RESUMO
Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient's subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy's sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07-10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval [CI] 2.17-18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8-12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy.
Assuntos
Fator de Transcrição CDX2 , Neoplasias do Colo , Neoplasias Colorretais , Inibidores de Checkpoint Imunológico , Humanos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Inibidores de Checkpoint Imunológico/uso terapêutico , Instabilidade de Microssatélites , Prognóstico , Estudos Retrospectivos , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismoRESUMO
BACKGROUND AND AIMS: An increased risk of small bowel carcinoma [SBC] has been reported in coeliac disease [CD] and Crohn's disease [CrD]. We explored clinico-pathological, molecular, and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] in comparison with sporadic SBC [spo-SBC]. METHODS: A total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC, 25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients' survival and histological and molecular features including microsatellite instability [MSI] and KRAS/NRAS, BRAF, PIK3CA, TP53, HER2 gene alterations. RESULTS: CD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancer-specific survival than CrD-SBC, whereas no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and median tumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series, both MSIâwhich was the result of MLH1 promoter methylation in all but one casesâand high TIL density were associated with improved survival at univariable and stage-inclusive multivariable analysis. However, only TILs retained prognostic power when clinical subgroups were added to the multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% of cases, respectively, without prognostic implications. CONCLUSIONS: In comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs more frequently and show better outcome. This seems mainly due to their higher TIL density, which at multivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutations and HER2 amplification might help in stratifying patients for targeted anti-cancer therapy.
Assuntos
Doença Celíaca/complicações , Neoplasias do Colo/etiologia , Doença de Crohn/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Celíaca/diagnóstico , Doença Celíaca/genética , Doença Celíaca/patologia , Criança , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Doença de Crohn/patologia , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética , Adulto JovemAssuntos
Medula Óssea/patologia , Microambiente Celular/efeitos dos fármacos , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Medula Óssea/metabolismo , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Mutação , Nitrilas , Mielofibrose Primária/genética , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas , Resultado do TratamentoRESUMO
We report the clinicopathologic, immunohistochemical and ultrastructural features of two unusual tumors of the uterus composed of spindle and epithelioid cells strongly positive for HMB45. The two patients of 56 and 48 years of age had, respectively, hemoperitoneum and abnormal uterine bleeding. Morphologically, both tumors showed atypia and extensive necrosis. The neoplastic cells express immunohistochemically both melanogenesis (HMB45) and smooth muscle markers (actin). Ultrastructural analysis showed the presence of intracytoplasmic membrane-bound granules. We viewed these neoplasms as perivascular epithelioid cell (PEC) tumors with aggressive features. Follow-up has shown the death of one patient whereas the other is alive without disease 36 months after the surgery. The two patients were evaluated for signs of tuberous sclerosis complex, and findings were negative.
