Fullerene and fullerene whisker are not carcinogenic to the lungs and pleura in rat long-term study after 2-week intra-tracheal intrapulmonary administration.

Fullerene whiskers (FLW)s are thin rod-like structures composed of C60 and C70 fullerene (FL). The shape of FLWs suggests potential toxic effects including carcinogenicity to the lung and pleura, similar to effects elicited by asbestos and multi-walled carbon nanotubes (MWCNT)s. However, no long-term carcinogenic studies of FL or FLW have been conducted. In the present study we investigated the pulmonary and pleural carcinogenicity of FL and FLW. Twelve-week-old male F344 rats were administered 0.25 or 0.5 mg FL, FLW, MWCNT-7, and MWCNT-N by intra-tracheal intra-pulmonary spraying (TIPS). Acute lung lesions and carcinogenicity were analyzed at 1 and 104 weeks after 8 doses/15 days TIPS administration. At week 1, FLW, MWCNT-7, and MWCNT-N significantly increased alveolar macrophage infiltration. Expression of Ccl2 and Ccl3, reactive oxygen species production, and cell proliferation were significantly increased by administration of MWCNT-7 and MWCNT-N but not FL or FLW. At week 104, the incidence of bronchiolo-alveolar adenoma plus adenocarcinoma was significantly increased in the MWCNT-7 and MWCNT-N groups, and the incidence of mesothelioma was significantly increased in the MWCNT-7 group. No significant induction of pulmonary or pleural tumorigenesis was observed in the FL or FLW groups. The number of 8-OHdG-positive cells in the alveolar epithelium was significantly increased in the MWCNT-7 and MWCNT-N groups but not in the FL or FLW groups. FL and FLW did not exert pulmonary or pleural carcinogenicity in our study. In addition, oxidative DNA damage was implicated in MWCNT-induced lung carcinogenesis, suggesting that it may be a useful initial marker of carcinogenicity.

The role of DPYD and the effects of DPYD suppressor luteolin combined with 5-FU in pancreatic cancer.

BACKGROUND: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5-fluorouracil (5-FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5-FU with Lut in PDACs. METHODS AND RESULTS: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5-FU. The xenograft tumors of DPYD-overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA-seq analysis of the DPYD-overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity-MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5-FU on DPYD-overexpressing xenograft tumors and PDAC of Pdx1-Cre; LSL-KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5-FU nor Lut showed significant inhibitory effects; however, the combined administration of 5-FU and Lut exhibited a significant tumor-suppressive effect in both the xenograft tumors and KPPC models. CONCLUSION: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5-FU resistance, in PDACs. The combination therapy of Lut and 5-FU holds the potential for enhanced efficacy against PDACs.

Hexane insoluble fraction from purple rice extract improves steatohepatitis and fibrosis via inhibition of NF-κB and JNK signaling.

Nonalcoholic fatty liver disease (NAFLD) is fatty liver mainly related to metabolic syndrome. NAFLD with inflammation and hepatocellular damage is defined as nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. We have previously reported that a hexane insoluble fraction from an anthocyanin-rich purple rice ethanolic extract (PRE-HIF) can suppress prostate carcinogenesis. However, the extract's effect on NASH has not yet been established. In the present study, we investigated the chemopreventive effect of a PRE-HIF on NASH and liver fibrosis using a connexin 32 (Cx32) dominant negative transgenic (Cx32ΔTg) rat NASH model. Seven-week-old male Cx32ΔTg rats were fed a control diet, a high-fat diet (HFD), or an HFD with 1% PRE-HIF and intraperitoneal administration of dimethylnitrosamine for 17 weeks. Histological findings of NASH such as fat deposition, lobular inflammation, hepatocyte ballooning injury, and bridging fibrosis were observed in the HFD group but not in the control group, and all histological parameters were significantly improved by PRE-HIF treatment. Corresponding to the histological changes, increased expression of inflammatory cytokine mRNAs (TNF-α, IL-6, IL-18, IFN-γ, IL-1ß, TGF-ß1, TIMP1, TIMP2, COL1A1), along with and activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) signaling were observed in the HFD group, which was significantly decreased by PRE-HIF. The number and area of hepatic precancerous glutathione S-transferase placental form-positive foci tended to be decreased by PRE-HIF. These results indicate that intake of purple rice as a dietary supplement may reduce steatohepatitis, liver injury, and fibrosis in NASH by inactivation of NF-κB or JNK.

Experience and Prognostic Analysis with Avelumab Switch Maintenance Treatment in Metastatic Urothelial Carcinoma.

INTRODUCTION: Avelumab (Ave) is approved for metastatic urothelial carcinoma (mUC) maintenance therapy and prolongs overall survival (OS). We explored trends related to Ave treatment of mUC patients. METHODS: A total of 72 patients with mUC treated with first-line chemotherapy, from January 2019 to November 2022, at our affiliated institutions, were analyzed. We compared clinical parameters and the prognosis of patients treated with Ave (n = 43) because of progression during first-line chemotherapy, with untreated patients (Ave-untreated; n = 29). Among the Ave-treated group, we classified patients showing a complete or partial response or stable disease in their best response to Ave maintenance therapy as Ave-suitable patients; these were retrospectively analyzed. Potential prognostic factors, including the Geriatric Nutritional Risk Index (GNRI) for determining patients suitable for Ave, were evaluated. RESULTS: The basic clinical parameters of patients when first-line treatment was initiated were not statistically different between the two groups. The Ave-suitable group (median 26.6 months, 95% confidence interval [CI]: 19.4-not reached [NR]) showed significantly longer median OS after first-line treatment than the Ave-untreated group (median 12.0 months, 95% CI: 7.5-NR) with tolerable adverse events. The cut-off values of prognostic factors were set by the receiver operating characteristic curve. Low age and GNRI sustainability were revealed as significant prognostic factors for being Ave-suitable both in univariate and multivariate analysis. CONCLUSION: In mUC, Ave maintenance prolonged OS within tolerable safety profiles. GNRI sustainability may be used as a biomarker to predict being Ave-suitable.

C-Reactive Protein Is a Potential Prognostic Marker in Patient with Advanced or Metastatic Urothelial Carcinoma Treated with Enfortumab Vedotin: A Multi-Center Retrospective Study.

BACKGROUND: In the EV-301 trial, enfortumab vedotin prolonged survival in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum-based therapy and programmed cell death 1/programmed death-ligand 1 inhibitor. However, real-world Asian data are limited, and potential prognostic markers are non-existent. We aimed to investigate potential prognostic markers for enfortumab vedotin therapy in Asian patients. METHODS: We retrospectively enrolled 61 Japanese patients treated with enfortumab vedotin therapy at our hospital and affiliated hospitals between January 2019 and September 2023. RESULTS: Enrolled patients (38 men, 23 women; median age 74 [IQR: 68-79] years) had bladder cancer (26 patients) or upper-tract urothelial carcinoma (35 patients). Fifty-four patients reported adverse events (grade >3 in 12). Skin disorders, pruritus, and neuropathy were common adverse effects. The median overall survival was 17.1 months (95% confidence interval: 10.0-not applicable). In multivariate analysis, the C-reactive protein level was an independent marker predicting favorable overall survival with enfortumab vedotin. Patient characteristics did not differ between C-reactive protein-high and -low groups. CONCLUSIONS: Our study provides real-world data showing that enfortumab vedotin prolonged survival in Asian patients similar to the EV-301 trial. Additionally, the C-reactive protein level might be considered a prognostic marker of enfortumab vedotin therapy in such patients.

Successful treatment with enfortumab-vedotin of metastatic signet ring cell cancer expressing nectin-4 and originating from the bladder.

Introduction: As an aggressive adenocarcinoma phenotype, primary signet ring cell carcinoma of the urinary bladder is an extremely rare variant. The prognosis of metastatic signet ring cell carcinoma of the urinary bladder is extremely poor and the clinical course for its specific pathogenesis remains unelucidated. Case presentation: A 64-year-old Japanese male patient was diagnosed with invasive urothelial carcinoma with glandular differentiation of a signet ring cell-type with pT4aN0M0, and he was eventually diagnosed with metastatic signet ring cell carcinoma of the urinary bladder. He was initially responsive to systemic combination induction chemotherapy of S-1 and cisplatin followed by avelumab switch maintenance therapy; however, signet ring cell carcinoma of the urinary bladder relapse occurred in the pathological findings of a biopsy from the right thigh. Immunohistochemical analysis of this specimen identified strong positive staining for nectin-4 and, following enfortumab-vedotin treatment, the patient showed a good response. Conclusion: We thus describe a rare case of metastatic signet ring cell carcinoma of the urinary bladder with nectin-4 expression diagnosed by a biopsy of a metastatic site.

Urothelial carcinoma occurring in a defunctionalized bladder after urinary diversion due to the bladder exstrophy-epispadias complex.

Introduction: The bladder exstrophy-epispadias complex is a rare congenital disease. Urothelial carcinomas rarely occur in patients with this disease, and there have been few reports on its treatment. Case presentation: We report the case of a 44-year-old man with a hemorrhage from the external urethral meatus. He was diagnosed with bladder exstrophy-epispadias complex and underwent urinary diversion with substitution cystoplasty and Mitrofanoff appendicovesicostomy. Because computed tomography and magnetic resonance imaging suggested invasive bladder carcinoma in the defunctionalized bladder, we performed a cystectomy. The patient was diagnosed with urothelial carcinoma with glandular differentiation. One month after the surgery, nivolumab adjuvant chemotherapy was administered. The patient showed no signs of recurrence or metastasis after the treatment. Conclusion: This is the first case of adjuvant nivolumab therapy for urothelial carcinoma with the bladder exstrophy-epispadias complex.

Incidence of pancreatic injury and pancreatitis in patients treated with immune checkpoint inhibitors.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are being increasingly used to treat advanced malignancies. ICI-induced pancreatic injury (ICI-PI), which is an immune-related adverse event that may be a risk factor for ICI-associated pancreatitis, is not well documented in the literature. METHODS: Consecutive patients who received ICIs for advanced malignancies from August 2015 through October 2022 were analyzed with regard to the incidence of ICI-PI based on the Common Terminology Criteria for Adverse Events and ICI-associated pancreatitis. The imaging, clinical, and pathological findings of ICI-associated pancreatitis were also assessed. RESULTS: This study enrolled 843 patients. In multivariable analyses, dual or simultaneous immunotherapy and ≥10 cycles of ICI administration were significant predictive factors for all grades of pancreatic injury, including grade ≥ 3. Notably, patients who received simultaneous immunotherapy exhibited a higher incidence of grade ≥ 3 pancreatic injuries compared to those receiving asynchronous immunotherapy in univariable analysis (p = 0.032). One-fifth of the patients (16/70) with grade ≥ 3 pancreatic injuries had imaging evidence of pancreatitis similar to mild acute pancreatitis. ICI-associated pancreatitis was observed in 5.7% (48/843) of patients, including 1.8% (15/843) with moderate-to-severe pancreatitis (grade ≥ 2). Symptomatic cases (0.36%, 3/843) were treated with steroids with favorable outcomes. Immunohistochemistry for CD4 and CD8 revealed greater infiltration of CD8+ than CD4+ lymphocytes. CONCLUSION: Simultaneous immunotherapy and dual immunotherapy are risk factors for ICI-PI. Although most patients diagnosed with ICI-PI and ICI-associated pancreatitis were asymptomatic and had a low mortality likelihood, long-term outcomes, including endocrine and exocrine function should be carefully monitored.

Metastases and treatment-resistant lineages in patient-derived cancer cells of colorectal cancer.

Circulating tumor cells (CTCs) play an important role in metastasis and recurrence. However, which cells comprise the complex tumor lineages in recurrence and are key in metastasis are unknown in colorectal cancer (CRC). CRC with high expression of POU5F1 has a poor prognosis with a high incidence of liver metastatic recurrence. We aim to reveal the key cells promoting metastasis and identify treatment-resistant lineages with established EGFP-expressing organoids in two-dimensional culture (2DOs) under the POU5F1 promotor. POU5F1-expressing cells are highly present in relapsed clinical patients' blood as CTCs. Sorted POU5F1-expressing cells from 2DOs have cancer stem cell abilities and abundantly form liver metastases in vivo. Single-cell RNA sequencing of 2DOs identifies heterogeneous populations derived from POU5F1-expressing cells and the Wnt signaling pathway is enriched in POU5F1-expressing cells. Characteristic high expression of CTLA4 is observed in POU5F1-expressing cells and immunocytochemistry confirms the co-expression of POU5F1 and CTLA4. Demethylation in some CpG islands at the transcriptional start sites of POU5F1 and CTLA4 is observed. The Wnt/ß-catenin pathway inhibitor, XAV939, prevents the adhesion and survival of POU5F1-expressing cells in vitro. Early administration of XAV939 also completely inhibits liver metastasis induced by POU5F1-positive cells.

Fundamental Characterization of Antibody Fusion-Single-Chain TNF Recombinant Proteins Directed against Costimulatory TNF Receptors Expressed by T-Lymphocytes.

The costimulatory signal regulated by the members of the tumor necrosis factor receptor (TNFR) superfamily expressed by T cells plays essential roles for T cell responses and has emerged as a promising target for cancer immunotherapy. However, it is unclear how the difference in TNFR costimulation contributes to T cell responses. In this study, to clarify the functional significance of four different TNFRs, OX40, 4-1BB, CD27 and GITR, we prepared corresponding single-chain TNF ligand proteins (scTNFLs) connected to IgG Fc domain with beneficial characteristics, i.e., Fc-scOX40L, Fc-sc4-1BBL, Fc-scCD27L (CD70) and Fc-scGITRL. Without intentional cross-linking, these soluble Fc-scTNFL proteins bound to corresponding TNFRs induced NF-kB signaling and promoted proliferative and cytokine responses in CD4+ and CD8+ T cells with different dose-dependencies in vitro. Mice injected with one of the Fc-scTNFL proteins displayed significantly augmented delayed-type hypersensitivity responses, showing in vivo activity. The results demonstrate that each individual Fc-scTNFL protein provides a critical costimulatory signal and exhibits quantitatively distinct activity toward T cells. Our findings provide important insights into the TNFR costimulation that would be valuable for investigators conducting basic research in cancer immunology and also have implications for T cell-mediated immune regulation by designer TNFL proteins.

Role of HIKESHI on Hyperthermia for Castration-Resistant Prostate Cancer and Application of a Novel Magnetic Nanoparticle with Carbon Nanohorn for Magnetic Hyperthermia.

The prognosis of castration-resistant prostate cancer (CRPC) is technically scarce; therefore, a novel treatment for CRPC remains warranted. To this end, hyperthermia (HT) was investigated as an alternative therapy. In this study, the analysis focused on the association between CRPC and heat shock protein nuclear import factor "hikeshi (HIKESHI)", a factor of heat tolerance. Silencing the HIKESHI expression of 22Rv1 cells (human CRPC cell line) treated with siRNAs inhibited the translocation of heat shock protein 70 from the cytoplasm to the nucleus under heat shock and enhanced the effect of hyperthermia. Moreover, a novel magnetic nanoparticle was developed via binding carbon nanohorn (CNH) and iron oxide nanoparticle (IONP) with 3-aminopropylsilyl (APS). Tumor-bearing model mice implanted with 22 Rv1 cells were examined to determine the effect of magnetic HT (mHT). We locally injected CNH-APS-IONP into the tumor, which was set under an alternative magnetic field and showed that tumor growth in the treatment group was significantly suppressed compared with other groups. This study suggests that HIKESHI silencing enhances the sensitivity of 22Rv1 cells to HT, and CNH-APTES-IONP deserves consideration for mHT.

Changes in zinc and manganese concentrations in cisplatin-induced acute kidney injury.

Cisplatin (CDDP) is a widely used anticancer drug, but acute kidney injury (AKI) is one of the most important dose-limiting factors. Trace metal elements are present in various concentrations in the body and play an important role in maintaining normal vital functions. However, the relationship between CDDP-induced AKI and trace metal elements is unknown. In this study, we cultured human renal proximal tubular epithelial cells in the presence of CDDP (0, 12.5, 25, 50 µM) and analyzed the concentration of trace elements in medium after 24 h. We found that CDDP significantly increased the concentrations of zinc (Zn) and manganese (Mn) in medium and significantly decreased them in lysate. Therefore, we examined the effects of CDDP (3 mg/kg, i.p.) administration on serum and urinary Zn and Mn concentrations in rats. The results showed that urinary excretion of Zn and Mn increased in CDDP-treated rats 5 days after administration. Also, 5 days after administration, pyknosis, nuclear loss, loss of the brush border membrane, and DNA fragmentation were observed, and serum creatinine and blood urea nitrogen levels were found to be significantly increased. These data suggested that 24-h excretion of Zn and Mn might reflect on CDDP induced nephropathy. Monitoring urinary Zn and Mn excretion may be beneficial in detecting AKI, but further studies are needed for clinical application.

High preoperative serum strontium levels increase the risk of acute kidney injury after cardiopulmonary bypass.

BACKGROUND: Acute kidney injury (AKI) is a common complication of cardiac surgeries. The incidence of AKI after cardiac surgeries using cardiopulmonary bypass (CPB-AKI) is high, emphasizing the need to determine strategies to prevent CPB-AKI. This study investigates the correlation between CPB-AKI and trace metal levels in clinical and animal studies. METHODS: Samples and clinical data were obtained from 74 patients from the Nagoya City University Hospital and Okazaki City Hospital. Blood samples were collected before, immediately after, and 2 h after CPB withdrawal. Trace metal levels were measured using inductively coupled plasma mass spectrometry. Sr or vehicle treatment was orally administered to the rats to determine if Sr was associated with CPB-AKI. After the treatment, ischemia-reperfusion (IR) injury was induced, and serum creatinine (SCr) and blood urea nitrogen (BUN) levels were measured. RESULTS: In this clinical study, the incidence of CPB-AKI was found to be 28% (21/74). The body mass index and estimated glomerular filtration rate were significantly different in patients with AKI. The intensive care unit and hospital stay were longer in AKI patients than in non-AKI patients. The Na, Fe, and Sr levels were significantly higher in AKI patients before CPB. Also, Fe and Sr were higher immediately after CPB withdrawal, and Sr was higher 2 h after CPB withdrawal in AKI patients. Animal studies showed that Sr-treated rats had significantly increased SCr and BUN levels than vehicle-treated rats at 24 h post-IR injury. CONCLUSIONS: High preoperative serum Sr levels may be associated with CPB-AKI.

Concomitant Pancreatic Ductal Adenocarcinoma and Type 1 Autoimmune Pancreatitis: A Potential Issue in the Diagnosis of Carcinoma by Endoscopic Ultrasound-guided Fine-needle Biopsy.

We herein report a 64-year-old man with concomitant pancreatic ductal adenocarcinoma (PDAC) and type 1 autoimmune pancreatitis (AIP). An endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) from the pancreatic head mass revealed level 2 histology of AIP and atypical glands. We diagnosed definitive focal AIP using the clinical diagnostic criteria. Computed tomography revealed that the pancreatic mass had not been reduced by steroid therapy. Surgery was performed after a histological PDAC diagnosis was made via a transpapillary biliary biopsy. The resected specimen revealed PDAC associated with AIP. It is important to consider the cooccurrence of PDAC and AIP even if the histological diagnosis via an EUS-FNB is AIP.

A rare case of long-term survival from metachronous bilateral adrenal metastasis of lung adenocarcinoma after combined surgical removal and immunochemotherapy.

Introduction: The prognosis of adrenal metastasis from non-small cell lung cancer is very poor. A recent report described the efficacy of the surgical removal of adrenal metastasis when solitary. However, metachronous bilateral adrenal metastasis is extremely rare, and a treatment strategy has not been established. Case presentation: Herein, we describe a 52-year-old Asian male who presented with a right adrenal metastasis of non-small cell lung cancer 8 months after immunochemotherapy and surgical resection of the lung. He underwent combined systemic treatment and a laparoscopic right adrenalectomy; however, after 9 months, a metachronous left adrenal metastasis emerged. A subsequent laparoscopic left adrenalectomy and systemic treatment led to long-term progression-free survival. Conclusion: The appropriate surgical indication and combined systemic treatment of a metachronous bilateral adrenal metastasis in non-small cell lung cancer may extend the prognosis.

A case of metastatic treatment-emergent small cell/neuroendocrine prostate cancer with BRCA2 mutation diagnosed by liver biopsy.

Introduction: Treatment-emergent small cell/neuroendocrine prostate cancer occurs predominantly in advanced or metastatic castration-resistant prostate cancer that arises when prostate adenocarcinoma is transformed after androgen deprivation therapy. The clinical course for the pathogenesis involved or associated genetic information have not been clearly elucidated. Case presentation: A Japanese male, 63-year-old, underwent a para-aortic lymph biopsy due to sudden severe bilateral leg edema, with a final diagnosis of stage IV prostate adenocarcinoma. He was initially responsive to upfront abiraterone with androgen deprivation therapy; however, relapse occurred in the liver and bone 10 months after initial treatment, with serum neuron-specific enolase elevation and without prostate-specific antigen elevation. Pathological findings of liver tumor revealed treatment-emergent small cell/neuroendocrine prostate cancer. FoundationOne® CDx was used for cancer-related gene profiling of liver tumor specimen; a BRCA2 mutation was identified. Conclusion: Early detection of this transformation and pathological diagnosis can improve patient survival when genetic mutations, including BRCA 1/2.

Derivatization-assisted immunoassays: application for group-specific detection of potent methamphetamine and amphetamine enantiomers.

Reliable and feasible tools for detecting (S)-methamphetamine [(S)-MAP] and (S)-amphetamine [(S)-AP] are required for regulating their illicit circulation. Antibodies that react equally to these stimulants are desirable for this purpose, but have been difficult to generate because of the crucial difference between their characteristic structures: i.e., N-methylamino (MAP) and amino (AP) groups. Furthermore, their small molecular masses (Mr < 150) have hampered the generation of high-affinity antibodies. To overcome these problems, we converted (S)-MAP and -AP into their 2-(trimethylsilyl)ethyl carbamate forms, Teoc-(S)-MAP and -AP, respectively, as surrogate analytes. The Teoc-derivatization not only increases their molecular masses, but also masks their structural differences. We generated a novel monoclonal antibody that showed a satisfactory affinity to Teoc-(S)-MAP residues (Kd = 13 nM as the IgG form) and developed a competitive enzyme-linked immunosorbent assay (ELISA) using microplates containing immobilized Teoc-(S)-MAP residues. Almost overlapping dose-response curves were obtained for Teoc-(S)-MAP and -AP, with the limit of detection of 0.078 and 0.10 ng per assay, respectively. A fixed amount of test powder sample (1 mg) was derivatized with Teoc-O-succinimidyl for 5 min, and subjected to ELISA using Teoc-(S)-MAP as the calibration standard. Under this protocol, (S)-MAP and -AP were converted to their Teoc derivatives with 30% and 34% yield, respectively, determined using ELISA as "Teoc-(S)-MAP equivalent," being distinguished from the derivatization products of (R)-MAP, (R)-AP, ephedrine, (S)-methylenedioxymethamphetamine, tyramine, dopamine, and ß-alanine. This ELISA detected as little as 10 µg of (S)-MAP and -AP, and (S)-MAP in urine obtained from (S)-MAP-administered rats. Immunochromatography devices were also developed using gold nanoparticles coated with the monoclonal antibody, with which 0.10 mg of (S)-MAP and -AP was detected by the naked eye. We conclude that the present derivatization-assisted immunoassays may be useful for the detection of (S)-MAP and/or -AP in early stage screening of suspicious substances.

Class III ß-Tubulin Expression Is of Value in Selecting nab -Paclitaxel and Gemcitabine as First-Line Therapy in Unresectable Pancreatic Cancer.

OBJECTIVES: Nab -paclitaxel and gemcitabine (GnP) or FOLFIRINOX (a combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin [FFX]) is currently recognized as the standard first-line regimen for unresectable pancreatic ductal adenocarcinoma (PDAC). Class III ß-tubulin (TUBB3) has the potential to predict resistance to taxane in various tumors; therefore, this study aimed to clarify whether TUBB3 is a predictive marker for GnP response. METHODS: We retrospectively reviewed 113 patients with PDAC who received GnP or FFX as first-line chemotherapy and examined immunohistochemically the TUBB3 expression in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration. RESULTS: High TUBB3 expression was associated with a significantly lower disease control rate ( P = 0.017) and shorter progression-free survival (PFS) ( P = 0.019), and multivariate analysis revealed that TUBB3 expression was an independent variable for PFS in the GnP first-line group ( P = 0.045). In addition, in the FFX first-line group, TUBB3 expression was not correlated with PFS or overall survival (OS). In all 113 patients, TUBB3 expression was not also associated with OS. CONCLUSIONS: Class III ß-tubulin might be a predictive factor for the response of GnP, but not a prognostic factor for OS, helping the selection of an optimized first-line chemotherapy regimen for unresectable PDAC.

Survival Outcome after Reduced-Port Laparoscopic Radical Cystectomy for Bladder Cancer: Long-Term Follow-Up Analysis.

INTRODUCTION: This study had two objectives: (i) to evaluate oncological outcomes in a long-term follow-up of patients with bladder cancer after reduced-port laparoscopic radical cystectomy (RP-LRC) and (ii) to assess the effect of modified Glasgow prognostic scores (mGPS) on patient outcomes. METHODS: Consecutive patients (n = 100) who received RP-LRC between March 2012 and December 2018 at our institution and affiliated hospital were retrospectively reviewed. Preoperative serum albumin and C-reactive protein levels were determined. Patients were grouped based on clinical T stage (≤cT2: n = 75, ≥cT3: n = 25) using pooled cumulative data. Oncological outcomes and mGPS as a prognostic biomarker were analyzed retrospectively. Kaplan-Meier curves displayed recurrence and survival rates. Univariate and multivariate Cox regression analyses evaluated potential prognostic factors for recurrence-free survival (RFS) and cancer-specific survival (CSS). RESULTS: Patient characteristics between the two groups were statistically similar for preoperative hematological and mGPS status, blood loss level, rate of allogeneic transfusion, and pneumoperitoneum time. After a median follow-up period of 55 months, 40/100 patients experienced disease relapse. RFS and CSS for ≤cT2 were significantly less than for ≥cT3 (p < 0.001, p < 0.05, respectively). Distant metastasis occurred in 30 patients with similar distributions of relapse sites between T-stage cohorts. Median RFS for mGPS 1/2 were 18.9 (95% confidence interval [CI]: 8.8-not assessed [NA]) and 35.0 (95% CI: 8.7-NA) months, respectively, significantly worse than for mGPS 0 (median NA, 95% CI: NA-NA); CSS was similar. Univariate and multivariate analyses revealed ≥cT3 stage, worse clinical N stage, and poor mGPS status were significant prognostic factors for short RFS and CSS. CONCLUSIONS: A large proportion of bladder cancer patients who undergo RP-LRC experience relapse, with ≥cT3 stage, worse clinical N stage or poor mGPS status identified as significant prognostic factors. Our findings may contribute to improved surgical procedures for such patients.