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Background: Immune-related adverse events (irAEs) in patients treated with immune check inhibitors are associated with favourable response rate and survivals in multiple cancers, including renal cell carcinoma (RCC). The aim of this study was to investigate how irAEs were associated with improved survivals in advanced RCC patients treated with nivolumab plus ipilimumab. Materials and methods: This retrospective study included patients who received nivolumab plus ipilimumab between September 2018 and February 2022 at six centres. We assessed associations of the development and the number of irAEs with overall survival (OS) and progression-free survival (PFS). To eliminate immortal time bias, landmark analysis and a Cox model with time-dependent variables were used. Results: This study included 129 patients with a median follow-up of 12.3 months. The 2-year OS and PFS rates were 55% and 42%, respectively. Ninety six patients experienced irAEs. The development of irAEs was positively associated with OS and PFS rates (hazard ratio [HR] 0.328, 95% confidence interval [CI] 0.165–0.648, p = 0.001; HR 0.334, 95% CI 0.151–0.737, p = 0.007). Patients who experienced multiple irAEs had longer OS (HR 0.507, 95% CI 0.235–1.097, p = 0.085 or HR 0.245, 95% CI 0.110–0.544, p < 0.001) and PFS (HR 0.572, 95% CI 0.316–1.036, p = 0.085 or HR 0.267, 95% CI 0.113–0.628, p = 0.002) compared with those who experienced single or zero irAE. Conclusions: Developing irAEs, particularly multiple irAEs, is associated with favourable survivals in advanced RCC patients treated with nivolumab plus ipilimumab.

Purpose:The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment.Patients and Methods:Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A.Results:Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients’ baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25–0.47).Conclusions:When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.

Background The Phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control; randomized 2:1 to olaparib or control) in men with homologous recombination repair gene alterations and metastatic castration-resistant prostate cancer whose disease progressed on prior next-generation hormonal agent. Methods We present efficacy and safety data from an exploratory post hoc analysis of olaparib in the PROfound Asian subset. Analyses were not planned, alpha controlled or powered. Of 101 Asian patients enrolled in Japan (n=57), South Korea (n=29) and Taiwan (n=15), 66 and 35 patients received olaparib and control, respectively. Results Radiographic progression-free survival (rPFS) and overall survival (OS) favored olaparib versus control in Cohort A [rPFS 7.2 vs. 4.5 months, HR 0.58, 95% CI 0.29–1.21, P = 0.14 (nominal); OS 23.4 vs. 17.8 months, HR 0.81, 95% CI 0.40–1.74, P = 0.57 (nominal)] and Cohorts A+B [rPFS 5.8 vs. 3.5 months, HR 0.69, 95% CI 0.42–1.16, P = 0.13 (nominal); OS 18.6 vs. 16.2 months, HR 0.96, 95% CI 0.56–1.70, P = 0.9 (nominal)]. Olaparib showed greatest improvement in patients harboring BRCA alterations [rPFS 9.3 vs. 3.5 months, HR 0.17, 95% CI 0.06–0.49, P = 0.0003 (nominal); OS 26.8 vs. 14.3 months, HR 0.62, 95% CI 0.24–1.79, P = 0.34 (nominal)]. Safety data were consistent with the known profile of olaparib, with no new safety signals identified. Conclusion In PROfound, there was a statistically significant improvement in outcomes reported in the global population of patients with metastatic castration-resistant prostate cancer and alterations in homologous recombination repair genes whose disease progressed on prior next-generation hormonal agent compared with control. For the subset of Asian patients reported here, exploratory analysis suggested that there was also an improvement in outcomes versus control. The safety and tolerability of olaparib in Asian patients were similar to that of the PROfound global population. Clinical trial number ClinicalTrials.gov NCT02987543

Supplementary Figure 2 from Loss of ΔNp63α Promotes Invasion of Urothelial Carcinomas via N-Cadherin/Src Homology and Collagen/Extracellular Signal-Regulated Kinase Pathway

p63 plays a critical role in normal development and maintenance of stratified epithelia, including the urothelium. In the normal urothelium, urothelial cells in the basal layers abundantly express the predominant p63 isoform ΔNp63α. We previously showed that (a) ΔNp63α expression at the similar level to the normal urothelium is retained in most low-grade papillary noninvasive (LPN) tumors, whereas frequently lost in high-grade invasive carcinomas, and that (b) loss of ΔNp63α is associated with poor prognosis of invasive bladder urothelial carcinoma patients. However, a functional role of ΔNp63α in progression of urothelial carcinomas remains to be elucidated. Here, we show that loss of ΔNp63α expression promotes invasion of urothelial carcinoma cells. In 5637 cells substantially expressing only ΔNp63α isoform at the protein level, knockdown of endogenous p63 upregulated N-cadherin, which recruited more Src homology and collagen to N-cadherin and activated extracellular signal-regulated kinase (ERK) signaling, and consequently potentiated cell motility, excretion of matrix metalloproteinase-9, and invasion. In T24 cells originally lacking endogenous ΔNp63α expression, exogenous expression of ΔNp63α attenuated invasion by downregulating N-cadherin expression and ERK activity, confirming an invasion-suppressive role of ΔNp63α in urothelial carcinoma cells. We further documented loss of ΔNp63 expression accompanied by N-cadherin upregulation during muscle-invasive recurrence in patients whose bladder cancer had progressed from LPN tumors to muscle-invasive disease. These results suggest that loss of ΔNp63α and subsequent upregulation of N-cadherin is one of the mechanisms underlying progression of bladder cancer. [Cancer Res 2009;69(24):9263–70]

Supplementary Figure 1 from Loss of ΔNp63α Promotes Invasion of Urothelial Carcinomas via N-Cadherin/Src Homology and Collagen/Extracellular Signal-Regulated Kinase Pathway

Purpose: The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment. Patients and Methods: Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A. Results: Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients’ baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25–0.47). Conclusions: When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.

The prevalence of Lynch syndrome (LS)-associated DNA mismatch repair (MMR)-deficient bladder cancer (BC) has scarcely been investigated. Immunohistochemistry for four MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed in formalin-fixed paraffin-embedded (FFPE) sections prepared from the resected specimens of 618 consecutive newly diagnosed BC cases. Genetic/epigenetic analyses were performed in patients displaying the loss of any MMR proteins in the tumor. Of the 618 patients, 9 (1.5%) showed the loss of MMR protein expression via immunohistochemistry; specifically, 3, 3, 2, and 1 patients displayed the loss of MLH1/PMS2, PMS2, MSH6, and MSH2/MSH6, respectively. All nine patients were male with a median age of 68 years (63–79 years). One had been previously diagnosed as having LS with an MSH2 variant. Genetic testing demonstrated the presence of a pathogenic PMS2 variant (n = 1), a variant of uncertain significance in MSH2 (n = 1), and no pathogenic germline variants of the MMR genes (n = 1). One patient with MSH6-deficient BC did not complete the genetic testing because of severe degradation of DNA extracted from the FFPE specimen, but the patient was strongly suspected to have LS because of their history of colon cancer and MSH6-deficient upper urinary tract cancer. There remained a possibility that the remaining four patients who refused genetic testing had LS. The prevalence of LS-associated MMR-deficient BC was estimated to be 0.6–1.1% among unselected BC cases.

Tyrosine kinase inhibitors (TKIs) are used as targeted drugs for advanced renal cell carcinoma (RCC), although most cases eventually progress by acquiring resistance. Cancer stemness plays critical roles in tumor aggressiveness and therapeutic resistance, and dipeptidyl peptidase IV (DPP4) has been recently identified as a cancer stemness-related protein. A question arises whether DPP4 contributes to TKI efficacy in RCC. We established patient-derived RCC spheroids and showed that DPP4 expression is associated with stemness-related gene expression. TKI sunitinib resistance was rescued by DPP4 inhibition using sitagliptin or specific siRNAs in RCC cells and tumors. DPP4 expression can be inducible by retinoic acid and repressed by ALDH1A inhibition. Among type 2 diabetes patients with clinical RCC tumors, higher TKI efficacy is observed in those bearing DPP4high tumors treated with DPP4 inhibitors. This study provides new insights into TKI resistance and drug repositioning of DPP4 inhibitor as a promising strategy for advanced RCC.

Objectives To evaluate the prognosis of newly diagnosed patients with metastatic hormone‐naïve prostate cancer (mHNPC) and develop a novel prognostic model based on ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) risk classifications. Patients and methods We retrospectively analyzed the data of 578 newly diagnosed mHNPC patients initially treated with androgen deprivation therapy. We evaluated three clinical factors, namely, CHAARTED risk classifications (high‐volume disease [HVD] vs low‐volume disease [LVD]), Gleason scores (GS, 9‐10 vs ≤8), and hemoglobin (Hb, ≤13.0 g/dL vs >13.0 g/dL), for their prognostic potential in predicting time to castration‐resistant prostate cancer (TTC) and overall survival (OS) of mHNPC patients by multivariate analysis. Moreover, we developed a novel prognostic model that consisted of significant prognostic factors. Results Of the entire cohort, the median TTC and OS values were 18.3 and 67.5 months, respectively. HVD, GS 9‐10, and Hb ≤13.0 g/dL were independent poor prognostic factors for both TTC and OS. We developed a novel prognostic model which could stratify mHNPC patients into four risk groups according to the numbers of poor prognostic factors: group 1, LVD with low‐risk (LVD patients without GS 9‐10 and Hb ≤13.0 g/dL); group 2, LVD with high‐risk (LVD patients with GS 9‐10, Hb ≤13.0 g/dL, or both); group 3, HVD with low‐risk (HVD patients without GS 9‐10 with or without Hb ≤13.0 g/dL); and group 4, HVD with high‐risk (HVD patients with GS 9‐10 with or without Hb ≤13.0 g/dL). The median TTC and OS of groups 1, 2, 3, and 4 were 124.8, 36.4, 17.9, and 11.2 months, and 117.2, 94.2, 67.9, and 46.2 months, respectively. A significant difference in TCC and OS was found between all groups. Conclusion We developed a prognostic model for mHNPC patients that consisted of CHAARTED risk classifications, GS, and Hb. Our prognostic model could significantly stratify the prognosis of patients with LVD and HVD into two groups each. This model might be a good reference for shared decision making between patients and physicians on the initial treatment for mHNPC.

Although nivolumab plus ipilimumab has become a standard treatment regimen for metastatic clear cell renal cell carcinoma (ccRCC), its efficacy in non-clear cell carcinoma (nccRCC) has not been fully examined. In the current study, we evaluated the clinical outcomes of nivolumab plus ipilimumab in nccRCC compared with ccRCC.We retrospectively analyzed 22 patients with metastatic and/or locally advanced unresectable nccRCC who received nivolumab plus ipilimumab as a first-line therapy and compared them with 107 patients with ccRCC. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicity were compared between the nccRCC and ccRCC groups.The histology of nccRCC included eight papillary, six unclassified, three chromophobe, two collecting duct carcinoma, and three other subtypes. Best objective response in nccRCC patients included three complete responses and five partial responses, resulting in an ORR of 36%, while that in ccRCC patients was 50% (p = 0.22). With a median follow-up of 11.9 months, OS was significantly shorter in patients with nccRCC than in those with ccRCC (median 20.8 months vs. not reached, p = 0.04), while there was no significant difference in PFS (median 6.3 vs. 10.8 months, p = 0.21). Treatment-related adverse events occurred in 14 (64%) nccRCC patients and 81 (76%) ccRCC patients.Combination treatment with nivolumab and ipilimumab demonstrated modest clinical efficacy in patients with nccRCC compared with patients with ccRCC, suggesting it could be a therapeutic option for metastatic nccRCC patients.

Lynch syndrome is an autosomal dominant hereditary cancer syndrome in which many cancers develop, the main one being colorectal cancer. Germline pathogenic variants in one of four mismatch repair (MMR) genes are known to be causative of this disease. Accurate diagnosis using genetic testing can greatly benefit the health of those affected. Recently, owing to the improvement of sequence techniques, complicated variants affecting the functions of MMR genes were discovered. In this study, we analyzed insertions of a retrotransposon-like sequence in exon 5 of the MSH6 gene and exon 3 of the MSH2 gene found in Japanese families suspected of having Lynch syndrome. Both of these insertions induced aberrant splicing, and these variants were successfully identified by mRNA sequencing or visual observation of mapping results, although a standard DNA-seq analysis pipeline failed to detect them. The insertion sequences were ~2.5 kbp in length and were found to have the structure of an SVA retrotransposon (SVA). One SVA sequence was not present in the hg19 or hg38 reference genome, but was in a Japanese-specific reference sequence (JRGv2). Our study illustrates the difficulties of identifying SVA insertions in disease genes, and that the possibility of polymorphic insertions should be considered when analyzing mobile elements.

Background The prevalence and molecular characteristics of deficient mismatch repair prostate cancer in the Japanese population have scarcely been investigated. Methods Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from resected primary prostate cancers in patients who underwent prostatectomy at our institution between January 2001 and May 2016. Genetic and/or epigenetic alterations of mismatch repair genes were investigated in patients with any loss of mismatch repair protein expression in the tumour. Results Of the 337 patients, four (1.2%) showed loss of mismatch repair protein expression on immunohistochemistry. All four patients showed loss of both MSH2 and MSH6 protein expression. Genetic testing was performed in two of the four patients, demonstrating no pathogenic germline alterations were present. In each of these two patients, at least one somatic alteration inactivating MSH2 without MSH2 hypermethylation was identified, leading to the diagnosis of supposed ‘Lynch-like syndrome’. Patients with deficient mismatch repair prostate cancer were at a significantly higher stage (pT2pN0 vs. pT3-4pN0/pTanypN1, P = 0.02) and had a greater Gleason score ( Conclusions The prevalence of deficient mismatch repair prostate cancer in the Japanese hospital-based prostatectomized population was extremely low. To improve screening efficacy for deficient mismatch repair prostate cancer, screening candidates can be limited to patients with locally advanced, node-positive and/or Gleason score of 8 or greater prostate cancer. Universal tumour screening for Lynch syndrome seems ineffective in patients with prostate cancer.

Real-world incidence of immune-related adverse events (irAEs) associated with nivolumab plus ipilimumab in patients with renal cell carcinoma (RCC) has been rarely demonstrated. The present study aims to report the safety outcomes of this combination therapy in the real-life population. We conducted a multi-institutional retrospective observational study that assessed the incidence and severity of irAEs associated with nivolumab plus ipilimumab in 41 Japanese patients with metastatic and/or locally advanced RCC. The irAEs were classified into endocrine and non-endocrine irAEs. The median age and follow-up period were 68 years and 13.0 months, respectively. Endocrine irAEs were observed in 66% of patients, including hypopituitarism in 44%, hyperthyroidism in 41%, and primary hypothyroidism in 22%, while non-endocrine irAEs were observed in 54%. All patients experiencing hypopituitarism presented with adrenocorticotropic hormone deficiency, causing secondary adrenal insufficiency, which required permanent corticosteroid replacement therapy. There was an association between the incidence of endocrine irAEs and high-grade non-endocrine irAEs other than skin-related irAEs (p = 0.027). When patients experienced two or more endocrine irAEs, they had a 35% chance of experiencing high-grade non-endocrine irAEs other than skin-related irAEs. Nivolumab plus ipilimumab may lead to a high prevalence of endocrine irAEs in “real-world” patients. Endocrine irAEs may be associated with non-endocrine irAEs other than skin-related irAEs.

Background Although the risk factors for coronavirus disease 2019 (COVID-19) mortality have been identified, there is limited information about the risk factors for disease progression after hospitalization among Japanese patients with COVID-19 exhibiting no or mild symptoms. Methods All 302 consecutive patients who were admitted to our institutions and diagnosed with COVID-19 between March and December 2020 were retrospectively assessed. Ultimately, 210 adult patients exhibiting no or mild symptoms on admission were included in the analysis. They were categorized into the stable (no oxygen needed) and worsened (oxygen needed) groups, and their characteristics and laboratory data were compared. Results Among 210 patients, 49 progressed to a severe disease stage, whereas 161 did not. The mean patient age was 52.14 years, and 126 (60.0%) patients were male. The mean body mass index (BMI) was 23.0 kg/m2, and 71 patients were overweight (BMI ≥ 25 kg/m2). Multivariate logistic analysis showed that old age, overweight, diabetes mellitus (DM), and high serum ferritin levels were independent risk factors for disease progression. Conclusions Clinicians should closely observe patients with COVID-19, especially those with risk factors such as old age, overweight, DM, and high serum ferritin levels, regardless of whether they have no or mild symptoms.

BackgroundThe prevalence of Lynch syndrome and the use of universal tumor screening to identify Lynch syndrome among unselected patients with upper urinary tract urothelial carcinoma, which is associated with Lynch syndrome, have not been closely investigated yet.MethodsA total of 166 tumors from 164 upper urinary tract urothelial carcinoma patients were tested for microsatellite instability and expression of mismatch repair proteins (MLH1, MHS2, MSH6 and PMS2) by immunohistochemistry. Genetic testing was performed for patients suspected of having Lynch syndrome. Clinicopathological factors, including familial and personal cancer history associated with mismatch repair deficiency, were evaluated.ResultsThe frequency of high-level microsatellite instability and loss of at least one mismatch repair protein was 2.4% (4/164); the microsatellite instability and immunohistochemistry results showed complete concordance. Of these four patients, three were genetically proven to have Lynch syndrome, while the remaining one was highly suggestive for Lynch syndrome based on their personal cancer history. Univariate analysis showed that ageConclusionsThe prevalence of Lynch syndrome among unselected upper urinary tract urothelial carcinoma patients was at least 1.8% in our study population. The screening efficacies of the microsatellite instability test and immunohistochemistry appear equivalent. Universal tumor screening may be a valid approach; however, selective screening methods that consider factors associated with mismatch repair loss/high-level microsatellite instability tumors require further investigation.

OBJECTIVES To develop a prediction tool based on physical findings and environmental conditions without utilizing color Doppler ultrasonography to guide non-urologists and patients' families in determining the testicular torsion possibility among patients with acute scrotal pain. METHODS Overall, 110 consecutive patients aged ≤30 years with acute scrotal pain at Saitama Medical Center between 2012 and 2014 were retrospectively evaluated. Physical examination results, including scrotal inspection, palpation and gait observation, and environmental conditions at pain onset (time range and ambient temperature) were collected. Multivariate analysis identified significant and independent risk factors for testicular torsion, and a nomogram predicting testicular torsion was constructed. The model underwent prospective validation in an independent set of 123 consecutive patients admitted with acute scrotal pain to our institution between 2015 and 2017. RESULTS Testicular torsion diagnosis rates were 27% (30/110) and 26% (32/123) in the training and validation cohorts, respectively. Logistic regression analysis showed four risk factors for developing testicular torsion: abnormal testicular position, walking difficulty, midnight to early morning onset and ambient temperature

Testicular germ cell tumor (GCT) is the most common type of malignancy in young males. Patients with nonseminomatous GCT still have poor prognosis. To identify new therapeutic targets, we generated patient-derived cells (PDCs) and their xenograft (PDCX) models from 3 distinct GCT patients' specimens. The pathological features of GCT PDCs and PDCX tumors recapitulated those of nonseminomatous components exhibiting in the corresponding patients' specimens. Notably, stemness-related markers and hypoxia-related genes, including hypoxia inducible factor 1α (HIF1A) and neuritin 1 (NRN1), were abundantly expressed in three-dimensional spheroid cultures of GCT PDCs. We identified functional HIF1α response elements in the NRN1 promoter and defined that their transcriptional activities were substantially activated by hypoxia. HIF1α inhibition by siRNAs or an inhibitor, 2-methoxyestradiol, significantly suppressed NRN1 expression and decreased the in vitro and in vivo growth of PDC spheroids. Moreover, NRN1 knockdown efficiently suppressed PDC proliferation. These results suggest that HIF1α and NRN1 are potential diagnostic and therapeutic targets, and that 2-methoxyestradiol could be applied to clinical management of GCT. Overall, our GCT PDC and PDCX models would be useful as preclinical models for precision medicine targeting each patient.

Background Abiraterone (AA) and enzalutamide (ENZA) are increasingly being used in chemotherapy-naive patients with metastatic castration-resistant prostate cancer owing to efficacy and favorable toxicity. However, the order in which they should be administered has not been determined. Patients and Methods We retrospectively reviewed the records of chemotherapy-naive patients with metastatic castration-resistant prostate cancer who had received sequential treatment with either AA followed by ENZA (AA-ENZA) or the converse (ENZA-AA). Prostate-specific antigen (PSA) response rates (defined as ≥ 50% PSA decline from baseline), first-line progression-free survival (PFS), second-line PFS, combined PFS (defined as first-line PFS plus second-line PFS), and overall survival are compared between the 2 sequence groups. Results A total of 97 patients received sequential treatment with AA and ENZA; 50 patients were in the AA-ENZA group, and 47 patients were in the ENZA-AA group. The PSA response rate to first-line treatment was not significantly different between AA (48%) and ENZA (51%) ( P = .840). However, a significant difference was observed in the PSA response rate to second-line treatment (AA, 6.4% vs. ENZA, 30%; P = .004). The median combined PFS was not significantly different between sequence groups (hazard ratio, 0.71; 95% confidence interval, 0.46-1.08; log-rank P = .105). The order of addition also had no significant effect on median overall survival (hazard ratio, 0.98; 95% confidence interval, 0.64-1.52; log-rank P = .834). Conclusion With the exception of the second-line PSA response, there was no significant difference in clinical outcomes between the AA-ENZA and ENZA-AA groups. Our results might be useful reference in daily practice, especially for patients who do not have a suitable general condition for chemotherapy.

Diffusion-weighted whole-body magnetic resonance imaging with background suppression (DWIBS) is increasingly used in cancer imaging. However, little is known about its usefulness in the management of metastatic seminoma, in which evaluation of the viability of postchemotherapy residual nodules is pivotal. To date, 2–18fluoro-deoxy-d-glucose positron emission tomography (FDG-PET) has been recommended for post-chemotherapeutic assessment. We describe a case of metastatic seminoma in a 27-year-old man in which the viability of post-chemotherapy residual nodules tested false-positive on FDG-PET, but true-negative on DWIBS. DWIBS may be a good alternative technique to evaluate post-chemotherapy seminoma, although further studies are required to determine its usefulness. Keywords: Whole-body imaging, Diffusion magnetic resonance imaging, Seminoma, Chemotherapy, Positron-emission tomography

A 47-year-old woman was transferred to our hospital in June 2014 in hemorrhagic shock due to rupture of a huge right renal angiomyolipoma (AML). Selective right renal arterial embolization performed that same day reversed the shock immediately. Despite the huge abdominal tumor, the patient was discharged 2 weeks later after refusing any further treatment.Two weeks later she noticed the abdominal tumor growing. One month after discharge, she was readmitted due to dyspnea caused by restriction of her breathing by the growing tumor mass. A CT revealed a massive increase in tumor size with internal liquefaction, a thrombus in the left common iliac vein, and a 12 mm aneurysm in the right renal artery. The patient requested removal of the abdominal tumor since her ADL had deteriorated. We decided to perform a right nephrectomy with consideration of the left common iliac vein thrombus and right renal arterial aneurysm.As a precaution against pulmonary embolism in case the left common iliac vein thrombus dislodged, a retrievable inferior vena cava (IVC) filter was inserted before surgery. We were also concerned about possible rupture of the right renal aneurysm, so the right renal artery was embolized before surgery. After these procedures, a right nephrectomy was performed via a transperitoneal approach.The surgery was uneventful. The tumor weighed about 11 kg including 7,000 mL of bloody fluid. The IVC filter was removed the day after surgery, but the thrombus in the left common iliac vein remained, and an anticoagulant was started. Three months later, the thrombus had disappeared, and the anticoagulant was discontinued six months after surgery.According to the treatment guidelines for deep vein thrombosis, anticoagulants are the drugs of choice. IVC filters are seldom used to prevent pulmonary embolism. We initially administered an anticoagulant for the thrombus in the left iliac vein. However, an increase in abdominal tumor size suggested the drug had caused internal rebleeding and it had to be discontinued. Ultimately, we used a temporary retrievable IVC filter during the right nephrectomy with success.There is currently no consensus on when to use an IVC filter. Moreover, very little data exists on the use of an IVC filter during the perioperative period. Therefore, given the risk of potential thromboembolism, although we were able to use it successfully in our surgery, it should not be employed without a thorough benefit-risk assessment.

Background The repeated-dose liver micronucleus (RDLMN) assay is an effective and important in vivo test for detecting genotoxic compounds, particularly for those that require metabolic activation to show genotoxicity. In a collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) – Mammalian Mutagenicity Study Group (MMS), micronucleus induction of 22 chemicals with the RDLMN assay employing the collagenase digestion method was examined and reported on. Recently, we have developed a method which enables retrospective evaluation of micronucleus induction in formalin-fixed liver tissues (the formalin-fixed method) obtained in general toxicity studies completed in the past. Using this method, we were able to easily evaluate clastogenic potential of chemicals from the formalin-fixed tissues obtained in the general toxicity studies. In this study, to evaluate the usefulness of the formalin-fixed method, we have conducted a liver micronucleus assay using the formalin-fixed liver samples obtained from the above collaborative study (18 of 22 test chemicals) and carried out a comparison with the results obtained by the collagenase digestion method. Results Comparison of the collagenase digestion and formalin-fixed methods was conducted using the results of the micronucleus assays with a total of 18 test chemicals which included 12 genotoxic hepatocarcinogens (Group A), 4 genotoxic carcinogens but not liver targeted (Group B), and 2 nongenotoxic hepatocarcinogens (Group C). The formalin-fixed method obtained the similar results as the collagenase digestion method in 10 out of the 12 chemicals of Group A, and all chemicals of Group B and Group C. Although the results were statistically contradictive due to different levels of concurrent negative control, the 2 other chemicals of Group A showed comparable responses between the two methods. Conclusion The present study shows that the formalin-fixed method is capable of detecting liver carcinogens with sensitivity equal to or higher than that of the collagenase digestion method. We recommend use of the formalin-fixed method because of its capability of enabling retrospective evaluation of micronucleus induction in the formalin-fixed liver tissues obtained in general toxicity studies completed in the past.

Acquired chemoresistance is a critical issue for advanced bladder cancer patients during long-term treatment. Recent studies reveal that a fraction of tumor cells with enhanced tumor-initiating potential, or cancer stem-like cells (CSCs), may particularly contribute to acquired chemoresistance and recurrence. Thus, CSC characterization will be the first step towards understanding the mechanisms underlying advanced disease. Here we generated long-term patient-derived cancer cells (PDCs) from bladder cancer patient specimens in spheroid culture, which is favorable for CSC enrichment. Pathological features of bladder cancer PDCs and PDC-dependent patient-derived xenografts (PDXs) were basically similar to those of their corresponding patients' specimens. Notably, CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), a critical enzyme that synthesizes retinoic acid (RA), was abundantly expressed in PDCs. ALDH1A1 inhibitors and shRNAs repressed both PDC proliferation and spheroid formation, whereas all-trans RA could rescue ALDH1A1 shRNA-suppressed spheroid formation. ALDH inhibitor also reduced the in vivo growth of PDC-derived xenografts. ALDH1A1 knockdown study showed that tubulin beta III (TUBB3) was one of the downregulated genes in PDCs. We identified functional RA response elements in TUBB3 promoter, whose transcriptional activities were substantially activated by RA. Clinical survival database reveals that TUBB3 expression may associate with poor prognosis in bladder cancer patients. Moreover, TUBB3 knockdown was sufficient to suppress PDC proliferation and spheroid formation. Taken together, our results indicate that ALDH1A1 and its putative downstream target TUBB3 are overexpressed in bladder cancer, and those molecules could be applied to alternative diagnostic and therapeutic options for advanced disease.

27 Background: ctDNA testing offers additional opportunities for homologous recombination repair (HRR) gene alteration determination in patients who are not able to access tumor tissue testing. Alteration testing in ctDNA, for BRCA1, BRCA2 and ATM alterations was performed retrospectively in the PROfound study (phase 3 trial of olaparib versus physician’s choice of abiraterone or enzalutamide in men with HRR gene-mutated mCRPC [NCT02987543]). Methods: ctDNA samples were sequenced at FMI, using the FoundationOne Liquid CDx assay for alterations in BRCA1, BRCA2 (BRCA) and ATM, using plasma samples collected during screening in PROfound. Only patients who consented and provided plasma samples from Cohort A (BRCA/ ATM alteration positive by tissue testing) were tested for ctDNA alterations. Radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) in patients positive for alterations in ctDNA was analysed via stratified log-rank test. Additional efficacy endpoints (Objective Response Rate [ORR], Overall Survival[OS]) were also assessed. Results: In total, 181/245 (73.9%) Cohort A patients consented and provided a plasma sample for ctDNA testing, of which 139/181 (76.8%) had a ctDNA result reported (either mutation positive or mutation negative) and 42 patient samples failed testing due to insufficient DNA yield or a technical failure of the test.BRCA/ ATM alterations were identified in111/139 (79.9%) patients and 28/139 patients did not report a BRCA/ATM mutation either due to lack of ctDNA shedding from the tumour or ctDNA levels below the sensitivity of the assay. Patients who carried BRCA/ ATM ctDNA alterations had comparable demography, baseline characteristics and proportions of BRCA1, BRCA2 and ATM mutated patients to the overall Cohort A patients. rPFS by BICR results, in patients with BRCA/ ATM alterations in ctDNA, are presented in the Table. Key secondary efficacy endpoints (ORR, OS) will also be reported for ctDNA alteration positive patients. Conclusions: ctDNA testing in patients with mCRPC is feasible and most, but not all patients have concordant results. Patients who were positive for alterations in BRCA1, BRCA2 or ATM showed a consistent rPFS improvement (hazard ratio [HR] 0.33 [0.21, 0.53]) when compared with the ITT population identified by tumor tissue testing (HR 0.34 [0.25, 0.47]). This suggests that using ctDNA to identify patients carrying BRCA1, BRCA2 or ATM alterations who will benefit from olaparib may be beneficial. Clinical trial information: NCT02987543. [Table: see text]

The proband was a 62-year-old man with ureter cancer. He had a history of metachronous colorectal and gastric cancer. Immunohistochemical staining showed the absence of both MSH2 and MSH6 proteins in the ureter cancer and other available cancer tissue specimens. Genetic testing was conducted to identify the causative genes of hereditary gastrointestinal cancer syndromes including mismatch repair genes. We detected a germline variant, c.2635-3delC, within the splice acceptor site of exon 16, in the MSH2 gene. To investigate whether this variant affected splicing of the gene, RNA sequencing was performed using blood samples. We observed a substantial amount of the transcripts that lacked proper splicing of intron 15 in the indexed case, whereas, a very low amount of such aberrant transcripts was detected in the controls, strongly indicating an association between the variant and splicing defect. These results indicate that MSH2 c.2635-3delC affects normal splicing and might be a cause of Lynch syndrome.