Neoadjuvant Immunotherapy Alone for Patients With Locally Advanced and Resectable Metastatic Colorectal Cancer of dMMR/MSI-H Status.

BACKGROUND: The use of programmed death-1 blockade has a significant therapeutic effect in patients with mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. However, data on preoperative single-agent programmed death-1 blockade are rare. OBJECTIVE: This study aims to evaluate the effectiveness and safety of preoperative programmed death-1 blockade as a conversion strategy in patients with locally advanced and resectable metastatic mismatch repair-deficient/microsatellite instability-high colorectal cancer. DESIGN: This is a retrospective observational study. SETTINGS: This study was conducted at a high-volume tertiary referral cancer center in China. PATIENTS: Twenty-four patients of consecutive cases since 2020 to 2022 with mismatch repair-deficient/microsatellite instability-high colorectal cancer who received preoperative single-agent programmed death-1 blockade were retrospectively reviewed. These patients had either bulking tumors scheduled for multivisceral resection, a strong desire for organ preservation, or potentially resectable metastatic lesions. MAIN OUTCOME MEASURES: Pathological complete response, clinical complete response, toxicity, R0 resection rate, and complications were evaluated. RESULTS: Patients tolerated preoperative immunotherapy well. The R0 resection rate was 95.2%, and the pathological complete response rate was 47.6%. Three patients (12.5%) were evaluated as having a clinical complete response and then underwent "watch and wait." One-half of the patients with cT4b were spared multivisceral resection, whereas 60% (3/5) achieved pathological complete response. All 3 patients with liver metastases obtained complete response of all liver lesions after programmed death-1 blockade treatment. Grade III postoperative complications occurred in 2 patients. LIMITATIONS: The limitations of this study are as follows: retrospective study, small sample size, and short follow-up. CONCLUSIONS: Preoperative anti-programmed death-1 therapy alone as a conversion strategy in initially resected difficult mismatch repair-deficient/microsatellite instability-high colorectal cancer can achieve a high tumor complete response. The use of immunopreoperative therapy in patients with T4b colon cancer or low rectal cancer can reduce multivisceral resection and achieve high organ function preservation. See the Video Abstract . INMUNOTERAPIA NEOADYUVANTE SOLA PARA PACIENTES CON CNCER COLORRECTAL LOCALMENTE AVANZADO Y METASTSICO RESECABLE CON ESTADO DMMR/MSIH: ANTECEDENTES:El uso del bloqueo de muerte programada-1 tiene un efecto terapéutico significativo en pacientes con cáncer colorrectal metastásico deficiente en reparación de desajustes/inestabilidad de microsatélites-alta (dMMR/MSI-H). Sin embargo, los datos sobre el bloqueo preoperatorio de muerte programada-1 con un solo agente son escasos.OBJETIVO:Este estudio tiene como objetivo evaluar la eficacia y seguridad del bloqueo preoperatorio de muerte programada-1 como estrategia de conversión en pacientes con cáncer colorrectal localmente avanzado y metastásico resecable con dMMR/MSI-H.DISEÑO:Este es un estudio observacional retrospectivo.ESCENARIO:Este estudio se realizó en un centro oncológico terciario de referencia de gran volumen en China.PACIENTES:Se revisaron retrospectivamente veinticuatro pacientes de casos consecutivos desde 2020-2022 con cáncer colorrectal y dMMR/MSI-H que recibieron bloqueo preoperatorio de muerte programada-1 con un solo agente. Estos pacientes tenían un tumor voluminoso programado para resección multivisceral, un fuerte deseo de preservación del órgano o lesiones metastásicas potencialmente resecables.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron la respuesta patológica completa, la respuesta clínica completa, la toxicidad, la tasa de resección R0 y las complicaciones.RESULTADOS:Los pacientes toleraron bien la inmunoterapia preoperatoria. La tasa de resección R0 fue del 95,2% y la tasa de respuesta patológica completa fue del 47,6%. Tres pacientes (12,5%) fueron evaluados como respuesta clínica completa y luego sometidos a "observar y esperar". La mitad de los pacientes cT4b se salvaron de la resección multivisceral, mientras que el 60% (3/5) lograron una respuesta patológica completa. Los tres pacientes con metástasis hepáticas obtuvieron respuesta completa de todas las lesiones hepáticas después del tratamiento de bloqueo de muerte programada-1. En dos pacientes se produjeron complicaciones postoperatorias de grado III.LIMITACIONES:Las limitaciones de este estudio son las siguientes: estudio retrospectivo, tamaño de muestra pequeño y seguimiento corto.CONCLUSIONES:La terapia preoperatoria anti muerte programada-1 sola como estrategia de conversión en el cáncer colorrectal inicialmente difícil de resecar con dMMR/MSI-H puede lograr una alta respuesta completa tumoral. El uso de terapia inmunopreoperatoria en pacientes con cáncer de colon T4b o cáncer de recto bajo puede reducir la resección multivisceral y lograr una alta preservación de la función del órgano. (Traducción-Dr. Felipe Bellolio ).

Exploring prognostic values of DNA ploidy, stroma-tumor fraction and nucleotyping in stage II colon cancer patients.

PURPOSE: To assess the prognostic value of three novel biomarkers, DNA ploidy, stroma-tumor fraction, and nucleotyping, seeking for more accurate stratification in stage II colon cancer. METHODS: A total of 417 patients with complete follow up information were enrolled in this study and divided into three clinical risk groups. IHC was performed to examine MSI status. DNA ploidy, stroma and nucleotyping were estimated using automated digital imaging system. Kaplan-Meier survival curves, Cox proportional hazards regression models, and correlation analyses were carried out to process our data. RESULTS: In the whole cohort of stage II colon cancer, nucleotyping and DNA ploidy were significant prognostic factors on OS in univariate analyses. The combination of nucleotyping and DNA ploidy signified superior OS and DFS. Difference was not significant between low-stroma and high-stroma patients. In multivariable analyses, nucleotyping and the combination of nucleotyping and DNA ploidy were proven the dominant contributory factors for OS. In the low-risk group, we found the combination of nucleotyping and DNA ploidy as the independent prognostic factor statistically significant in both univariate and multivariable, while in the high-risk group, the nucleotyping. CONCLUSIONS: Our study has proven nucleotyping and the combination of DNA ploidy and nucleotyping as independent prognostic indicators, thus expanding the application of nucleotyping as a predictor from high risk stage II colon cancer to whole risks.

KRAS, NRAS, BRAF signatures, and MMR status in colorectal cancer patients in North China.

We assessed the clinicopathological features and prognostic values of KRAS, NRAS, BRAF, and DNA mismatch repair status in colorectal cancer (CRC) to provide real-world data in developing countries. We enrolled 369 CRC patients and analyzed the correlation between RAS/BRAF mutation, mismatch repair status with clinicopathological features, and their prognostic roles. The mutation frequencies of KRAS, NRAS, and BRAF were 41.7%, 1.6%, and 3.8%, respectively. KRAS mutations and deficient mismatch repair (dMMR) status were associated with right-sided tumors, aggressive biological behaviors, and poor differentiation. BRAF (V600E) mutations are associated with well-differentiated and lymphovascular invasion. The dMMR status predominated in young and middle-aged patients and tumor node metastasis stage II patients. dMMR status predicted longer overall survival in all CRC patients. KRAS mutations indicated inferior overall survival in patients with CRC stage IV. Our study showed that KRAS mutations and dMMR status could be applied to CRC patients with different clinicopathological features.

Colorectal cancer lymph node metastasis prediction with weakly supervised transformer-based multi-instance learning.

Lymph node metastasis examined by the resected lymph nodes is considered one of the most important prognostic factors for colorectal cancer (CRC). However, it requires careful and comprehensive inspection by expert pathologists. To relieve the pathologists' burden and speed up the diagnostic process, in this paper, we develop a deep learning system with the binary positive/negative labels of the lymph nodes to solve the CRC lymph node classification task. The multi-instance learning (MIL) framework is adopted in our method to handle the whole slide images (WSIs) of gigapixels in size at once and get rid of the labor-intensive and time-consuming detailed annotations. First, a transformer-based MIL model, DT-DSMIL, is proposed in this paper based on the deformable transformer backbone and the dual-stream MIL (DSMIL) framework. The local-level image features are extracted and aggregated with the deformable transformer, and the global-level image features are obtained with the DSMIL aggregator. The final classification decision is made based on both the local and the global-level features. After the effectiveness of our proposed DT-DSMIL model is demonstrated by comparing its performance with its predecessors, a diagnostic system is developed to detect, crop, and finally identify the single lymph nodes within the slides based on the DT-DSMIL and the Faster R-CNN model. The developed diagnostic model is trained and tested on a clinically collected CRC lymph node metastasis dataset composed of 843 slides (864 metastasis lymph nodes and 1415 non-metastatic lymph nodes), achieving the accuracy of 95.3% and the area under the receiver operating characteristic curve (AUC) of 0.9762 (95% confidence interval [CI]: 0.9607-0.9891) for the single lymph node classification. As for the lymph nodes with micro-metastasis and macro-metastasis, our diagnostic system achieves the AUC of 0.9816 (95% CI: 0.9659-0.9935) and 0.9902 (95% CI: 0.9787-0.9983), respectively. Moreover, the system shows reliable diagnostic region localizing performance: the model can always identify the most likely metastases, no matter the model's predictions or manual labels, showing great potential in avoiding false negatives and discovering incorrectly labeled slides in actual clinical use.

Different clinico-pathological and prognostic features of vulvar, vaginal, and cervical melanomas.

Female genital tract melanoma (FGTM) is a rare and aggressive melanocytic malignancy, and its clinico-pathological and prognostic features at different anatomic sites have not yet been fully described. We retrospectively analyzed and compared the clinico-pathological data and survival outcomes of patients with primary lower genital tract melanoma enrolled between January 2005 and December 2020. We identified 95 patients with FGTM, of whom 46 had vulvar melanomas (VuM), 43 had vaginal melanomas (VaM), and six had cervical melanomas (CM). The clinical characteristics of all 95 cases, including symptoms, single or multiple primary lesions, clinical stage, surgery, and histopathological characteristics of 62 primary untreated cases, including pigmentation, predominant cytology, histological pattern, mitotic figures, and tumor-infiltrating lymphocytes of VuM, VaM, and CM, differed significantly. In comparison, only trend differences in molecular alternations were evident (p = 0.077). Disease-specific survival (DSS) was 30.7% at 5 years (46.5%, 25.6%, and 44.4% for VuM, VaM and CM, respectively). Seventy-one (85.5%) patients experienced FGTM recurrence. The median time to the first recurrence was 11 months, and VaM recurred earlier than VM and CM (16, 6, and 10 months for VuM, VaM, and CM, respectively, p = 0.038). A univariate analysis of 50 cases revealed the negative factors of disease-specific survival (DSS), including the location of the vagina and the presence of ulceration, and the negative factors of recurrence-free survival (RFS), including multiple lesions, the presence of ulceration, and the presence of lymphovascular invasion. Multiple lesions showed a borderline correlation with DSS. A multivariate Cox regression analyses of 50 cases revealed that the presence of ulceration was associated with shorter DSS and RFS (yes vs. no, Hazard Ratio = 2.400 and 2.716, respectively). Vaginal location showed a significant correlation with DSS (Hazard Ratio = 2.750, p = 0.024). In conclusion, vulval, vaginal, and cervical melanomas may differ in terms of their clinico-pathological features and associations with DSS and RFS. Ulceration and vaginal location were significantly associated with shorter DSS, and ulceration was associated with an increased risk of FGTM recurrence.