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1.
Anticancer Res ; 41(10): 4687-4695, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593416

RESUMO

Remarkable developments in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have been achieved over the past decade. Although targeting the novel androgen receptor axis and using chemotherapeutic agents have improved survival, mCRPC is still a lethal disease. A better molecular characterization of cancer resulted in the determination of the important role of homologous recombination repair (HRR) genes in cancer development, and poly (ADP-ribose) polymerase (PARP) is one of the most attractive therapeutic targets. Recent clinical studies have demonstrated that PARP inhibitors significantly improve oncological outcomes in patients with mCRPC harboring BRCA mutations, and PARP inhibitors are becoming a standard of care for these patients. However, not only PARP inhibitors, but also chemotherapeutic agents such as platinum agents, taxanes, and radium-223 are active in HRR gene mutation carriers, and platinum sensitivity may predict the efficacy of PARP inhibitors for mCRPC. The combination of PARP inhibitors with other anti-cancer agents may overcome resistance mechanisms against PARP inhibitors and lead to survival benefits. Appropriate treatment sequences and combinations may change the therapeutic landscape of DNA repair deficient mCRPC.


Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Mutação , Platina/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Reparo de DNA por Recombinação/genética , Resultado do Tratamento
2.
J Clin Pharm Ther ; 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34669974

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Sunitinib is used as a first-line therapy for metastatic renal cell carcinoma. The primary aim of this study was to determine the optimal total sunitinib (sunitinib plus N-desethyl sunitinib) trough concentration for the alternative dosing schedule: 2-week-on and 1-week-off schedule (2/1 schedule). METHODS: Patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib, whose total sunitinib concentrations were available, were recruited for this study. Out of 19 patients, 17 whose sunitinib dosage was not changed until the measurement of drug concentration were eligible for the analysis of the relationship between total sunitinib concentration and clinical outcome. Individual pharmacokinetic parameters in 19 patients were estimated via the Bayesian analysis. RESULTS: The onset of severe (grade ≥3) adverse effects among 17 patients during 3 weeks as a first course of sunitinib therapy was observed in 7 (41.2%) patients. The median total sunitinib concentration in patients with severe adverse effects was significantly higher compared with that in patients without severe adverse effects [median: 119 (113-131) vs. 87.8 (77.4-102) ng/mL, p = 0.01]. According to the receiver operating characteristic analysis of the onset of severe adverse effects, the cut-off value of the total sunitinib concentration was 108 ng/mL. Patients with a total sunitinib concentration lower than 108 ng/mL had a longer time to first dose reduction or withdrawal due to adverse effects compared with those with a total sunitinib concentration of 108 ng/mL or higher (p = 0.03). The probability without treatment failure was not significantly different between the two concentration groups. In addition, the estimated sunitinib apparent oral clearance (CL/F) was significantly lower in the severe adverse effects group. Our simulation demonstrated that 0.67-time dose is needed for patients with approximately 90.0 ng/mL of sunitinib concentration on day 7 to maintain the concentration at the same level as the patients with higher CL/F. WHAT IS NEW AND CONCLUSION: Maintaining the total sunitinib trough concentrations of less than 108 ng/mL is safe to avoid the onset of serious adverse effects without increasing the treatment failure in patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib.

3.
Int J Clin Exp Pathol ; 14(9): 987-992, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646417

RESUMO

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic fibroinflammatory disorder that can involve multiple organs. It is often challenging to distinguish IgG4-related sclerosing cholangitis (IgG4-SC) from cholangiocarcinoma because of overlap in their clinical findings. A 75-year-old man presented to a hospital for a detailed examination of the elevation of some biliary enzymes. Radiographic examination revealed segmental bile duct with wall thickening of the common hepatic bile duct, and dilation of the peripheral branches. Transampullary biopsy showed a non-specific inflammatory reaction with several IgG4-positive cell infiltrations. There were no signs of malignancy. The liver biopsy showed bile duct injury accompanied by IgG4-positive cell infiltration. We then performed bile duct biopsy and finally diagnosed the patient with cholangiocarcinoma. We should remember that the IgG4 reaction is neither completely sensitive nor specific for IgG4-RD and avoid resting solely on the IgG4 reaction to precisely distinguish IgG4-SC from cholangiocarcinoma.

4.
Virchows Arch ; 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34415430

RESUMO

Although many germinal centers (GCs) have been reported in immunoglobulin (Ig) G4-related disease, the significance of GCs in IgG4-related disease has not received attention. Both T follicular regulatory cells (Tfr), which are regulatory T cells (Treg) in GCs, and T follicular helper cells (Tfh) produce the cytokine interleukin (IL)-10 and regulate GC development. In whole-slide image analysis in surgical specimens using immunohistochemistry, IgG4-related sclerosing sialadenitis (IgG4-SS, n = 17) was characterized by markedly numerous, large, and irregular-shaped GCs with increased IL-10 + cells and Tfr and Tfh in the total area of the salivary gland compared with controls, including patients with chronic sialadenitis (n = 17) and Sjögren syndrome (n = 15). In particular, the central area of GC in IgG4-SS showed a higher Tfr number and Tfr/Tfh ratio than controls. The number of Tfr in the central area was significantly correlated with the number of IgG4 + plasmacytes and the number, size, and irregularity of GCs. In the mantle area, which surrounds GCs, IgG4-SS showed a higher Treg number and Treg/T helper cells (Th) ratio than controls. In IgG4-SS, the Treg/Th ratio was highest in the mantle area outside GCs and the Tfr/Tfh ratio was highest in the central area inside GCs. However, in controls, the Treg/Th ratio gradually decreased from outside to inside GCs. Our findings reveal that the morphological abnormality of GCs and the characteristic localization and altered balance of Treg and Th in the different compartments of inside and outside GCs would be the novel hallmarks of IgG4-SS.

6.
Chemosphere ; 284: 131378, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34217930

RESUMO

Cyanobacteria produce numerous volatile organic compounds (VOCs) that show a lytic activity against other cyanobacteria. We found the lytic phenomenon under natural conditions and during densification experiments, and also observed the species change of the cyanobacteria during the lysis processes, in which Microcystis finally became dominant. The species change of the cyanobacteria was strongly suggested to depend on the susceptibility of the cyanobacteria toward the VOCs. To verify this suggestion, the susceptibility of the species was evaluated by the minimal inhibitory concentration (MIC) using axenic cyanobacterial strains against ß-cyclocitral, its oxidation products and ß-ionone with the aid of log D. It was found that the difference depended on the susceptibility of the cyanobacteria toward the VOCs, in which ß-cyclocitral played a crucial role and Microcystis had a significantly protective ability compared to the other cyanobacteria. In addition, the species change of cyanobacteria was consistent with the cyanobacterial seasonal succession in Lakes Sagami and Tsukui, based on data that had been accumulated for 10 years. Conventionally, although this phenomenon could be explained by nutrient availability or the physical structure of the environment, the results of this study revealed that it was controlled by the VOCs, particularly ß-cyclocitral produced by the cyanobacteria.


Assuntos
Cianobactérias , Microcystis , Compostos Orgânicos Voláteis , Lagos , Estações do Ano
7.
Int J Clin Oncol ; 26(11): 2073-2084, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34291367

RESUMO

BACKGROUND: Programmed death-ligand 1 (PD-L1) positivity is associated with poor prognosis in renal cell carcinoma (RCC). Because the prognostic impact and effect of confounding factors are less known, we investigated the prognostic significance of PD-L1 expression in Japanese patients with recurrent/metastatic RCC who started systemic therapy in 2010-2015. METHODS: This multicenter, retrospective study recruited patients from 29 Japanese study sites who had prior systemic therapy for RCC (November 2018 to April 2019) and stored formalin-fixed paraffin-embedded primary lesion samples. The primary outcome was overall survival (OS) by PD-L1 expression. Secondary outcomes included OS in subgroups and duration of first- and second-line therapies by PD-L1 expression. OS distributions were estimated using Kaplan-Meier methodology. RESULTS: PD-L1 expression (on immune cells [IC] ≥ 1%) was observed in 315/770 (40.9%) patients. PD-L1 positivity was more prevalent in patients with poor risk per both Memorial Sloan Kettering Cancer Center [MSKCC] and International Metastatic RCC Database Consortium, and high-risk pathological features (higher clinical stage, nuclear grade and sarcomatoid features). Median OS for PD-L1-positive patients was 30.9 months (95% CI 25.5-35.7) versus 37.5 months (95% CI 34.0-42.6) for PD-L1-negative patients (HR 1.04 [90% CI 0.89-1.22, p = 0.65]; stratified by MSKCC risk and liver metastases). Propensity score weight (PSW)-adjusted OS was similar between PD-L1-positive and -negative patients (median 34.4 versus 31.5 months; estimated PSW-adjusted HR 0.986). CONCLUSIONS: This study suggests PD-L1 status was not an independent prognostic factor in recurrent/metastatic RCC during the study period because PD-L1 positivity was associated with poor prognostic factors, especially MSKCC risk status.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Antígeno B7-H1 , Carcinoma de Células Renais/genética , Humanos , Japão , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos
8.
Int J Urol ; 28(10): 1054-1059, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34279058

RESUMO

OBJECTIVES: To compare functional and surgical outcomes of robot-assisted partial nephrectomy for complex tumors with RENAL scores ≥10 and non-complex tumors at a single academic institution. METHODS: We retrospectively analyzed the data of all patients who underwent robot-assisted partial nephrectomy at Kobe University Hospital (Kobe, Hyogo, Japan) from 2011 to 2020. Functional and surgical outcomes for complex tumors (RENAL score ≥10) were compared with those of patients with non-complex tumors (RENAL <10). Outcomes analyzed included blood loss, warm ischemia time, console time, perioperative complications, and preoperative and postoperative renal function. RESULTS: A total of 348 patients were included in our present study, with a median follow-up time of 35.1 months. Of these, 299 patients (85.9%) had non-complex tumors and 49 patients (14.1%) had complex tumors. Warm ischemia time and console time were significantly longer in the complex tumors group. Major perioperative complications (Clavien-Dindo classification system ≥3) were significantly more frequent in the complex tumors group than the non-complex tumor group (16.3% vs 5.7%, P = 0.018). Postoperative preservation of estimated glomerular filtration rate and percentage of chronic kidney disease upstage by 1 year were significantly inferior in the complex tumors group. The positive surgical margin rate was 0% and 0.3% in the complex and non-complex tumor groups, respectively. There were no significant differences in recurrence-free survival between the two groups (P = 0.11). CONCLUSIONS: Robot-assisted partial nephrectomy for complex renal tumors is safe, with no difference in oncological outcomes, although more postoperative complications and decreased renal function can be observed than non-complex tumors.


Assuntos
Neoplasias Renais , Procedimentos Cirúrgicos Robóticos , Robótica , Taxa de Filtração Glomerular , Humanos , Rim/fisiologia , Rim/cirurgia , Neoplasias Renais/cirurgia , Nefrectomia/efeitos adversos , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Resultado do Tratamento
9.
Hepatol Res ; 51(9): 943-956, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34260795

RESUMO

AIM: To evaluate the efficacy, safety, and tolerability of apararenone 10 mg/day in patients with nonalcoholic steatohepatitis (NASH). METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase II study, patients received apararenone 10 mg or placebo once daily for 72 weeks. The primary efficacy end-point was percent change in serum alanine aminotransferase (ALT) from baseline to 24 weeks after randomization. Secondary efficacy end-points included changes in liver fibrosis markers. Adverse drug reactions (ADRs) and serum potassium levels were evaluated. RESULTS: Forty-eight patients were randomly assigned to treatment (placebo, 23; apararenone, 25). The percent change in ALT at 24 weeks was -3.0% and -13.7% with placebo and apararenone, respectively (p = 0.308). The apararenone group showed greater reductions from baseline in fibrosis markers (type IV collagen 7S and procollagen-3 N-terminal peptide) and noninvasive tests of fibrosis (enhanced liver fibrosis score and Fibrosis-4 index) at all time points versus placebo. The percentage of patients with improvement of 1 point or more in fibrosis stage/without nonalcoholic fatty liver disease activity score worsening was 41.7% with apararenone and 26.1% with placebo (p = 0.203). Adverse drug reactions were reported in three (13.0%) and three (12.5%) patients in the placebo and apararenone groups, respectively. Serum potassium levels increased in the apararenone group during the study and decreased to near baseline after the end of treatment. CONCLUSIONS: In patients with NASH, apararenone 10 mg/day for 72 weeks was effective in decreasing ALT levels, improved multiple potential fibrosis markers, and was safe and well tolerated. Pathological findings showed anti-inflammatory and antifibrotic effects of apararenone.

10.
Hepatol Res ; 51(10): 1044-1057, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34124830

RESUMO

AIM: To develop a novel noninvasive test using an artificial intelligence (AI)/neural network (NN) system (named Fibro-Scope) to determine the fibrosis stage in nonalcoholic steatohepatitis (NASH). METHODS: Three hundred twenty-four and 110 patients with histologically diagnosed nonalcoholic fatty liver disease (NAFLD) were enrolled for training and validation studies, respectively. Two independent pathologists histologically diagnosed patients with NAFLD for the validation study. Fibro-Scope was undertaken using 12 items: age, sex, height, weight, waist circumference, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, cholesterol, triglyceride, platelet count, and type 4 collagen 7s. RESULTS: Differentiation of F0 versus F1-4 using the Fibro-Scope revealed 99.5% sensitivity, 90.9% specificity, 97.4% positive predictive value, and 98.0% negative predictive value in a training study with gray zone analysis, which was also effective in the analysis without gray zone. Discrimination was also excellent when comparing F0-1 versus F2-4 and F0-2 versus F3-4. In a validation study with gray zone analysis, differentiation of F0 from F1-4 using Fibro-Scope was also excellent. The discrimination of F0-1 from F2-4 using Fibro-Scope with gray zone analysis showed over 80% sensitivity and specificity in the histological diagnosis of both pathologists, but was lower without the gray zone analysis. The discrimination of F0-2 from F3-4 was effective in the analysis with gray zone; however, their sensitivity and specificity were slightly inferior in the analysis without gray zone. CONCLUSIONS: Artificial intelligence/neural network algorithms termed Fibro-Scope are easy to use and can accurately differentially diagnose minimal, moderate, and advanced fibrosis. Fibro-Scope will promote rapid NASH diagnosis and facilitate diagnosing the fibrosis stage in NASH.

11.
Int J Urol ; 28(9): 955-963, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34148264

RESUMO

OBJECTIVE: To determine prognostic factors including the Bone Scan Index in prostate cancer patients receiving standard hormonal therapy and chemotherapy. METHODS: This multicenter Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index study involved 30 hospitals and enrolled 247 patients (age 71 ± 8 years) with metastatic hormone-sensitive prostate cancer (n = 148) under hormone therapy and metastatic castration-resistant prostate cancer (n = 99) under chemotherapy. The Bone Scan Index (%) was determined by whole-body bone scintigraphy using 99m Tc-methylenediphosphonate. Patients were classified into tertiles and binary groups, and predictors of all-cause death including Bone Scan Index, prostate-specific antigen, and bone metabolic markers were determined using survival and proportional hazard analyses. RESULTS: During a mean follow-up period of 716 ± 404 days, 81 (33%) of the patients died, and 3-year mortality rates were 20% and 52% in the metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer groups, respectively. Survival analysis showed that a Bone Scan Index >3.5% was a significant determinant of death in the metastatic hormone-sensitive prostate cancer group, whereas prostate-specific antigen >55 ng/mL before chemotherapy was a determinant of prognosis in the metastatic castration-resistant prostate cancer group. A Bone Scan Index >3.5% was also associated with a high incidence of prostate-specific antigen progression in the metastatic hormone-sensitive prostate cancer group. Patients with metastatic hormone-sensitive prostate cancer and a better Bone Scan Index response (>45%) to treatment had lower mortality rates than those without such response. CONCLUSION: The Bone Scan Index and hot spot number are significant determinants of 3-year mortality, and combining the Bone Scan Index with prostate-specific antigen should contribute to the management of prostate cancer patients with bone metastasis.


Assuntos
Neoplasias Ósseas , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Idoso , Neoplasias Ósseas/diagnóstico por imagem , Estudos de Coortes , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Antígeno Prostático Específico , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Sistema de Registros
12.
Stem Cell Res ; 54: 102425, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34119957

RESUMO

Adipose tissue-derived stem cells (ADSCs) have been suggested as a novel treatment for non-alcoholic steatohepatitis (NASH); however, the mechanisms underlying their therapeutic effect remain poorly understood. In this study, we aimed to investigate the association of Notch signaling, which is crucial for cellular proliferation and differentiation in ADSC-mediated treatment of NASH. Flow cytometry analysis of ADSCs showed that they expressed the Notch ligands JAG1, DLL1, and DLL4. The expression of genes associated with the Notch signaling pathway was attenuated in hepatocytes of NASH model mice. We further observed ADSC-mediated activation of Notch signaling in these hepatocytes in addition to an increase in proliferating cell nuclear antigen+ cells and a decrease in TdT-mediated dUTP-biotin nick end labeling+ apoptotic cells. Co-culture of palmitic acid-induced steatotic hepatocytes and ADSCs resulted in the activation of Notch signaling and reduction of apoptosis of steatotic hepatocytes. Moreover, inhibition of Notch signaling by a γ-secretase inhibitor and knockdown of Notch ligands using siRNA attenuated the anti-apoptotic effect of co-cultured ADSCs in vitro. Our findings show that the Notch signaling pathway is involved in the inhibition of apoptosis and restoration of cellular proliferation of hepatocytes from NASH mice following ADSC treatment.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Tecido Adiposo , Animais , Hepatócitos , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/terapia , Transdução de Sinais , Células-Tronco
13.
Pathol Int ; 71(8): 521-529, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34166554

RESUMO

The Notch signaling pathway plays a key role in the morphogenesis of the biliary tree, but its involvement in cystic biliary diseases, such as Caroli disease (CD) and polycystic liver disease (PLD), has yet to be determined. Immunostaining was performed using liver sections of CD and PLD, and the results were compared with those of congenital hepatic fibrosis (CHF) and von Meyenburg complex (VMC). The expression of Notch receptor 1 (Notch1) was increased in the nuclei of biliary epithelial cells in all cases of CD and PLD, whereas it remained at a low level in CHF and VMC. In addition, Notch2 and Notch3 were preferably expressed in the nuclei of biliary epithelial cells of PLD. Accordingly, the Notch effector Hes1 was highly expressed in biliary epithelial cells of CD and PLD, and the cell proliferative activity was significantly higher in CD and PLD. The expression of the Notch ligand Delta-like 1 was significantly increased in biliary epithelial cells of CD and PLD, which may be causally associated with the nuclear overexpression of Notch1 and Hes1. These results indicate that aberrant activation of the Notch-Hes1 signaling pathway may be responsible for the progression of biliary cystogenesis in CD and PLD.

14.
Regen Ther ; 18: 97-101, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34095367

RESUMO

Introduction: Liver cirrhosis is the ultimate condition of chronic liver diseases. Non-alcoholic steatohepatitis and fatty liver diseases are emerging in association with metabolic syndrome largely due to excess nutrition. Stromal cells of adipose tissue are enriched mesenchymal stem cells which are pluripotent and immunomodulatory, which are expected to be applied for repairing/regenerative therapy of the impaired organs. Methods: We conducted the multi-institutional clinical trial (Japanese UMIN Clinical Trial Registry: UMIN000022601) of cell therapy using freshly isolated autologous adipose tissue-derived regenerative (stem) cells (ADRCs), which are obtained by the investigational trial device, adipose tissue dissociation device, for liver cirrhosis patients due to non-alcoholic steatohepatitis or fatty liver disease, to exploratory assess efficacy as well as safety of this trial. We completed treatment and 24 weeks follow-up for 7 patients. Results: We observed that 6 out of 7 patients' serum albumin concentration was improved. As for prothrombin activity, 5 out of 7 patients showed improvement. No trial-related adverse events, which were serious or non-serious, was observed. Besides, no malfunction of the investigational trial device was encountered. Conclusion: Thus, treatment with autologous ADRCs obtained with the investigational trial device in steatohepatitis-related cirrhosis was confirmed to be safely conductible and potentially promising for the retaining or improving the impaired hepatic reserve.

15.
Urol Int ; : 1-7, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34134119

RESUMO

BACKGROUND: Patients with solitary metastasis of renal cell carcinoma (RCC) have shown to be ideal candidates for surgical metastasectomy (SM). However, whether SM will show more benefit than systemic therapy remains unclear. METHODS: We included 73 patients treated for solitary metastasis after nephrectomy at our institute from April 2008 to December 2018. We compared the clinical outcomes between the SM (n = 29) and no-SM (n = 44) group which were treated with only systemic therapy. RESULTS: Eleven of 29 patients in the SM group received presurgical targeted therapy (PTT). Although 13 of 29 patients in the SM group showed recurrence during the study period, a Cox proportional hazards model showed that SM was significantly associated with a favorable overall survival (hazard ratio: 0.18; p = 0.007). Patients receiving PTT prior to SM showed a longer recurrence-free survival after SM in comparison to those who underwent SM without PTT (median: not reached vs. 27.7 months; p = 0.009). CONCLUSIONS: If resection is feasible, SM may be beneficial for patients with solitary metastasis of RCC, and we showed the possibility that PTT prior to SM may be effective for avoiding recurrence after SM. Further large-scale prospective studies are needed to clarify the ideal treatment strategy for metastatic RCC.

16.
Int J Clin Oncol ; 26(8): 1533-1540, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34047889

RESUMO

BACKGROUND: Although bone metastasis beyond the vertebrae and pelvis has been a key factor in prognostic models of metastatic hormone-sensitive prostate cancer (mHSPC), the clinical significance of it is still unclear. The present study evaluated the prognostic impact of the volume of bone metastasis beyond the vertebrae and pelvis on the outcomes of mHSPC and created an ideal risk classification based on it. METHODS: We retrospectively reviewed 197 patients with mHSPC who were treated with combined androgen blockade as the initial treatment between June 2003 and October 2019. We calculated the bone scan index (BSI), including the BSI beyond the vertebrae and pelvis (bBSI), using BONENAVI, and investigated the association between the BSI and the overall survival (OS) of mHSPC. RESULTS: According to the CHAARTED criteria, 91 and 106 patients were classified into the low- and high-volume groups, respectively. Of the 79 patients who did not have visceral metastasis in the high-volume group, those with a bBSI ≤ 0.27 (n = 16) showed a favorable OS, as did those in the low-volume group. The modified CHAARTED high-volume group (presence of visceral metastases or 4 bone lesions with a bBSI > 0.27) showed a significantly shorter OS than others, with a hazard ratio (HR) of 4.69 (p < 0.001), which was higher than that observed with the original CHAARTED criteria (HR = 4.33). CONCLUSIONS: Our data suggested that considering the volume of bone metastasis beyond the vertebrae and pelvis may help to improve the accuracy of risk classification. Further large-scale prospective studies are needed to validate our findings.

17.
Hepatology ; 74(4): 1971-1993, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33931882

RESUMO

BACKGROUND AND AIMS: Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy. APPROACH AND RESULTS: Loss of all Rb family members in transformation related protein 53 (Trp53)-/- mouse liver resulted in liver tumor reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)ß inhibitor Bay 11-7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/ß phosphorylation and NF-κB activation. Combination therapy using palbociclib with Bay 11-7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK-NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. CONCLUSIONS: In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor.

18.
Histopathology ; 79(5): 731-750, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34018212

RESUMO

AIMS: Mass-forming intrahepatic cholangiocarcinomas (MF-iCCAs), involving small bile ducts, bile ductules or canals of Hering, remain treated as a single entity. We aimed to examine the diversity in histology, phenotype and tumour vasculature of MF-iCCAs. METHODS AND RESULTS: Based on morphology and immunophenotype, we classified MF-iCCAs into small bile duct (SBD), cholangiolocarcinoma (CLC), ductal plate malformation (DPM) and hepatocellular carcinoma (HCC)-like subtypes. Genetic correlations among the histological subtypes were examined by multi-region tumour sequencing. Vasculatures and other clinicopathological features were compared among tumour groups with various proportions of the histological subtypes in 62 MF-iCCAs. Cases of pure SBD, CLC, DPM and HCC-like subtypes numbered 18 (29%), seven (11.3%), none (0%) and two (3%), respectively; the remaining 35 (56.4%) cases comprised several components. Genetic alterations, isocitrate dehydrogenase (IDH)1/2, KRAS, TP53, polybromo-1 (PBRM1) and BRCA1-associated protein 1 (BAP1), were shared among SBD, CLC, DPM and hepatoid components within a tumour. We uncovered distinct vascularisation mechanisms among SBD, CLC and DPM subtypes with a prominent vessel co-option in CLC tumours. iCCA with a DPM pattern had the highest vascular densities (mean microvascular density,140/mm2 ; arterial vessel density, 18.3/mm2 ). Increased CLC component was correlated with longer overall survival time (r = 0.44, P = 0.006). Pure SBD tumours had a lower 5-year overall survival rate compared with MF-iCCA with CLC pattern (30.5 versus 72.4%, P = 0.011). CONCLUSIONS: MF-iCCAs comprise four histological subtypes. Given their sharing some driver gene alterations, indicating they can have a common cell origin, SBD, CLC and DPM subtypes, however, differ in cell differentiation, histology, phenotype or tumour vasculature.

20.
Jpn J Clin Oncol ; 51(8): 1313-1318, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33954587

RESUMO

OBJECTIVE: The purpose of this study was to assess the therapeutic efficacy of molecular targeted therapies following nivolumab in metastatic renal cell carcinoma and to examine the relationship between therapeutic efficacy and the specific molecular targeted therapy used. METHODS: We retrospectively reviewed the medical records of 115 metastatic renal cell carcinoma patients who were treated with nivolumab at our institution and five affiliated hospitals. Among them, 52 patients who received subsequent molecular targeted therapy following nivolumab were selected to survey treatment outcomes. Progression-free survival and overall survival were estimated with Kaplan-Meier curves, and differences were analyzed by the log-rank test. RESULTS: Among the 52 eligible patients, 40 (76.9%) were treated with tyrosine kinase inhibitors and 12 (23.1%) were treated with mammalian target of rapamycin inhibitor. The median time to treatment failure and progression-free survival of subsequent molecular targeted therapy were 5.6 and 8.0 months, respectively. The median overall survival from the initiation of first-line therapy was not reached. The disease control rate of subsequent molecular targeted therapy was 69.2% (partial response: 25.0%, stable disease: 44.2%). The median progression-free survival of subsequent tyrosine kinase inhibitor and mammalian target of rapamycin inhibitor were 9.2 and 8.0 months, respectively (P = 0.37). The progression-free survival of patients whose best response to prior nivolumab was either progressive disease or stable disease/partial response were 6.3 and 11.3 months, respectively (P = 0.36). CONCLUSIONS: Molecular targeted therapies following nivolumab had comparatively better therapeutic efficacy, which was confirmed regardless of the type of molecular targeted agent used.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Nivolumabe , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular , Metástase Neoplásica , Nivolumabe/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
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