bone metastases (≥4, ≥6, ≥11, ≥16, and ≥21) to investigate the prognostic values. Patients with ≥11 bone metastases showed the highest HR for OS (2.766). Patients with 11 to 20 bone metastases had a significantly shorter OS than those with ≤10 metastases (P = .0001). We, therefore, proposed modified CHAARTED and LATITUDE high criteria (extending bone metastases ≥11). In multivariate analysis, the modified criteria were the only independent prognostic factors for OS (P = .0272 and P = .042, respectively). Conversely, no significant differences in OS were seen between patients with 1 to 3 bone metastases and 4 to 10 (P = .7513). CONCLUSION: Our exploratory study suggested ≥11 bone metastases as a suitable definition for "high-volume" prostate cancer in Asians. A larger, prospective study is warranted to verify our findings.

Prognostic factors influencing overall survival in de novo oligometastatic prostate cancer patients.

BACKGROUND: Oligometastatic cancer has been suggested as an intermediate state between localized disease and wide-ranging metastases. The clinical significance of local treatment in oligometastatic prostate cancer (PCa) has been a recent topic of interest. However, standard definitions of oligometastasis are lacking. Here we studied risk factors among Japanese de novo oligometastatic patients with PCa. METHODS: We retrospectively assessed clinical data from 264 patients, including locally advanced (T3 or T4N0M0) cancer, lymph-node-positive cancer (Tany N1M0), and cancer with ≤10 bone metastases. All patients received androgen deprivation therapy only. The number of bone metastases and clinical factors were evaluated in association with overall survival (OS) and progression-free survival (PFS). The Mann-Whitney U test, Cox proportional hazard models, and Kaplan-Meier methods were used as statistical analyses. RESULTS: Median age, PSA at baseline and OS were 74 years, 55.2 ng/mL, and 129.0 months, respectively. The cutoff for the number of bone metastases having the greatest impact on OS was ≥3 (hazard ratio [HR]: 2.67; P = .0001). In multivariate analysis, non-regional lymph node (LN) metastases (HR: 2.15; P = .0222), ISUP grade group (GG) 5 (HR: 2.04; P = .0186) and ≥3 bone metastases (HR: 1.82; P = .0390) were independent predictors of OS. In risk classification based on these factors, OS and PFS were significantly classifiable into poor (2-3 factors), intermediate (1 factor), and good (no factors) risk groups (P < .0001). CONCLUSION: Not only the number of bone metastases, but also non-regional LN metastases predict OS in patients with de novo oligometastatic PCa.

Relationship between post-void residual urine volume, preoperative pyuria and intravesical recurrence after transurethral resection of bladder carcinoma.

OBJECTIVES: To evaluate the relationship between residual urine volume, pyuria and bladder carcinoma recurrence. METHODS: The clinical data of 305 patients who had post-void residual urine volume measured and preoperative pyuria were retrospectively collected. The patients were classified into three risk groups based on the presence of residual urine and pyuria: good (negative residual urine and pyuria), intermediate (positive residual urine or pyuria) and poor (positive residual urine and pyuria). Predictive factors for intravesical recurrence-free survival were statistically analyzed using Cox proportional hazard models and Kaplan-Meier methods. The propensity score matching method was used to adjust the patients' backgrounds. RESULTS: The median follow-up period for all patients was 44 months. The presence of residual urine (P = 0.0164) and pyuria (P = 0.0233) were two independent prognostic factors for recurrence. After patients were classified into risk groups, the poor-risk group showed significantly shorter recurrence-free survival compared with that of the good- (P = 0.0002) and intermediate-risk groups (P = 0.0090). Even after matching, the presence of residual urine was related to short recurrence-free survival in male patients (P = 0.0012). When stratified by European Organization for Research and Treatment of Cancer risk groups, the presence of pyuria was related to short recurrence-free survival, especially for intermediate-risk patients without bacillus Calmette-Guérin treatment. CONCLUSIONS: Post-void residual urine and preoperative pyuria are two risks for recurrence-free survival in non-muscle-invasive bladder cancer.

[A Case of Subcutaneous Scrotal Metastasis from Primary Gastric Cancer].

Metastases to the subcutaneous scrotum are extremely rare. Here, we report a 78-year-old man who presented with pain to the scrotum and inguinal area. Two years ago, he underwent total gastrectomy for gastric cancer. The pain was attributed to increased scrotal wall thickness. Incisional biopsy of the thickened scrotal wall revealed diffused infiltration of the subcutaneous tissue by islands of scirrhous type malignant cells. Moreover, immunohistochemical studies showed that the tumor cells were positive for CK7, CK20, and CDX-2. These features suggested a metastatic adenocarcinoma of upper gastrointestinal origin. Although there were no visceral metastases, the tumor cells were too widely spread to be dissected curatively. Palliative chemotherapy with tegafur, gimeracil, and oteracil (S-1) was restarted, and local pain was subsequently ameliorated. Since scrotal metastasis is unlikely to occur it is difficult to diagnose. Therefore, in patients with groin discomfort or swelling and a history of gastric cancer, metastatic adenocarcinoma should be included in the differential diagnosis for early detection of a tumor.

Impact of post-void residual urine volume on intravesical recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma.

OBJECTIVE: To examine the impact of post-void residual urine volume on the risk of postoperative recurrence of intravesical carcinoma in patients with upper urinary tract urothelial carcinoma undergoing nephroureterectomy. METHODS: We retrospectively reviewed the data of 81 patients who were admitted to Chiba University Graduate School of Medicine Hospital and underwent nephroureterectomy for upper urinary tract urothelial carcinoma without bladder carcinoma. We assessed the predictive factors for intravesical recurrence after nephroureterectomy in all patients. Next, we compared patients with and without a residual urine volume using propensity score-matching analysis. The presence of a residual urine volume was defined as ≥30 mL. RESULTS: The median follow-up period among all patients was 48 months. The presence of pyuria and a residual urine volume were associated with bladder recurrence in the multivariate analysis. A total of 19 patients each were selected after matching, and we confirmed a significant difference between the presence and absence of a residual urine volume (P = 0.0291). The 2-year postoperative recurrence-free rate of patients with and without a residual urine volume was 32% and 82%, respectively. CONCLUSIONS: This is the first study to evaluate the post-void residual urine volume and intravesical recurrence rate after nephroureterectomy for upper urinary tract urothelial carcinoma. The presence of residual urine might be a risk factor for postoperative recurrence of intravesical carcinoma.

Intravesical irrigation might prevent bladder recurrence in patients undergoing radical nephroureterectomy for upper urinary tract urothelial carcinoma.

OBJECTIVES: To examine the effectiveness of intravesical irrigation with physiological saline solution or distilled water for the prevention of bladder recurrence in patients undergoing laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma. METHODS: This retrospective study involved 109 upper urinary tract urothelial carcinoma patients who underwent laparoscopic nephroureterectomy, and were evaluated at Chiba University Hospital and Yokohama Rosai Hospital between 2001 and 2018. We investigated the outcomes and analyzed various clinical factors including with or without intravesical irrigation related to bladder carcinoma recurrence after surgery. Physiological saline solution or distilled water was used for irrigation, which was carried out only during surgery. RESULTS: The median follow-up period after surgery was 26.1 months. Bladder recurrence was confirmed within 2 years for 45 of the 109 patients in the present study. Irrigation was carried out for 48 cases (distilled water, 26 patients; physiological saline solution, 22 patients). Tumor grade (G1-2 vs G3; P = 0.05) and intravesical irrigation (yes vs no; P = 0.0058) were related to bladder recurrence on univariate analyses. On multivariate analyses, intravesical irrigation was the independent factor involved in the prevention of bladder recurrence (P = 0.0051). Comparison between the irrigation and non-irrigation groups showed that bladder recurrence rates were significantly lower in the irrigation group (irrigation group vs non-irrigation group: 25.0% vs 52.5%, P = 0.0066). There was no significant difference in the recurrence rate between the two solutions used for irrigation. CONCLUSIONS: Intravesical irrigation during surgery of upper urinary tract urothelial carcinoma might decrease postoperative bladder recurrence rates.

Magnified endoscopic observation of small depressed gastric lesions using linked color imaging with indigo carmine dye.

BACKGROUND AND STUDY AIMS: Magnifying linked color imaging with indigo carmine dye (M-Chromo-LCI) enables sterically enhanced and color image-magnified observation of the superficial gastric mucosa. This study investigated the usefulness of M-Chromo-LCI for the differential diagnosis of gastric lesions. PATIENTS AND METHODS: 100 consecutive small depressed lesions were examined with conventional white-light imaging (C-WLI), magnifying blue-laser imaging (M-BLI), and M-Chromo-LCI. Endoscopic images were reviewed by three experts and three non-experts. Diagnostic accuracy and interobserver agreement were compared among the modalities. RESULTS: For experts, M-BLI showed a significantly higher diagnostic accuracy than C-WLI (82.7 % vs. 67.0 %; P < 0.001). The diagnostic accuracy of M-Chromo-LCI was not different from M-BLI (87.7 % vs. 82.7 %; P = 0.31). For non-experts, M-BLI showed a significantly higher diagnostic accuracy than C-WLI (69.3 % vs. 52.3 %; P < 0.001). M-Chromo-LCI additionally showed a significantly higher diagnostic accuracy than M-BLI (79.7 % vs. 69.3 %; P = 0.005). M-Chromo-LCI had the highest interobserver agreement for each group. CONCLUSIONS: M-Chromo-LCI is expected to become a useful modality for the accurate diagnosis of gastric lesions.

Lung abscess following bronchoscopy due to multidrug-resistant Capnocytophaga sputigena adjacent to lung cancer with high PD-L1 expression.

Lung abscess following flexible bronchoscopy is a rare and sometimes fatal iatrogenic complication. Here, we report the first case of a lung abscess caused by multidrug-resistant Capnocytophaga sputigena following bronchoscopy. A 67-year-old man underwent bronchoscopy to evaluate a lung mass. Seven days after transbronchial lung biopsy, he presented with an abscess formation in a lung mass. Empirical antibiotic therapy, including with garenoxacin, ampicillin/sulbactam, clindamycin and cefepime, was ineffective. Percutaneous needle aspiration of lung abscess yielded C. sputigena resistant to multiple antibiotics but remained susceptible to carbapenem. He was successfully treated by the combination therapy with surgery and with approximately 6 weeks of intravenous carbapenem. Finally he was diagnosed with a lung abscess with adenocarcinoma expressing high levels of programmed cell death ligand 1. The emergence of multidrug-resistant Capnocytophaga species is a serious concern for effective antimicrobial therapy. Clinicians should consider multidrug-resistant C. sputigena as a causative pathogen of lung abscess when it is refractory to antimicrobial treatment.

Contralateral adrenal width predicts the duration of prolonged post-surgical steroid replacement for subclinical Cushing syndrome.

OBJECTIVES: To identify pre-treatment factors affecting the duration of post-surgical steroid replacement in patients undergoing adrenalectomy for subclinical Cushing syndrome. METHODS: The present retrospective analysis included 64 patients who underwent unilateral laparoscopic adrenalectomy for subclinical Cushing syndrome. Adrenal tumor and contralateral adrenal sizes together with various clinical factors were studied in association with the duration of post-surgical steroid replacement. Adrenal tumor and contralateral adrenal size were measured at the level of the maximum transverse plane of the adrenal glands using computed tomography scan or magnetic resonance imaging. Cox's proportional hazards model was used for the statistical analysis. RESULTS: All 64 patients were treated with post-surgical steroid replacement after adrenalectomy. The median duration of the steroid treatment was 6 months. When assessing the duration of post-surgical steroid replacement, contralateral adrenal volume <0.745 cm3 , contralateral adrenal width <6.15 mm and serum cortisol after a 1-mg dexamethasone suppression test >2.65 µg/dL were significant predictors of prolonged post-surgical steroid treatment on univariate analysis. On multivariate analysis, contralateral adrenal width <6.15 mm was the only independent predictive factor for the prolonged post-surgical steroid replacement. CONCLUSIONS: Contralateral adrenal width seems to represent a significant predictive factor for the duration of post-surgical steroid replacement in subclinical Cushing syndrome patients. Pre-surgical assessment of image findings might help clinicians determine the total duration of steroid therapy after adrenalectomy.

Na+/H+ exchange regulatory factor 1 is required for ROMK1 K+ channel expression in the surface membrane of cultured M-1 cortical collecting duct cells.

The ROMK1 K+ channel, a member of the ROMK channel family, is the major candidate for the K+ secretion pathway in the renal cortical collecting duct (CCD). ROMK1 possesses a PDZ domain-binding motif at its C-terminus that is considered a modulator of ROMK1 expression via interaction with Na+/H+ exchange regulatory factor (NHERF) 1 and NHERF2 scaffold protein. Although NHERF1 is a potential binding partner of the ROMK1 K+ channel, the interaction between NHERF1 and K+ channel activity remains unclear. Therefore, in this study, we knocked down NHERF1 in cultured M-1 cells derived from mouse CCD and investigated the surface expression and K+ channel current in these cells after exogenous transfection with EGFP-ROMK1. NHERF1 knockdown resulted in reduced surface expression of ROMK1 as indicated by a cell biotinylation assay. Using the patch-clamp technique, we further found that the number of active channels per patched membrane and the Ba2+-sensitive whole-cell K+ current were decreased in the knockdown cells, suggesting that reduced K+ current was accompanied by decreased surface expression of ROMK1 in the NHERF1 knockdown cells. Our results provide evidence that NHERF1 mediates K+ current activity through acceleration of the surface expression of ROMK1 K+ channels in M-1 cells.

Dose escalation and pharmacokinetic study of carboplatin plus pemetrexed for elderly patients with advanced nonsquamous non-small-cell lung cancer: Kumamoto thoracic oncology study group trial 1002.

OBJECTIVES: This study was designed to determine the recommended dose of carboplatin and pemetrexed for elderly (≥70-year-old) chemotherapy-naïve patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of pemetrexed. METHODS: The patients were treated with 4-6 cycles of carboplatin plus a fixed dose of pemetrexed (500 mg/m(2)) every 3 weeks; the dose of carboplatin was escalated [from area under the curve (AUC) 4 to AUC 6]. To examine the pharmacokinetics of pemetrexed, blood samples were collected before and after pemetrexed infusion, and the blood levels of pemetrexed were measured by liquid chromatography-mass spectrometry. RESULTS: Grade 3 infection as a dose-limiting toxicity was observed at a carboplatin dose of AUC 6. We therefore determined a carboplatin dose of AUC 5 and a pemetrexed dose of 500 mg/m(2) as the recommended doses from this study. The pharmacokinetic study showed a significant inverse correlation between the AUC of pemetrexed and the creatinine clearance. CONCLUSIONS: For elderly chemotherapy-naïve patients with advanced nonsquamous NSCLC, the combination of carboplatin AUC 5 plus pemetrexed 500 mg/m(2) is recommended as a promising regimen; however, a reduction of the pemetrexed dose may be required for patients with renal dysfunction because of the high risk of hematotoxicities.

Proinflammatory Cytokines and Potassium Channels in the Kidney.

Proinflammatory cytokines affect several cell functions via receptor-mediated processes. In the kidney, functions of transporters and ion channels along the nephron are also affected by some cytokines. Among these, alteration of activity of potassium ion (K(+)) channels induces changes in transepithelial transport of solutes and water in the kidney, since K(+) channels in tubule cells are indispensable for formation of membrane potential which serves as a driving force for the transepithelial transport. Altered K(+) channel activity may be involved in renal cell dysfunction during inflammation. Although little information was available regarding the effects of proinflammatory cytokines on renal K(+) channels, reports have emerged during the last decade. In human proximal tubule cells, interferon-γ showed a time-dependent biphasic effect on a 40 pS K(+) channel, that is, delayed suppression and acute stimulation, and interleukin-1ß acutely suppressed the channel activity. Transforming growth factor-ß1 activated KCa3.1 K(+) channel in immortalized human proximal tubule cells, which would be involved in the pathogenesis of renal fibrosis. This review discusses the effects of proinflammatory cytokines on renal K(+) channels and the causal relationship between the cytokine-induced changes in K(+) channel activity and renal dysfunction.