RESUMO
A Darwinian evolutionary shift occurs early in the neutral evolution of advanced colorectal carcinoma (CRC), and copy number aberrations (CNA) are essential in the transition from adenoma to carcinoma. In light of this primary evolution, we investigated the evolutionary principles of the genome that foster postoperative recurrence of CRC. CNA and neoantigens (NAG) were compared between early primary tumors with recurrence (CRCR) and early primary tumors without recurrence (precancerous and early; PCRC). We compared CNA, single nucleotide variance (SNV), RNA sequences, and T-cell receptor (TCR) repertoire between 9 primary and 10 metastatic sites from 10 CRCR cases. We found that NAG in primary sites were fewer in CRCR than in PCRC, while the arm level CNA were significantly higher in primary sites in CRCR than in PCRC. Further, a comparison of genomic aberrations of primary and metastatic conditions revealed no significant differences in CNA. The driver mutations in recurrence were the trunk of the evolutionary phylogenic tree from primary sites to recurrence sites. Notably, PD-1 and TIM3, T cell exhaustion-related molecules of the tumor immune response, were abundantly expressed in metastatic sites compared to primary sites along with the increased number of CD8 expressing cells. The postoperative recurrence-free survival period was only significantly associated with the NAG levels and TCR repertoire diversity in metastatic sites. Therefore, CNA with diminished NAG and diverse TCR repertoire in pre-metastatic sites may determine postoperative recurrence of CRC.
Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor de Morte Celular Programada 1/genética , Adenoma/imunologia , Adenoma/patologia , Adenoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Variações do Número de Cópias de DNA/genética , Feminino , Deriva Genética , Genoma Humano/genética , Humanos , Imunidade/genética , Imunidade/imunologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Período Pós-Operatório , Intervalo Livre de Progressão , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
PURPOSE: To establish if it is appropriate to treat the inguinal lymph node (LN) of anal canal adenocarcinoma (ACA) as the intermediate LN according to the Japanese classification. METHODS: The characteristics of 346 ACA patients were examined from the nationwide registry. The effect of LN dissection was evaluated using the therapeutic value index (TVI). Furthermore, the prognostic classification ability of N factors and stage was evaluated using Akaike's information criterion (AIC), the concordance index (C-index), and the 5-year overall survival (OS) rate. RESULTS: The rate of metastasis of the inguinal LN was 7.5% and the TVI was 3.05. Evaluation using AIC and the C-index showed better results when the inguinal LN was treated as the intermediate LN. The 5-year OS rate for 66 patients with perirectal or intermediate LN metastasis, 7 with inguinal LN metastasis, and 13 with inguinal and perirectal or intermediate LN metastasis were 49.2%, 68.6%, and 47.6%, respectively. When inguinal LN metastases were treated as N3, the 5-year OS rates were 66.7% for those with T1N3 and T2N3 disease, and 49.2% for those with T3N3 disease. CONCLUSIONS: The inguinal LN of ACA was evaluated and staged as the intermediate LN to devise an appropriate treatment strategy.
RESUMO
BACKGROUND: Serum microRNAs (miRNAs) have been recognized as potential stable biomarkers for various types of cancer. Considering the clinical applications, there are certain critical requirements, such as minimizing the number of miRNAs, reproducibility in a longitudinal clinical course, and superiority to conventional tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9. This study aimed to identify serum miRNAs that indicate the recurrence of colorectal cancer (CRC), surpassing inter-tumor heterogeneity. METHODS: We conducted an analysis of 434 serum samples from 91 patients with CRC and 71 healthy subjects. miRNAs were obtained from Toray Co., Ltd, and miRNA profiles were analyzed using a three-step approach. miRNAs that were highly expressed in patients with CRC than in the healthy controls in the screening phase, and those that were highly expressed in the preoperative samples than in the 1-month postoperative samples in the discovery phase, were extracted. In the validation phase, the extracted miRNAs were evaluated in 323 perioperative samples, in chronological order. RESULTS: A total of 12 miRNAs (miR-25-3p, miR-451a, miR-1246, miR-1268b, miR-2392, miR-4480, miR-4648, miR-4732-5p, miR-4736, miR-6131, miR-6776-5p, and miR-6851-5p) were significantly concordant with the clinical findings of tumor recurrence, however their ability to function as biomarkers was comparable with CEA. In contrast, the combination of miR-1246, miR-1268b, and miR-4648 demonstrated a higher area under the curve (AUC) than CEA. These three miRNAs were upregulated in primary CRC tissues. CONCLUSION: We identified ideal combinatorial miRNAs to predict CRC recurrence.
Assuntos
Neoplasias Colorretais , MicroRNAs , Humanos , MicroRNAs/genética , Reprodutibilidade dos Testes , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgiaRESUMO
The definition of the anal canal was revised in the TNM classification (8th edition). The Japanese Society for Cancer of the Colon and Rectum (JSCCR) conducted a retrospective multi-institutional study to clarify the characteristics of anal canal cancer (ACC) in Japan. The diagnoses of 1781 patients treated for ACC were squamous cell carcimoma (SCC; n = 428; 24.0%), adenosquamous cell carcinoma (n = 7; 0.4%), and adenocarcinoma (n = 1260; 70.7%). Anal carcinoma is associated with human papillomavirus (HPV) infection and is risk factor for anal SCC. Among 40 cases analyzed at Takano Hospital and 47 cases analyzed at National Cancer Center Hospital, 34 cases (85.0%) and 40 cases (85.1%), respectively were infected with HPV; HPV-16 was the most common genotype (79.4% and 82.5%). In the JSCCR retrospective multi-institutional study, the prognosis analysis by stage was performed for anal SCC cases (202 cases treated by CRT and 91 cases treated by surgery). The 5-year overall survival (OS) rates by stage did not differ between the two treatment groups to a statistically significant extent. Regarding the results of cancer treatment of patients who underwent HPV infection tests, although the 5-year OS rates by stage did not differ to a statistically significant extent due to the small number of cases, HPV-positive patients had better survival. While an HPV vaccine for anal canal SCC has already been approved internationally, HPV vaccination has already been implemented in Japan as a national immunization program for young women but not for men at present. An HPV vaccination for men is urgently needed.
Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Masculino , Humanos , Feminino , Infecções por Papillomavirus/complicações , Canal Anal/patologia , Japão , Estudos Retrospectivos , Carcinoma de Células Escamosas/patologia , Papillomaviridae/genéticaRESUMO
PURPOSE: Anal canal adenocarcinoma (AC) is rare and its surgical outcomes and prognostic factors (PFs) are not well understood. The aim of this retrospective study was to identify the characteristics and PFs of AC, using population-based data in Japan. METHODS: Patients with AC (n = 390) or lower rectal adenocarcinoma (LR) (n = 12,477) diagnosed between1991 and 2006 were enrolled in this study. We compared the clinical- and patient-related factors of the two diseases and then examined propensity score matching, overall survival (OS), and PFs. RESULTS: AC tended to develop more often in women and in patients of advanced age. Macroscopically, AC was of an unclassified type and microscopically, it was of high-grade histological types such as mucinous adenocarcinoma, poorly differentiated adenocarcinoma (por), or signet-ring cell carcinoma (sig), with a high frequency of inguinal node metastasis (P < 0.05). The 5 year OS rates were 56.9% for AC and 67.9% for LR (P = 0.002). The PFs of AC were a high-grade histological type (por/sig), T, N, and M. CONCLUSIONS: AC has a significantly worse prognosis than LR. Moreover, the AC lymph node metastatic sites for AC, especially the inguinal nodes, are different from those for LR.
Assuntos
Adenocarcinoma , Canal Anal , Adenocarcinoma/patologia , Canal Anal/patologia , Feminino , Humanos , Japão/epidemiologia , Estadiamento de Neoplasias , Prognóstico , Pontuação de Propensão , Estudos RetrospectivosRESUMO
PURPOSE: There is currently no adequate biomarker for predicting colorectal cancer (CRC) recurrence. Chemokine (C-C motif) ligand 2 (CCL2) induces macrophages and fibroblasts to occupy metastatic niches in distant organs. The purpose of this study was to examine CCL2 as a potential predictive biomarker for CRC recurrence. METHODS: Plasma samples (n = 402) were collected from 80 stage II/III/IV CRC cases and the relationship between CCL2 profiles and recurrence was investigated. The tumor immune response genes associated with CCL2 mRNA expression in a subgroup of 8 stage I/II CRC cases with 12 recurrent sites and The Cancer Genome Atlas database were also analyzed retrospectively. RESULTS: Sixteen stage II/III/IV postoperative recurrent CRC cases experienced a significant increase in plasma CCL2 levels 6 months after surgery and continuously increased even after R0-1 resection. The 6-month postoperative CCL2 levels in recurrent cases of ≥ 1 year were significantly higher than in non-recurrent cases and recurrent cases of < 1 year. The CCL2 level in the primary tumor cases significantly correlated with the cytolytic activity, thus indicating a tumor immune response from the CD163-expressing macrophages. CONCLUSION: Plasma CCL2 was found to be a predictive biomarker of postoperative CRC recurrence. CCL2 in metastatic sites derives from metastatic niches that surpass the host immune response.
Assuntos
Biomarcadores Tumorais/sangue , Quimiocina CCL2/sangue , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/cirurgia , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Macrófagos/imunologia , Masculino , Estadiamento de Neoplasias , Período Pós-Operatório , Valor Preditivo dos Testes , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Gastrointestinal lymphomas like diffuse large B-cell lymphoma (DLBCL) are rare complications of ulcerative colitis (UC), and only a few studies have reported intestinal ulcers caused by DLBCL, which got perforated during the treatment of UC. CASE PRESENTATION: A 43-year-old man with severe lower abdominal pain and an 8-year history of UC was admitted in our hospital. He was diagnosed UC since 8 years and received a maintenance oral dose of 5-aminosalicylic acid, and no other immunosuppressive drugs. A deep rectal ulcer was endoscopically diagnosed 10 months before admission, no malignancy or cytomegalovirus infection was detected on biopsy. After 7 months a further endoscopy with biopsies confirmed the finding and the absence of malignancy. Three months later the patient developed sudden abdominal pain and was admitted in our hospital. Rectal perforation was suspected on X-ray and computed tomography imaging, and an emergency surgery was performed. Surgical exploration revealed a perforation on the anterior wall of the rectum. A subtotal colectomy with temporary ileostomy was performed. Pathology examinations showed lymphocyte infiltration of all of the layers of the perforated site and an immunohistochemical evaluation revealed DLBCL. Clinical staging was stage IV, and the patient received a 6-months regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. Positron emission tomography restaging revealed disappearance of distant uptake and a slight uptake in the residual rectum, and completion proctectomy with ileal pouch-anal anastomosis was performed. No residual tumor in the specimen was found, and the patient was disease-free at 2 years follow-up. CONCLUSIONS: DLBCL may increase the frequency of perforation and is a poor prognostic risk factor for patients with UC. This case study emphasizes the importance of careful medical surveillance and repeated endoscopic biopsies during the treatment of UC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Colite Ulcerativa , Perfuração Intestinal/cirurgia , Linfoma Difuso de Grandes Células B , Neoplasias Retais , Adulto , Colectomia , Colite Ulcerativa/complicações , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/cirurgia , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Ileostomia , Perfuração Intestinal/etiologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/cirurgia , Masculino , Prednisona/uso terapêutico , Prognóstico , Neoplasias Retais/diagnóstico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/etiologia , Neoplasias Retais/cirurgia , Reto/lesões , Reto/patologia , Reto/cirurgia , Rituximab/uso terapêutico , Vincristina/uso terapêuticoRESUMO
In the original publication Fig. 2 and Table 4 were incorrectly published. The corrected figure and table are given in this Correction.
RESUMO
Intersphincteric resection (ISR) is the ultimate sphincter-preserving procedure for low rectal cancer. A questionnaire about the standardization of ISR was given to 2125 patients who underwent curative ISR for low rectal cancer between 2005 and 2012 at 127 affiliated institutions of the Japanese Society for Cancer of the Colon and Rectum (JSCCR), and the results were compared with the results of a systematic review. The findings revealed that although mortality and morbidity were relatively low and the survival rate after ISR was good, the rates of local recurrence and postoperative fecal incontinence were relatively high. The radicality of ISR was compared with that of abdominoperineal resection and low anterior resection using the propensity score matching prognosis analysis of patients in the JSCCR nationwide registry. The local recurrence rate was significantly higher after ISR, and especially high in patients with T3 (invasion into the external anal sphincter) and T4 disease. These results provide evidence about the factors related to fecal incontinence after ISR. As measures for the standardization of ISR, it is important to reconfirm that ISR is not indicated for patients with cT3 and cT4 disease and those with poor preoperative defecatory function, based on the ISR indication criteria.
Assuntos
Canal Anal/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Tratamentos com Preservação do Órgão/métodos , Neoplasias Retais/cirurgia , Idoso , Defecação , Procedimentos Cirúrgicos do Sistema Digestório/mortalidade , Incontinência Fecal/epidemiologia , Incontinência Fecal/fisiopatologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/epidemiologia , Tratamentos com Preservação do Órgão/mortalidade , Complicações Pós-Operatórias/epidemiologia , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Inquéritos e Questionários , Taxa de Sobrevida , Tempo , Resultado do TratamentoRESUMO
The detection and sequencing of the mutated ctDNA is one of the irreplaceable clinical measures in the postoperative management of colorectal cancer (CRC) cases. However, we are curious to comprehend the essential traits of mutated genes comprising metastatic sites out of whole mutated genes in primary sites. In the current retrospective study, we conducted target resequencing of ctDNA using 47 plasma samples and established a cancer panel carrying the commonly mutated genes between primary and recurrent tumors. We found that mutated genes in ctDNA indicated immune-resistance traits with respect to the impaired ability to present neoantigens by loss of expression or binding affinity to HLA in the primary tumor. Compared with the estimated neoantigens from all mutated genes in primary tumors, the neoantigen peptides from commonly mutated genes on the panel showed abundant expression but no binding affinity to HLA. Therefore, ctDNA mutations can be frequently and postoperatively detected to identify recurrence; however, these mutated genes were derived from immune-tolerated clones owing to the loss of neoantigen presentation in primary CRC tumors.
Assuntos
Neoplasias Colorretais , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/genética , Mutação , Antígenos de Neoplasias/genéticaRESUMO
The accurate and early diagnosis and classification of cancer origin from either tissue or liquid biopsy is crucial for selecting the appropriate treatment and reducing cancer-related mortality. Here, we established the CAncer Cell-of-Origin (CACO) methylation panel using the methylation data of the 28 types of cancer in The Cancer Genome Atlas (7950 patients and 707 normal controls) as well as healthy whole blood samples (95 subjects). We showed that the CACO methylation panel had high diagnostic potential with high sensitivity and specificity in the discovery (maximum AUC = 0.998) and validation (maximum AUC = 1.000) cohorts. Moreover, we confirmed that the CACO methylation panel could identify the cancer cell type of origin using the methylation profile from liquid as well as tissue biopsy, including primary, metastatic, and multiregional cancer samples and cancer of unknown primary, independent of the methylation analysis platform and specimen preparation method. Together, the CACO methylation panel can be a powerful tool for the classification and diagnosis of cancer.
Assuntos
Metilação de DNA , Neoplasias , Biomarcadores Tumorais/genética , Epigenoma , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Sensibilidade e EspecificidadeRESUMO
PURPOSE: Intersphincteric resection has been performed as an alternative to abdominoperineal resection for low rectal cancer. The purpose of this study was to assess the long-term results after intersphincteric resection in terms of the morbidity, oncologic safety, and defecatory function. METHODS: Between 1994 and 2006, 107 consecutive patients with low rectal cancer had curative intersphincteric resection, categorized as total, subtotal, or partial resection of the internal anal sphincter. RESULTS: There were no mortalities. Neorectal mucosal prolapse in patients with total intersphincteric resection and coloanal anastomotic stenosis in patients with subtotal or partial intersphincteric resection were observed as characteristic late complications. The five-year disease-free survival rates classified according to the TNM stage were 100 percent for stage I, 83.5 percent for stage II, and 72.0 percent for stage III cases. The five-year cumulative local recurrence rate after intersphincteric resection was 2.5 percent. Defecatory function, which was evaluated by bowel movement in a 24-hour period, and continence after intersphincteric resection were objectively good. The results of the multivariate analysis revealed that age was the only factor associated with a risk of fecal incontinence. CONCLUSION: Provided strict selection criteria are used, intersphincteric resection may be the optimal sphincter-preserving surgery for low rectal cancer.