Background
Pembrolizumab is effective in a limited number of patients with advanced urothelial carcinoma (UC). Therefore, we evaluated the prognostic value of clinical biomarkers following ...pembrolizumab treatment in patients with advanced UC.
Methods
We retrospectively reviewed the medical records of 121 patients with platinum-refractory advanced UC who received pembrolizumab. Inflammation-based prognostic scores before and 6 weeks after the treatment were recorded. The categorical variables influencing overall survival (OS) and objective response rate (ORR) were analyzed.
Results
Multivariate analyses showed that pretreatment Eastern Cooperative Oncology Group (ECOG) performance score (PS), presence of only lymph node metastasis (only LN mets), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for OS (
P
= 0.0077; RR = 2.42,
P
= 0.0049; RR = 0.36,
P
= 0.0047; RR = 2.53, and
P
= 0.0079; RR = 2.33, respectively). The pretreatment risk stratification using ECOG PS, only LN mets, CRP, and NLR was used for estimating the OS (
P
< 0.0001) and ORR (
P
< 0.0001). Furthermore, changes in NLR in response to pembrolizumab were significantly associated with the OS (
P
= 0.0002) and ORR (
P
= 0.0023). This change was also significantly correlated with OS even in the high-risk group stratified by this pretreatment risk stratification (
P
= 0.0069).
Conclusions
This pretreatment risk stratification may be used for estimating the OS and ORR of patients with advanced UC treated with pembrolizumab. If changes in NLR in response to pembrolizumab treatment improve, pembrolizumab should be continued.
Objectives
To evaluate operative and oncological outcomes of laparoscopic adrenalectomy through a transperitoneal approach and retroperitoneal approach for large (>5 cm in diameter) ...pheochromocytomas.
Methods
We retrospectively compared the results of a transperitoneal approach with those of a retroperitoneal approach in 22 patients (mean age 57.5 years, range 38–76 years) with unilateral large pheochromocytomas (12 right, 10 left). The mean body mass index, operation time, pneumoperitoneum time, estimated blood loss, fluctuation in blood pressure and complication rate were compared between the two approaches.
Results
The mean tumor diameter (range) was 7.0 cm (range 5.2–15.5 cm), and no significant differences were observed between the transperitoneal approach and retroperitoneal approach in any baseline clinical parameter. For right‐sided procedures, significant differences were found for operation time (113 vs 85 min), pneumoperitoneum time (93 vs 64 min) and estimated blood loss (96 vs 23 mL; P < 0.05, transperitoneal approach and retroperitoneal approach, respectively). No open conversion or recurrence was reported, but one right transperitoneal approach case required blood transfusion. No difference in these parameters was noted on the left side.
Conclusions
For right side procedures, the retroperitoneal approach is feasible, safer and faster than the transperitoneal approach for large pheochromocytomas. Early transection of the feeding artery is beneficial for managing the tumor and reducing the risk of bleeding.
Background
Currently, there is no consensus regarding which patients with high-risk prostate cancer (PCa) would benefit the most by radical prostatectomy (RP). We aimed to identify patients with ...high-risk PCa who are treatable by RP alone.
Methods
We retrospectively reviewed data on 315 patients with D’Amico high-risk PCa who were treated using RP without neoadjuvant or adjuvant therapy at the institutions of the Yamaguchi Uro-Oncology Group between 2009 and 2013. The primary endpoint was biochemical progression-free survival (bPFS) after RP. Risk factors for biochemical progression were extracted using the Cox proportional hazard model. We stratified the patients with high-risk PCa into 3 subgroups based on bPFS after RP using the risk factors.
Results
At a median follow-up of 49.9 months, biochemical progression was observed in 20.5% of the patients. The 2- and 5-year bPFS after RP were 89.4 and 70.0%, respectively. On multivariate analysis, Gleason score (GS) at biopsy (≥ 8, HR 1.92,
p
< 0.05) and % positive core (≥ 30%, HR 2.85,
p
< 0.005) were independent predictors of biochemical progression. Patients were stratified into favorable- (0 risk factor; 117 patients), intermediate- (1 risk factor; 127 patients), and poor- (2 risk factors; 57 patients) risk groups, based on the number of predictive factors. On the Cox proportional hazard model, this risk classification model could significantly predict biochemical progression after RP (favorable-risk, HR 1.0; intermediate-risk, HR 2.26; high-risk, HR 5.03;
p
< 0.0001).
Conclusion
The risk of biochemical progression of high-risk PCa after RP could be stratified by GS at biopsy (≥ 8) and % positive core (≥ 30%).
Summary Recent studies have reported that centrosome amplification is closely related to chromosomal instability and patient prognosis in human malignancies. The purpose of this study was to ...elucidate the relationship between centrosome amplification and genomic alterations in urothelial carcinomas. Centrosomes were evaluated by immunohistochemistry using anti– γ -tubulin antibody. Array-based comparative genomic hybridization technology using DNA chips spotted with 4030 bacterial artificial chromosome clones was applied to 70 urothelial carcinomas to examine DNA copy number aberrations. Studying aberrations in the number of chromosomes 7, 9, and 17 using fluorescence in situ hybridization allowed the estimation of the degree of chromosomal instability. DNA copy number gains at 20p12.2, 5p15.2, 5p15.31, and 17q25.3 and losses at 17p12, 8p22, 2q37.3, 5q31.1, and 2q37.3 were more frequent in tumors with centrosome amplification than in those without it. The total numbers of DNA copy number aberrations and frequency of chromosomal instability were also larger in tumors with centrosome amplification than in those without it ( P = .0263 and P < .0001, respectively). These parameters were more closely associated with centrosome amplification than with the subjectively assigned tumor grade ( P = .0405 and P = .0020, respectively). Thus, these data suggest that centrosome amplification may have great potential as a biomarker for improved objective classification of urothelial carcinoma and estimation of prognosis.
Rac1, one of the Rho family small guanosine triphosphatases, has been shown to work as a "molecular switch" in various signal transduction pathways. To assess the function of Rac1 in the ...differentiation process of CD4 single-positive (CD4-SP) T cells from CD4CD8 double-positive (DP) cells, we used a DP cell line DPK, which can differentiate into CD4-SP cells upon TCR stimulation in vitro. DPK expressing dominant-negative (dn)Rac1 underwent massive apoptosis upon TCR stimulation and resulted in defective differentiation of CD4-SP cells. Conversely, overexpression of dnRac2 did not affect differentiation. TCR-dependent actin polymerization was inhibited, whereas early ERK activation was unaltered in dnRac1-expressing DPK. We found that TCR-dependent induction of Bcl-2 was suppressed greatly in dnRac1-expressing DPK, and this suppression was independent of actin rearrangement. Furthermore, introduction of exogenous Bcl-2 inhibited TCR-dependent induction of apoptosis and restored CD4-SP generation in dnRac1-expressing DPK without restoring TCR-induced actin polymerization. Collectively, these data indicate that Rac1 is critical in differentiation of CD4-SP from the DP cell line by preventing TCR-induced apoptosis via Bcl-2 up-regulation.
Abstract only
Phosphoinositide 3‐kinase (PI3K) plays important roles in BCR‐dependent signal transduction, therefore it is critical in B cell development and activation. B cell tolerance to self ...antigen is induced and maintained mainly by clonal deletion and peripheral anergy. To assess the function of PI3K in the regulation of B cell self tolerance, mice lacking the gene for p85α (p85α−/−), the most important regulatory subunit of the class IA PI3Ks, were bred with anti‐hen egg lysozyme (HEL) immunoglobulin (HEL‐Ig) and membrane HEL (mHEL) or soluble HEL (sHEL). We found that development of monoclonal anti‐HEL‐Ig B cells was severely impaired in p85α−/− HEL‐Ig mice. Massive deletion of HEL‐specific B cells were observed in HEL‐Ig/mHEL double‐transgenic mice, even in the absence of p85α. Furthermore, anergy induction in HEL‐Ig/sHEL mice, represented by reduced production of anti‐HEL IgM antibody and impaired proliferative responses of B cells was maintained in p85α−/− double‐transgenic (HEL‐Ig/sHEL) mice. These results suggest that PI3K is essential for B cell maturation but not required for clonal deletion and anergy induction of self‐reactive clones.
Stereoselective halogenation is a highly useful organic transformation for multistep syntheses because the resulting chiral organohalides can serve as precursors for various medicinally relevant ...derivatives. Even though decarboxylative halogenation of aliphatic carboxylic acids is a useful and fundamental synthetic method for the preparation of a variety of organohalides, an enantioselective version of this reaction has not been reported. Here we report a highly enantioselective decarboxylative chlorination of β-ketocarboxylic acids to obtain α-chloroketones under mild organocatalytic conditions. The present method is also applicable for the enantioselective synthesis of tertiary α-chloroketones. The conversions of the resulting α-chloroketones into α-aminoketones and α-thio-substituted ketones via S
2 reactions at the tertiary carbon centres are also demonstrated. These results constitute an efficient approach for the synthesis of chiral organohalides and are expected to enhance the availability of enantiomerically enriched chiral compounds with heteroatom-substituted chiral stereogenic centres.
Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare glioneuronal neoplasm newly included in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. Owing to ...the wide spectrum of its histopathological and radiological features, accurate diagnosis can be challenging. Recently, molecular testing including DNA methylation array has been introduced with the possibility of improving diagnostic accuracy and contributing to the subtyping especially for brain tumors with ambiguous histology. Two molecularly distinct subtypes of DLGNT have been reported: methylation class‐1 (MC‐1) with an indolent clinical course and MC‐2, the latter aggressive. Herein, we report a case of a 14‐year‐old girl with a conspicuous hypothalamic mass lesion and diffuse leptomeningeal enhancement on magnetic resonance imaging. Biopsy specimens obtained from the hypothalamic lesion endoscopically were mainly composed of oligodendrocyte‐like cells. However, it was difficult to make a definite diagnosis from these non‐specific histological findings. Thus, DNA methylation array analysis was performed additionally by using formalin‐fixed, paraffin‐embedded tissue, resulting in a diagnosis of “MC‐1 subtype of DLGNT” with a high calibrated score (0.99). Consequently, she was treated conservatively, with neither progression of the tumor nor aggravation of symptoms for the next 12 months. It was concluded that DNA methylation array analysis for DLGNT, a rare glioneuronal tumor, could be a powerful tool not only for accurate diagnosis but also decision‐making in selecting the best treatment.
The highly enantioselective fluorination of α-branched aldehydes was achieved using newly developed chiral primary amine catalyst
. Furthermore, the C-F bond cleavage of the resulting ...α-fluoroaldehydes proceeded smoothly under alcoholic alkaline conditions to yield the corresponding α-hydroxyacetals in a stereospecific manner. Accordingly, the one-pot conversion of α-branched aldehydes into α-hydroxyacetals was achieved for the first time in high enantioselectivity.
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