RESUMEN
Overcoming cisplatin (CDDP) resistance is a major issue in urothelial cancer (UC), in which CDDP-based chemotherapy is the first-line treatment. WEE1, a G2 /M checkpoint kinase, confers chemoresistance in response to genotoxic agents. However, the efficacy of WEE1 blockade in UC has not been reported. MK-1775, a WEE1 inhibitor also known as AZD-1775, blocked proliferation of UC cell lines in a dose-dependent manner irrespective of TP53 status. MK-1775 synergized with CDDP to block proliferation, inducing apoptosis and mitotic catastrophe in TP53-mutant UC cells but not in TP53-WT cells. Knocking down TP53 in TP53-WT cells induced synergism of MK-1775 and CDDP. In UMUC3 cell xenografts and two patient-derived xenograft lines with MDM2 overexpression, in which the p53/cell cycle pathway was inactivated, AZD-1775 combined with CDDP suppressed tumor growth inducing both M-phase entry and apoptosis, whereas AZD-1775 alone was as effective as the combination in RT4 cell xenografts. Drug susceptibility assay using an ex vivo cancer tissue-originated spheroid system showed correlations with the in vivo efficacy of AZD-1775 alone or combined with CDDP. We determined the feasibility of the drug susceptibility assay using spheroids established from UC surgical specimens obtained by transurethral resection. In conclusion, WEE1 is a promising therapeutic target in the treatment of UC, and a highly specific small molecule inhibitor is currently in early phase clinical trials for cancer. Differential antitumor efficacy of WEE1 blockade alone or combined with CDDP could exist according to p53/cell cycle pathway activity, which might be predictable using an ex vivo 3D primary culture system.
Asunto(s)
Antineoplásicos/administración & dosificación , Proteínas de Ciclo Celular/antagonistas & inhibidores , Cisplatino/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/administración & dosificación , Pirimidinonas/administración & dosificación , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Animales , Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratones SCID , Mitosis/efectos de los fármacos , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Transfección , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The biological processes of urothelial carcinogenesis are not fully understood, particularly regarding the relationship between specific genetic events, cell of origin, and molecular subtypes of subsequent tumors. N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced mouse bladder cancer is widely accepted as a useful model that recapitulates the pathway of human bladder tumorigenesis from dysplasia to invasive cancer via carcinoma in situ. However, the long and variable time of tumorigenesis often hinders efficient preclinical or translational research. We hypothesized that Trp53 mutation in specific types of urothelial cells facilitates efficient development of clinically relevant bladder cancer. Using lineage tracing, we showed that Trp53 mutation in Krt5-expressing cells resulted in more efficient tumorigenesis of mouse muscle-invasive bladder cancer (MIBC) with squamous differentiation compared with Trp53 mutation in Upk2-expressing cells, or wild-type or hemizygous Trp53 in the entire urothelium. Mouse MIBC that developed at 24 weeks of BBN treatment showed morphologic and genetic similarities to the basal squamous subtypes of human MIBC, irrespective of pre-induction of Trp53 mutation or whether the cell of origin was Krt5- or Upk2-expressing cells. Our findings suggest that intermediate cells as well as basal cells also can give rise to basal-like MIBC, with pre-induction of Trp53 mutation accelerating MIBC. Thus, in BBN chemical carcinogenesis, pre-induction of Trp53 mutation in basal cells facilitates efficient modeling of the basal squamous subtype of human MIBC.
Asunto(s)
Carcinogénesis/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Transicionales/genética , Queratina-5/genética , Proteína p53 Supresora de Tumor/genética , Neoplasias de la Vejiga Urinaria/genética , Vejiga Urinaria/patología , Animales , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Regulación Neoplásica de la Expresión Génica , Queratina-5/metabolismo , Ratones , Mutación , Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Serotonin (5-hydroxytryptamine [5-HT]) synthesized and released in enterochromaffin (EC) cells participates in various functions in the gastrointestinal tract by acting on a diverse range of 5-HT receptors (HTRs) expressed on smooth muscle, enteric neurons, and epithelial cells. We previously observed that genes encoding HTR2A, HTR2B, and HTR4 are expressed in murine intestinal organoids, suggesting the expression of these HTRs in intestinal epithelial cells. The present study investigated the localization of these HTRs in the murine intestine by immunofluorescence staining. HTR2A, HTR2B, and HTR4 localized in individual solitary cells in the epithelium, while HTR2C was observed in the lamina propria. In the epithelium, HTR2A, HTR2B, and HTR4 colocalized with 5-HT, and HTR4 colocalized with glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). Murine intestinal organoids show a colocalization pattern that is similar to in vivo HTR2A and HTR4 with 5-HT, GLP-1, and PYY. Intraperitoneal and intragastric administration of tegaserod, an HTR4 agonist, failed to alter plasma GLP-1 levels in fasted mice. However, intragastric but not intraperitoneal administration of tegaserod reduced dietary lipid-induced increases of plasma GLP-1 levels. This action of tegaserod was inhibited by co-administration of RS39604, an HTR4 antagonist. These results suggest that murine ileal GLP-1/PYY-producing enteroendocrine (EE) cells express HTR4, while 5-HT-producing EC cells express HTR2A, HTR2B, and HTR4. In addition, the observations regarding in vivo GLP-1 secretion suggest that HTR4 signaling in ileal EE cells suppresses dietary lipid-induced GLP-1 secretion. We thus propose that EC and EE cells may interact with each other through paracrine signaling mechanisms.
Asunto(s)
Células Enteroendocrinas/metabolismo , Receptores de Serotonina 5-HT4/metabolismo , Animales , Células Cultivadas , Células Enteroendocrinas/citología , Células Enteroendocrinas/efectos de los fármacos , Fármacos Gastrointestinales/farmacología , Péptido 1 Similar al Glucagón/genética , Péptido 1 Similar al Glucagón/metabolismo , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Serotonina 5-HT4/genética , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Antagonistas del Receptor de Serotonina 5-HT4/farmacologíaRESUMEN
BACKGROUND: Since the standard gemcitabine and cisplatin (GC) chemotherapy for advanced bladder cancer yields limited therapeutic effect due to chemoresistance, it is a clinical challenge to enhance sensitivity to GC. METHODS: We performed high-throughput screening by using a library of known chemicals and repositionable drugs. A total of 2098 compounds were administered alone or with GC to human bladder cancer cells, and chemicals that enhanced GC effects were screened. RESULTS: Disulfiram (DSF), an anti-alcoholism drug, was identified as a candidate showing synergistic effects with cisplatin but not with gemcitabine in multiple cell lines. Co-administration of DSF with GC affected cellular localisation of a cisplatin efflux transporter ATP7A, increased DNA-platinum adducts and promoted apoptosis. Micellar DSF nanoparticles (DSF-NP) that stabilised DSF in vivo, enhanced the inhibitory effect of cisplatin in patient-derived and cell-based xenograft models without severe adverse effects. A drug susceptibility evaluation system by using cancer tissue-originated spheroid culture showed promise in identifying cases who would benefit from DSF with cisplatin. CONCLUSIONS: The present study highlighted the advantage of drug repurposing to enhance the efficacy of anticancer chemotherapy. Repurposing of DSF to a chemotherapy sensitiser may provide additional efficacy with less expense by using an available drug with a well-characterised safety profile.
Asunto(s)
Cisplatino/farmacología , Disulfiram/farmacología , Detección Precoz del Cáncer , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Disulfiram/química , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Humanos , Nanopartículas/química , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We evaluated the safety of laparoscopic radical cystectomy (LRC) during initial phases and its learning curve in a Japanese multicenter cohort by studying 436 patients who underwent LRC with no robot assistance at 10 institutions in Japan. We divided the patients into three groups according to cumulative surgical volume at each institution (first 10 cases, 11-30 cases, after 31 cases in each institution), and compared perioperative and pathologic variables among the three groups. The first, second, and third groups included 100, 166, 170 patients, respectively. The preoperative variables were similar in the three groups except for the rate of neoadjuvant chemotherapy. The methods of LRC procedure, such as urinary diversion, the extent of lymph node dissection, and concomitant urethrectomy or nephroureterectomy, were similar in the three groups. Mean operative time was 629, 562 and 531 minutes, respectively, and mean blood loss was 755, 650 and 435 ml, respectively. Both values decreased over time with the institution's experience. There was no significant difference among the three groups in the rate of positive surgical margin, the number of retrieved lymph nodes, and the rate of intra- and postoperative complications. LRC was safely performed during initial phases with an acceptable complication rate and without compromising oncological results, although operative time was longer and blood loss increased.
Asunto(s)
Laparoscopía , Cistectomía , Humanos , Japón , Resultado del Tratamiento , Neoplasias de la Vejiga UrinariaRESUMEN
A man aged 83 years under treatment with enzalutamide for castration-resistant prostate cancer presented with general malaise and exertional dyspnea. The underlying cause could not be identified by further investigations. On the 5th hospital day, he died due to a sudden exacerbation of dyspnea. The results of an autopsy indicated tumor emboli and stenosis of small pulmonary arteries with the fibrocellular intimal thickening, and therefore our final diagnosis was pulmonary tumor thrombotic microangiopathy.
Asunto(s)
Neoplasias Pulmonares/secundario , Neoplasias de la Próstata Resistentes a la Castración/patología , Microangiopatías Trombóticas/diagnóstico por imagen , Anciano de 80 o más Años , Disnea/etiología , Resultado Fatal , Humanos , Masculino , Microangiopatías Trombóticas/etiología , Tomografía Computarizada por Rayos XRESUMEN
We investigated the surgical outcome for robotic-assisted laparoscopic radical prostatectomy (RALP) withinitial 70 prostate cancer cases performed by a single surgeon between June 2014 and May 2016. The surgeon had a previous experience of more than 400 cases of laparoscopic radical prostatectomy (LRP). Comparative study of the surgical outcome was made between the first 35 patients (group 1) and the second 35 patients (group 2). The console time without lymph node dissection significantly decreased from group 1 to 2 (193 min vs 158 min, p=0.002). Among specific 3 parts of the console operation (part 1 : until the bladder neck transection, part 2 : until the prostate removal and part 3 : urethrovesical anastomosis), duration of parts 1 and 2 similarly decreased witha significant difference of 0. 001 and 0. 002, respectively. Continence recovery rates 1 month after RALP were significantly higher in group 2 than in group 1 (group1 : 48.5% vs group 2 : 74.2%, p=0.02). Between groups 1 and 2, the positive surgical margin rates of both pT2 and pT3 were similar (group 1 : 20. 8 and 50. 0%, group 2 : 17. 2 and 50. 0%, respectively). The perioperative 8 complications (11.4%) were classified into Clavien-Dindo grades 1 and 2. Our surgical outcome of initial 70 RALP cases was considered as comparable to that reported from the high volume centers.
Asunto(s)
Prostatectomía , Neoplasias de la Próstata/cirugía , Procedimientos Quirúrgicos Robotizados , Anciano , Anciano de 80 o más Años , Humanos , Laparoscopía , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
A 73-year-old man presented to our hospital due to postejaculation gross hematuria and dysuria. Three months after onset, urinary retention occurred repeatedly. Under general anesthesia, cystourethroscopy following drug-induced erection was performed. A solitary sessile lesion with varicosis was found between the verumontanum and external sphincter. The tumor was resected endoscopically and recurrence was not observed during the follow-up period. Histological examination revealed a cavernous hemangioma of the urethra. Urologists should keep in mind that urethral hemangioma can be a cause of hematuria after erection or ejaculation.
Asunto(s)
Hemangioma/complicaciones , Hematuria/etiología , Neoplasias Uretrales/complicaciones , Retención Urinaria/etiología , Anciano , Humanos , Masculino , Neoplasias Uretrales/patologíaRESUMEN
Intestinal organoids were recently established as an ex vivo model of the intestinal epithelium. The present study investigated the serotonin (5-hydroxytryptamine, 5-HT) system using organoids. Organoids from murine small intestinal and colonic crypts were successfully cultured. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that small intestinal and colonic organoids express mRNAs encoding tryptophan hydroxylase-1 (TPH1) (the rate-limiting enzyme of 5-HT synthesis), serotonin reuptake transporter (SERT), 5-HT receptor (HTR)2A, HTR2B, and HTR4. SERT mRNA levels were significantly higher in the small intestine than in the colon in both the mucosal tissues and organoids, as estimated by quantitative real-time RT-PCR. Although the 5-HT concentration and levels of chromogranin A (CgA) (an enteroendocrine cell marker), TPH1, and HTR4 mRNAs were significantly higher in the colonic mucosa than the small intestinal mucosa, they were the same in small intestinal and colonic organoids. There were no significant differences in HTR2A and HTR2B mRNA levels between the small intestine and colon in either the mucosal tissues or organoids. Immunofluorescence staining showed that the number of CgA-positive cells in the colonic organoids appeared to increase upon culturing with acetate. Acetate supplementation significantly increased CgA, TPH1, and HTR4 mRNA levels in the colonic organoids. We propose that organoids are useful for investigating the 5-HT system in the intestinal epithelium, even though colonic organoids may require gut microbiota-derived factors such as short-chain fatty acids.
Asunto(s)
Colon/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Técnicas de Cultivo de Órganos/métodos , Organoides/metabolismo , Serotonina/metabolismo , Animales , Células Cultivadas , Femenino , Ratones , Ratones Endogámicos C57BL , Modelos AnimalesRESUMEN
A 55-year-old woman was referred to our hospital with dysuria. We were unable to catheterize her using a nelaton catheter because of a urethral stricture, resulting in a large residual urine volume on ultrasonography. The circumference of the periurethral tissue was also thickened and the entire length of the urethra was stenotic, without apparent cause, on magnetic resonance imaging. Biopsy did not reveal malignancy. The pathological diagnosis of the periurethral tissue was simply fibrosis, and there was no definitive diagnosis. We decided to place a guidewire to attempt transurethral dilation, but it was unsuccessful because of the urethral stricture. The patient then underwent Mitrofanoff appendicovesicostomy. Three years later, there was no difficulty with catheterization through the appendix, despite her suffering from a bladder stone during the interim. We consider the Mitrofanoff appendicovesicostomy a good substitute technique for catheterization in patients with very severe urethral stricture.
Asunto(s)
Estrechez Uretral/cirugía , Cistostomía , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Ultrasonografía , Estrechez Uretral/diagnóstico por imagenRESUMEN
Although leptin and adiponectin are the predominant adipokines, how their circulating levels are regulated is incompletely understood. The present study tested whether intestinal epithelial cells influence the expression and secretion of these adipokines by adipocytes. Leptin gene expression and secretion by cultured human primary adipocytes and Simpson-Golabi-Behmel Syndrome adipocytes increased upon coculture with human enterocytic Caco-2 cells or incubation in conditioned medium of Caco-2 cells. Although adiponectin secretion increased, its mRNA levels decreased. Tissue homogenate of the ileum (but not the jejunum, colon, or liver) of nonobese C57BL/6J mice also stimulated leptin and adiponectin secretion by cultured murine 3T3-L1 adipocytes. However, ileal homogenate of obese KK-Ay mice had no effect on leptin and adiponectin secretion. We propose that as yet unidentified humoral factors released from intestinal epithelial cells are involved in regulating circulating leptin and adiponectin levels. Decreased production of such factors may contribute to hyperphagia in KK-Ay mice.
Asunto(s)
Adipocitos/metabolismo , Adiponectina/metabolismo , Comunicación Celular/fisiología , Células Epiteliales/metabolismo , Íleon/metabolismo , Mucosa Intestinal/metabolismo , Leptina/metabolismo , Animales , Células CACO-2 , Células Epiteliales/citología , Humanos , Íleon/citología , Mucosa Intestinal/citología , Ratones , Ratones Endogámicos C57BL , Regulación hacia Arriba/fisiologíaRESUMEN
A 58-year-old man had undergone laparoscopic radical nephrectomy for right renal cell carcinoma. The histopathological diagnosis was clear cell carcinoma, grade 2ï¼3, pT1b. Two years and 10 months postoperatively, computed tomography scans demonstrated an enhanced mass on the right adrenal gland. As we could not detect other metastatic lesions, it was diagnosed as solitary adrenal metastasis of renal cell carcinoma. Albeit metastasectomy was planned with curative intent, right hemihepatectomy was also required for surgical removal because the tumor was adherent to the right lobe of the liver broadly and had indistinct margins. So we started neoadjuvant therapy with sunitinib. Eight courses of treatment shrunk the metastatic tumor enough to allow it to be removed completely without partial hepatectomy. Neoadjuvant therapy with the molecular targeted drugs may provide an effective option for metastasectomy in renal cell carcinoma regarding increased curability and decreased the risk of an operation.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/secundario , Neoplasias de las Glándulas Suprarrenales/terapia , Carcinoma de Células Renales/patología , Indoles/uso terapéutico , Neoplasias Renales/patología , Terapia Neoadyuvante/métodos , Pirroles/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , SunitinibRESUMEN
In cases of advanced renal cell carcinoma with inferior vena cava (IVC) thrombus, surgical resection of both tumor and thrombus contributes to the improvement of patient's prognosis, but the risk of perioperative complication is still high. We experienced two cases of advanced renal tumors with IVC tumor thrombus down-sized by presurgical treatment of axitinib. Axitinib treatment showed a marked tumor reduction effect without any severe adverse event. We could remove both tumor and thrombus without perioperative complications. In these two cases, downsizing of IVC thrombus enabled us to reduce the extent of the surgery.
Asunto(s)
Carcinoma de Células Renales/cirugía , Imidazoles/administración & dosificación , Indazoles/administración & dosificación , Neoplasias Renales/cirugía , Células Neoplásicas Circulantes/patología , Cuidados Preoperatorios , Inhibidores de Proteínas Quinasas/administración & dosificación , Vena Cava Inferior , Anciano , Axitinib , Carcinoma de Células Renales/patología , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana EdadRESUMEN
In robot-assisted surgery, in which haptics should be absent, surgeons experience haptics-like sensations as "pseudo-haptic feedback". As surgeons who routinely perform robot-assisted laparoscopic surgery, we wondered if we could make these "pseudo-haptics" explicit to surgeons. Therefore, we created a simulation model that estimates manipulation forces using only visual images in surgery. This study aimed to achieve vision-based estimations of the magnitude of forces during forceps manipulation of organs. We also attempted to detect over-force, exceeding the threshold of safe manipulation. We created a sensor forceps that can detect precise pressure at the tips with three vectors. Using an endoscopic system that is used in actual surgery, images of the manipulation of excised pig kidneys were recorded with synchronized force data. A force estimation model was then created using deep learning. Effective detection of over-force was achieved if the region of the visual images was restricted by the region of interest around the tips of the forceps. In this paper, we emphasize the importance of limiting the region of interest in vision-based force estimation tasks.
Asunto(s)
Aprendizaje Profundo , Riñón , Laparoscopía , Animales , Porcinos , Riñón/cirugía , Riñón/fisiología , Laparoscopía/métodos , Procedimientos Quirúrgicos Robotizados/métodosRESUMEN
We prospectively investigated the rates of incidence of surgical site infection (SSI), urinary tract infection (UTI), and remote infection (RI) in 4,677 patients who underwent urological surgery from January to December 2010, including 2,507 endourological cases, 1,276 clean cases, 807 clean-contaminated cases, and 87 contaminated cases involving bowel segments. A single dose of antimicrobial prophylaxis (AMP) was administered in the endourological, clean, and clean-contaminated surgery cases, except for patients who underwent transurethral resection of the prostate (TURP) or percutaneous nephrolithotripsy (PNL). AMP was administered within 72 h in TURP and PNL, and AMP was administered within 48 h in contaminated surgery cases. In cases of endourological surgery, UTI was observed in 4% and RI in 0%, and SSI, UTI, and RI were seen in 1%, 1%, and 1%, respectively, of clean surgery cases, in 3%, 3%, and 2%, respectively, of clean-contaminated surgery cases, and in 17%, 30%, and 10%, respectively, of contaminated surgery cases. In multivariate analysis of the risk factors for infection, operative time was a significant risk factor for UTI in endourological surgery, and American Society of Anesthesiologists score and operative time were significant risk factors for RI in clean surgery. No significant risk factor was found in analyses of clean-contaminated and contaminated surgery cases. A single-dose AMP regimen was shown to be effective and feasible for prevention of perioperative infection in urological surgery.
Asunto(s)
Infección de la Herida Quirúrgica/prevención & control , Infecciones Urinarias/prevención & control , Procedimientos Quirúrgicos Urológicos/métodos , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Profilaxis Antibiótica , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Factores de Riesgo , Infección de la Herida Quirúrgica/tratamiento farmacológico , Infecciones Urinarias/tratamiento farmacológico , Procedimientos Quirúrgicos Urológicos/efectos adversosRESUMEN
BACKGROUND/AIM: Considering the limited data available on immune checkpoint inhibitors and radiation combination therapy in advanced urothelial carcinoma, this study evaluated the survival benefit and associated toxicity of adding radiation therapy to second-line pembrolizumab. PATIENTS AND METHODS: We retrospectively examined 24 consecutive patients with advanced bladder or upper urinary tract urothelial carcinoma and for whom second-line pembrolizumab was initiated between August 2018 and October 2021 in combination with radiation therapy (with curative intent in 12 patients, and palliative intent in 12 patients). Their survival outcomes and toxicities were compared with those of propensity-score-matched cohorts from a Japanese multicenter study with similar characteristics who received pembrolizumab monotherapy. RESULTS: The median follow-up periods after pembrolizumab initiation were 15 months for the curative cohort and 4 months for the palliative cohort. The median overall survival was 27.7 months for the curative cohort and 4.8 months for the palliative cohort. Compared with the matched pembrolizumab monotherapy cohort, overall survival was better among the curative cohort although not statistically significant (p=0.13), but similar between the palliative and matched pembrolizumab monotherapy cohorts (p=0.44). There was no difference in the incidence of grade ≥2 adverse events between the combination and monotherapy cohorts, irrespective of the intent of radiation therapy. CONCLUSION: The combination of radiation therapy and pembrolizumab can be performed with a clinically acceptable safety profile, and the addition of radiation therapy to immune checkpoint inhibitors may improve survival outcome after pembrolizumab treatment in cases where the intent of radiation therapy is curative.
Asunto(s)
Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/radioterapia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/radioterapia , Estudios Retrospectivos , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
A 54-year-old man presented with pollakiuria and dysuria. Ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) showed a retroperitoneal tumor 10 cm in diameter. Pathological examination of a transrectal biopsy specimen obtained from the patient revealed the presence of an inflammatory myofibroblastic tumor (IMT). The patient underwent surgical resection of the tumor. Histopathologically, the tumor was composed of 3 parts : the largest part was compatible with an inflammatory pseudotumor: the second part, well-differentiated liposarcoma: and the third part, a myxoid liposarcoma. He has been followed up for 14 months ; but there was no evidence of local recurrence of the tumor. We believe that the inflammatory pseudotumor complicated in repairing the inflammation arising from the liposarcoma.
Asunto(s)
Liposarcoma/complicaciones , Seudotumor Cerebral/complicaciones , Neoplasias Retroperitoneales/complicaciones , Humanos , Liposarcoma/patología , Masculino , Persona de Mediana Edad , Seudotumor Cerebral/patología , Neoplasias Retroperitoneales/patologíaRESUMEN
Although immune checkpoint inhibitors have shown benefit for advanced urothelial carcinoma (aUC) patients, prognostication of treatment efficacy and response duration remains a clinical challenge. We evaluated the expression of immune markers in the tumor microenvironment and assessed their associations with response to and survival after pembrolizumab treatment in 26 aUC patients. High levels of CD8+ tumor-infiltrating lymphocytes (TILs) were associated with favorable objective responses (23.0% vs. 15.3%, p = 0.0425), progression-free survival (median, 8.8 vs 2.1 months; hazard ratio (HR), 0.24; 95% confidence interval (CI), 0.07-0.66, p = 0.0060), and overall survival (median, >24.0 vs. 5.3 months; HR, 0.17; 95% CI, 0.04-0.56, p = 0.0034) compared with low levels. High interferon-gamma (IFNγ) expression levels were associated with longer post-progression survival (median, 4.9 vs. 1.0 months; HR, 0.18; 95% CI, 0.04-0.59, p = 0.0027) compared with low expression. Multivariate analysis incorporating clinical prognosticators demonstrated that the coincidence of low CD8+ T cells/IFNγ was an independent factor for unfavorable overall survival after pembrolizumab treatment (HR, 4.07; 95% CI, 1.36-12.73; p = 0.0125). The combination of low CD8+ TILs and IFNγ expression was an independent prognostic factor with predictive ability equivalent to previously reported clinical prognosticators.
RESUMEN
PURPOSE: To investigate the correlation between tumor size changes during the initial 4 cycles of first-line chemotherapy and tumor shrinkage following 2 additional cycles of chemotherapy in patients with advanced urothelial carcinoma (aUC) who experienced disease control after initial chemotherapy. METHODS: We retrospectively reviewed 128 patients with aUC who received first-line chemotherapy. We analyzed 51 patients with disease control (stable disease or better) at the end of the fourth cycle. Of these, 47 patients received 1 to 2 additional cycles of chemotherapy, whereas the remaining patients underwent observation. For patients who received additional chemotherapy, the change in tumor size after additional chemotherapy (cycles 5-6) was defined as "no shrinkage" (tumor growth), "minor shrinkage" (no tumor growth or ≤10% reduction in tumor size), or "shrinkage" (>10% reduction in tumor size). Then, we investigated the relationship between the rate of tumor size change during the initial 4 cycles and that after additional chemotherapy. RESULTS: Of the patients who received additional chemotherapy, the change in tumor size was categorized as no shrinkage in 21 patients (44.7%), minor shrinkage in 18 patients (38.3%), and shrinkage in 8 patients (17%). Regarding predictors of tumor shrinkage after additional chemotherapy, the rate of tumor size change between the cycles 3 and 4 (area under the receiver operating characteristics curveâ¯=â¯0.642) was correlated with the trend of the tumor shrinkage (Pâ¯=â¯0.009) and the likelihood of beneficial tumor shrinkage after additional chemotherapy (minor shrinkageâ¯+â¯shrinkage; Pâ¯=â¯0.02). However, the change in tumor size between cycles 1 and 2, cycles 1 and 4, or cycles 3 and 4 was not satisfactorily predictive of further tumor shrinkage because of substantial overlaps of the tumor size changes. CONCLUSIONS: Only a small subset of patients would have substantial tumor shrinkage by additional cycles after successful induction of 4 cycle chemotherapy. Tumor size dynamics during the initial 4 cycles of chemotherapy displayed limited ability to predict the subset of patients with further tumor shrinkage after additional chemotherapy. Therefore, it might be better to consider switch maintenance immunotherapy for patients who experience disease control after the fourth cycle of first-line chemotherapy.
Asunto(s)
Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/tratamiento farmacológico , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
BACKGROUND/AIM: Standard chemotherapy for advanced urothelial carcinoma (UC) patients with moderate renal dysfunction has not yet been established. PATIENTS AND METHODS: We retrospectively assessed outcomes of patients with advanced UC who underwent first-line chemotherapy with full-/reduced-dose gemcitabine plus cisplatin (GC-f/GC-r) or full-/reduced-dose gemcitabine plus carboplatin (G-Car-f/G-Car-r) according to renal function. RESULTS: Seventy-eight patients were included in this study. The objective response rate was 42%, 30%, 42%, and 27% for the GC-f, GC-r, G-Car-f, and G-Car-r groups, respectively. For the GC-r and G-Car-f groups, the median progression-free survival and the median overall survival was 4.5 vs. 7.0 months (p=0.07) and 7.5 months vs. 12.0 months (p=0.124), respectively. Grade 3/4 thrombocytopenia occurred more frequently in the GC-r group than the G-Car-f group (80% vs. 38%, p=0.021). CONCLUSION: G-Car-f could be more beneficial than GC-r for patients with advanced UC who have moderate renal dysfunction.