Cancer of unknown primary (CUP) site poses diagnostic challenges due to its elusive nature. Many cases of CUP manifest as pleural and peritoneal serous effusions. Leveraging cytological images from 57,220 cases at four tertiary hospitals, we developed a deep-learning method for tumor origin differentiation using cytological histology (TORCH) that can identify malignancy and predict tumor origin in both hydrothorax and ascites. We examined its performance on three internal (n = 12,799) and two external (n = 14,538) testing sets. In both internal and external testing sets, TORCH achieved area under the receiver operating curve values ranging from 0.953 to 0.991 for cancer diagnosis and 0.953 to 0.979 for tumor origin localization. TORCH accurately predicted primary tumor origins, with a top-1 accuracy of 82.6% and top-3 accuracy of 98.9%. Compared with results derived from pathologists, TORCH showed better prediction efficacy (1.677 versus 1.265, P < 0.001), enhancing junior pathologists’ diagnostic scores significantly (1.326 versus 1.101, P < 0.001). Patients with CUP whose initial treatment protocol was concordant with TORCH-predicted origins had better overall survival than those who were administrated discordant treatment (27 versus 17 months, P = 0.006). Our study underscores the potential of TORCH as a valuable ancillary tool in clinical practice, although further validation in randomized trials is warranted.

BACKGROUND: The characteristics of patients with colorectal cancer who have benign mesenteric lymph node enlargement are not well documented. OBJECTIVE: The aim of this study is to assess the clinical and prognostic significance of benign mesenteric lymph node enlargement in patients with colorectal cancer. DESIGN: This is a prospective cohort study. SETTING: This study was conducted at multitertiary institutions. PATIENTS: We included 601 patients with stage 0, I, and II colorectal cancer in Tianjin, Shandong, and Zhejiang from January 2010 to April 2014. Patients underwent curative surgery and were separated into 2 groups by the presence of benign mesenteric lymph node enlargement: the enlargement group (n = 275) and the control group (n = 326). MAIN OUTCOME MEASURES: Univariate log rank and multivariate Cox regression analyses were constructed to identify risk factors for recurrence and mortality. RESULTS: The risk of recurrence in the enlargement group after curative resection was significantly lower than in the control group, with the 1-, 3-, and 5-year disease-free survival rates being 97.1%, 91.6%, and 86.9% in the enlargement group and 95.7%, 86.2%, and 78.2% in the control group (p = 0.004). The postoperative 1-, 3-, and 5-year overall survival rates were 99.6%, 94.9%, and 90.5% in the enlargement group and 99.4%, 91.4%, and 82.1% in the control group (p = 0.001). Patients in the enlargement group had a higher percentage of patients at a younger age, family tumor history, right-sided tumors, and larger tumor size compared with the control group. For patients in the enlargement group, no significant correlation was observed between the number of enlarged lymph nodes and disease-free survival or overall survival (p = 0.113 and 0.386). Adjusted Cox regression model showed that benign mesenteric lymph node enlargement was an independent prognostic risk factor for both disease-free survival (HR, 0.587; 95% CI, 0.399–0.861; p = 0.007) and overall survival (HR, 0.506; 95% CI, 0.328–0.779; p = 0.002). LIMITATIONS: No immunological results could be compared with clinicopathological findings. CONCLUSIONS: The study indicates that benign mesenteric lymph node enlargement can be a useful positive factor in predicting recurrence and long-term survival concerning patients with colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B785. CARACTERÍSTICAS PRONÓSTICAS DE LOS PACIENTES PORTADORES DE CÁNCER COLORRECTAL CON AGRANDAMIENTO BENIGNO DE LOS GANGLIOS LINFÁTICOS MESENTÉRICOS: UN ESTUDIO DE COHORTE MULTIINSTITUCIONAL: ANTECEDENTES: Las características de los pacientes portadores de cáncer colorrectal con agrandamiento benigno de los ganglios linfáticos mesentéricos no se encuentran bien documentados. OBJETIVO: El objetivo de este estudio es evaluar la importancia clínica y pronóstica del agrandamiento benigno de los ganglios linfáticos mesentéricos en pacientes con cáncer colorrectal. DISEÑO: Este es un estudio de cohorte de tipo prospectivo. AJUSTE: Este estudio se llevó a cabo en instituciones de educación superior. PACIENTES: Incluimos a 601 pacientes con cáncer colorrectal en estadio 0, I, II en Tianjin, Shandong y Zhejiang desde enero de 2010 hasta abril de 2014. Los pacientes fueron sometidos a cirugía curativa y fueron separaron en dos grupos tomando en cuenta la presencia del agrandamiento benigno de los ganglios linfáticos mesentéricos: grupo con agrandamiento (n = 275) y grupo control (n = 326). PRINCIPALES MEDIDAS DE RESULTADO: Se construyeron análisis de rango logarítmico de una variante y de regresión de Cox con variante múltiple para identificar los factores de riesgo de recurrencia y mortalidad. RESULTADOS: El riesgo de recurrencia en el grupo con agrandamiento tras la resección curativa fue significativamente menor que en el grupo de control, con tasas de periodo libre de enfermedad a los 1, 3 y 5 años de 97,1, 91,6, y 86,9% en el grupo de agrandamiento y con tasas de 95,7, 86,2, y 78,2% en el grupo control respectivamente (p = 0,004). Las tasas postoperatorias de supervivencia general a los 1, 3 y 5 años fueron 99,6, 94,9, y 90,5% en el grupo de agrandamiento y de 99,4, 91,4, y 82,1% en el grupo de control, respectivamente (p = 0,001). Los pacientes del grupo con agrandamiento tenían un porcentaje más elevado de menor edad, antecedente familiar tumoral, tumores del lado derecho y de mayor tamaño tumoral con respecto al grupo de control. Para los pacientes con agrandamiento, no se observó una correlación significativa entre el número de ganglios linfáticos agrandados y el periodo libre de enfermedad o la supervivencia general (p = 0,113 y 0,386). El modelo de regresión de Cox ajustado mostró que el agrandamiento benigno de los ganglios linfáticos mesentéricos era un factor de riesgo pronóstico independiente tanto para la supervivencia libre de enfermedad (cociente de riesgo 0,587; IC del 95%: 0,399-0,861; p = 0,007) como para la supervivencia global (cociente de riesgo 0,506; IC del 95%: 0,328- 0,779; p = 0,002). LIMITACIONES: No fue posible comparar los resultados inmunológicos con los hallazgos clínico-patológicos. CONCLUSIONES: El estudio indica que el agrandamiento benigno de los ganglios linfáticos mesentéricos puede ser un factor positivo útil para predecir la recurrencia y la supervivencia a largo plazo en pacientes con cáncer colorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B785. (Traducción—Dr. Osvaldo Gauto)

Resistance to temozolomide (TMZ), the first-line chemotherapeutic drug for glioblastoma (GBM) and anaplastic gliomas, is one of the most significant obstacles in clinical treatment. TMZ resistance is regulated by complex genetic and epigenetic networks. Understanding the mechanisms of TMZ resistance can help to identify novel drug targets and more effective therapies. CUL4B has been shown to be upregulated and promotes progression and chemoresistance in several cancer types. However, its regulatory effect and mechanisms on TMZ resistance have not been elucidated. The aim of this study was to decipher the role and mechanism of CUL4B in TMZ resistance. Western blot and public datasets analysis showed that CUL4B was upregulated in glioma specimens. CUL4B elevation positively correlated with advanced pathological stage, tumor recurrence, malignant molecular subtype and poor survival in glioma patients receiving TMZ treatment. CUL4B expression was correlated with TMZ resistance in GBM cell lines. Knocking down CUL4B restored TMZ sensitivity, while upregulation of CUL4B promoted TMZ resistance in GBM cells. By employing senescence β-galactosidase staining, quantitative reverse transcription PCR and Chromatin immunoprecipitation experiments, we found that CUL4B coordinated histone deacetylase (HDAC) to co-occupy the CDKN1A promoter and epigenetically silenced CDKN1A transcription, leading to attenuation of TMZ-induced senescence and rendering the GBM cells TMZ resistance. Collectively, our findings identify a novel mechanism by which GBM cells develop resistance to TMZ and suggest that CUL4B inhibition may be beneficial for overcoming resistance.