Prognostic impact of histological categorisation of epithelial-mesenchymal transition in colorectal cancer.

BACKGROUND: The crosstalk between cancer cells and stroma is involved in the acquired capability for metastasis through the induction of epithelial-mesenchymal transition (EMT). We aimed to clarify the prognostic value of the histological category of EMT in colorectal cancer (CRC). METHODS: Tumour EMT was graded into one of three histological categories on the basis of integrated assessment of poorly differentiated clusters and pro-EMT desmoplasia at the leading edge of the primary tumour (Histology(EMT)). Stage II and III CRC patients (cohort 1, N=500) and stage IV patients (cohort 2, N=196) were retrospectively analysed. RESULTS: In cohort 1, patients were stratified into three groups with widely different disease-free survival rates (95%, 83% and 39%) on the basis of Histology(EMT) (P<0.0001). In cohort 2, Histology(EMT) significantly stratified overall survival of patients irrespective of metasectomy. Multivariate analyses indicated that Histology(EMT) had a strong prognostic impact independent of staging factors. Statistically, Histology(EMT) had a better prognostic stratification power than T and N stages; however, in cohort 2, the power of M substage was superior. CONCLUSIONS: A histological model to categorise EMT by integrated assessment of dedifferentiation and desmoplastic environment is a potent prognostic index independent of staging factors.

Multidisciplinary management of locally recurrent rectal cancer with carbon ion radiotherapy followed by prophylactic removal of the irradiated bowel: a case report.

BACKGROUND: Locally recurrent rectal cancer (LRRC) involving the upper sacrum is typically incurable, and palliative treatment is the only option for most patients, resulting in a poor prognosis and reduced quality of life. Carbon ion radiotherapy (CIRT) has emerged as a promising modality for treating LRRC. This report presents a case of LRRC with sacral involvement that was managed via multidisciplinary therapy incorporating CIRT. CASE PRESENTATION: A 55-year-old male was diagnosed with an anastomotic recurrence of rectal cancer 15 months after undergoing anterior resection. Computed tomography (CT) suggested that the lesion was at an anastomosis site and broadly adherent to the upper sacrum, and colonoscopy confirmed the diagnosis of LRRC. Histopathological examination of the biopsy specimens revealed adenocarcinoma cells and that lesion was genetically RAS-wild. Induction chemotherapy with mFOLFOX6 and panitumumab was used as the first treatment. The recurrent lesion shrank and no signs of distant metastasis were observed after 11 cycles, although the range of the lesions attached to the sacrum remained unchanged. Therefore, we provided CIRT for this inoperable lesion and prophylactically removed the radiation-exposed bowel including the recurrent lesion, because radiation-induced ulcers can cause bleeding and perforation. Despite the presence of considerable fibrosis in the irradiated region, the operation was successful and the postoperative course had no untoward incidents. He is still recurrence-free 24 months following surgery, despite the lack of adjuvant chemotherapy. This is the first report of CIRT followed by CIRT-irradiated bowel removal for an unresectable anastomosis recurrent lesion. CONCLUSIONS: The clinical course of this case suggests that CIRT could be a potentially effective therapeutic option for LRRC involving the bowel, as long as the prophylactic removal of the irradiated bowel is performed at the optimal time. Further research involving larger sample sizes is warranted to validate the findings and conclusions of this case report.

Evaluation of the seventh edition of the tumour, node, metastasis (TNM) classification for colon cancer in two nationwide registries of the United States and Japan.

AIM: The new TNM classification is currently being implemented. We evaluated the TNM-7 staging system based on the two nationwide colon cancer registries in the United States and Japan to clarify whether this system better stratifies patients' prognoses than the TNM-6 did and to determine whether stratification can be effectively simplified. METHODS: The Surveillance, Epidemiology, and End Results population-based data from 1988 to 2001 for 50139 colon cancer patients and the multi-institutional registry data from the Japanese Society for Cancer of the Colon and Rectum from 1984 to 1994 for 10754 patients were analysed. We devised a modified version of the TNM-7 staging system to allow simpler classification of the TN categories and compared the TNM-6, TNM-7, modified TNM-7, and the Dukes staging system based on survival curves and objective statistical tests such as likelihood ratio χ(2) tests, Akaike's information criterion, and Harrell's c-index. RESULTS: The TNM-7 was superior to the TNM-6 in all objective statistical tests in the United States (c-index; 0.700 vs 0.696, P<0.001) as well as in the Japan data sets (0.732 vs 0.729, P=0.035). The modified TNM-7 is much simpler, but it nevertheless showed similar values to those of the original TNM-7 (c-index; the United States 0.702, Japan 0.733). CONCLUSIONS: The new TNM-7 is complicated but better at stratifying patients than the TNM-6 in the United States and Japan, and could be effectively simplified.

Optimal margins and lymphadenectomy in colonic cancer surgery.

BACKGROUND: A standard management policy has not yet been established with respect to the extent of lymphadenectomy for colonic cancer. METHODS: A total of 914 consecutive patients who underwent potentially curative surgery for T2-T4 colonic cancer were reviewed retrospectively. The number of lymph nodes (LNs) examined and the potential contributions to the staging accuracy of the distinct area were analysed. The survival benefit of dissection was compared for pericolic (local), mesocolic (intermediate) and main arterial trunk (main) LN. RESULTS: Removal of the pericolic LNs within 5 cm of the tumour and intermediate LNs resulted in a mean LN number of 15.9, a sensitivity for overall node positivity of 97.5 per cent, and a survival benefit calculated as a therapeutic value index of 31.4 points. The additional removal of LNs more than 5 cm from the tumour and main LNs did not improve the staging accuracy, while adding only 3.4 points to the survival benefit. CONCLUSION: Current guidelines may encourage needlessly extensive surgery. Clinical trials to establish the optimal extent of lymphadenectomy are warranted.

Prognostic and predictive values of tumour budding in stage IV colorectal cancer.

BACKGROUND: Tumour budding is an important prognostic feature in early-stage colorectal cancer, but its prognostic significance in metastatic disease has not been fully investigated. METHODS: Patients with stage IV disease who had primary colorectal tumour resection without previous chemotherapy or radiotherapy from January 2000 to December 2018 were reviewed retrospectively. Budding was evaluated at the primary site and graded according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) (BD1, low; BD2, intermediate; BD3, high). Patients were categorized by metastatic (M1a, M1b) and resectional (R0/R1, R2/unresected) status. Subgroups were compared for overall (OS) and recurrence-free (RFS) survival in R0/R1 subgroups; R2/unresected patients were evaluated for the rate of tumour progression, based on change in tumour size from baseline. RESULTS: Of 371 patients observed during the study, 362 were analysed. Patients with BD3 had a lower 5-year OS rate than those with BD1 + BD2 (18·4 versus 40·5 per cent; P < 0·001). Survival analyses according to metastatic and resection status also showed that BD3 was associated with shorter OS than BD1 + BD2. In multivariable analysis, BD3 (hazard ratio (HR) 1·51, 95 per cent c.i. 1·11 to 2·10; P = 0·009), T4 status (HR 1·39) and R2/unresected status (HR 3·50) were associated with decreased OS. In the R0/R1 subgroup, the 2-year RFS rate was similar for BD3 and BD1 + BD2 according to metastatic status. There was no significant difference between BD3 and BD1 + BD2 for change in tumour size in the R2/unresected subgroup (P = 0·094). Of 141 patients with initially unresectable metastases who had chemotherapy, 35 achieved conversion from unresectable to resectable status. The conversion rate was significantly higher for BD1 + BD2 than for BD3 (36 versus 18 per cent; P = 0·016). CONCLUSION: Stage IV colorectal cancer with high-grade tumour budding according to ITBCC criteria correlates with poor prognosis.

ANTECEDENTES: La esofaguectomía por cáncer se asocia con un descenso de la calidad de vida relacionada con la salud (health-related quality of life, HRQoL) a largo plazo. El objetivo de este estudio fue evaluar el efecto de las comorbilidades sobre la HRQOL entre pacientes supervivientes de cánceres de esófago o de la unión gastroesofágicas después de 10 años o más. MÉTODOS: Este estudio incluye una cohorte de base poblacional recogida de forma prospectiva que incluía todos los pacientes operados de cáncer de esófago o de la unión gastroesofágica en Suecia en 2001-2005 con seguimiento hasta el 31 de diciembre de 2016. Todos los datos relacionados con las características de los pacientes y del tumor, detalles del tratamiento y HRQoL se recogieron en una base de datos prospectiva. Se utilizaron modelos de regresión multivariable ANCOVA, ajustados por edad, sexo, histología del tumor, estadio, y técnica quirúrgica, para calcular las puntuaciones medias ajustadas con los i.c. del 95% para todas las variables de la HRQoL. RESULTADOS: Un total de 92 (88%) supervivientes respondieron a los cuestionarios. En función del impacto de las comorbilidades en la salud en general, se clasificaron a los pacientes en los grupos de bajo versus alto impacto. Los resultados muestran que los pacientes en el grupo de alto impacto presentaban un descenso clínicamente significativo de la HRQoL y un aumento en el nivel de síntomas, pero las diferencias entre estos dos grupos no fueron estadísticamente significativas. CONCLUSIÓN: A los 10 años de la esofaguectomía por cáncer, las comorbilidades con un alto impacto sobre la salud general siguen contribuyendo en el deterioro de la HRQoL.

Predictive immunohistochemical features for tumour response to chemoradiotherapy in rectal cancer.

BACKGROUND: Reduced expression of cluster of differentiation (CD) 133 and cyclo-oxygenase (COX) 2, and increased density of CD8+ tumour-infiltrating lymphocytes, are associated with a favourable tumour response to preoperative chemoradiotherapy (CRT). This study aimed to evaluate these markers in relation to tumour response after preoperative CRT in two rectal cancer cohorts. METHODS: Patients with low rectal cancer who underwent radical resection and preoperative short-term CRT in 2001-2007 (retrospective cohort) and long-term CRT in 2011-2017 (prospective cohort) were analysed. Pretreatment biopsies were stained immunohistochemically using antibodies to determine CD133 and COX-2 expression, and increased CD8+ density. Outcome measures were tumour regression grade (TRG), tumour downstaging and survival. RESULTS: For 95 patients in the retrospective cohort, the incidence of TRG 3-4 was 67 per cent when two or three immunohistochemistry (IHC) features were present, but only 20 per cent when there were fewer features (P < 0·001). The incidence of tumour downstaging was higher in patients with at least two IHC features (43 versus 22 per cent with fewer features; P = 0·029). The 49 patients in the prospective cohort had similar rates to those in the retrospective cohort (TRG 3-4: 76 per cent for two or more IHC features versus 25 per cent with fewer features, P < 0·001; tumour downstaging: 57 versus 25 per cent respectively, P = 0·022). Local recurrence-free survival rates in patients with more or fewer IHC features were similar in the retrospective and prospective cohort (P = 0·058 and P = 0·387 respectively). CONCLUSION: Assessment of CD133, COX-2 and CD8 could be useful in predicting a good response to preoperative CRT in patients with lower rectal cancer undergoing neoadjuvant therapy. Further studies are needed to validate the results in larger cohorts and investigate a survival benefit.

ANTECEDENTES: La expresión reducida de CD133 and COX-2, y un aumento en la densidad de los linfocitos infiltrantes del tumor CD8+ se han asociado recientemente con una respuesta favorable del tumor a la quimiorradioterapia preoperatoria (preoperative chemoradiotherapy, CRT). Este estudio evaluó estos marcadores respecto a la respuesta del tumor tras CRT preoperatoria en dos cohortes de cáncer colorrectal. MÉTODOS: Se analizaron pacientes con cáncer de recto bajo sometidos a resección radical y CRT preoperatoria de corta duración entre 2001-2007 (cohorte retrospectiva) y CRT de larga duración entre 2011-2017 (cohorte prospectiva). Se realizó tinción inmunohistoquímica (immunohistochemical, IHC) con anticuerpos para CD133, COX-2 y CD8 en las biopsias previas al tratamiento. Las características de interés incluyeron la disminución en las expresiones de CD133 y COX-2, y la densidad aumentada de CD8+. Las variables de interés fueron los grados de regresión tumoral (tumour regression grades, TRG) de acuerdo con Rödel, la reducción del estadio tumoral y las supervivencias. RESULTADOS: La cohorte retrospectiva incluyó 95 pacientes. En este subgrupo, la incidencia de TRGs 3-4 fue del 66,7% en pacientes con dos o tres características de la IHC, mientras que solo fue del 20,0% en pacientes con ninguna o con una característica (P < 0,001). Además, la incidencia de disminución del estadio tumoral fue más alta en pacientes que mostraban al menos dos características IHC (43,3%) que en los controles (21,5%; P = 0,029). En la cohorte prospectiva se incluyeron 49 pacientes y la incidencia de estos hallazgos fue similar (TRG 3-4, 76,2% en ≥ 2 características IHC versus 25,0% en los controles, P < 0,001; disminución del estadio tumoral, 57,1% en ≥ 2 características IHC versus 25,0% en los controles, P = 0,022). La supervivencia libre de recidiva local fue similar en las cohortes retrospectiva y prospectiva, cuando se compararon subgrupos de acuerdo con las características IHC (P = 0,058 y 0,387, respectivamente) CONCLUSIÓN: Este estudio sugiere que la evaluación de CD133, COX-2 y CD8 podría ser útil para la predicción de una buena respuesta a la CRT preoperatoria en pacientes con cáncer de recto bajo sometidos a tratamiento neoadyuvante. Se necesitan estudios adicionales para validar los resultados en amplias cohortes e investigar el beneficio en la supervivencia.

A novel classification of tumour budding in colorectal cancer based on the presence of cytoplasmic pseudo-fragments around budding foci.

AIMS: Tumour budding is an adverse prognostic factor in colorectal cancer (CRC). We have investigated the significance of cytoplasmic fragments occurring in the immediate vicinity of tumour budding foci. METHODS AND RESULTS: Seventy-three CRCs with high-grade budding (> 10 budding foci in a x 20 objective field) were classified according to extent of budding (10-19 versus 20+ foci) and by the presence or absence of cytoplasmic fragments identified by immunostaining for cytokeratin. In serial sections, cytoplasmic fragments were shown to be dendritic cell processes in continuity with budding tumour cells and were renamed pseudo-fragments. Cytoplasmic pseudo-fragments, but not extent of budding, were associated with aberrant expression of beta-catenin (P = 0.045) and laminin-5 gamma2 (P < 0.0001), and with absent peritumoral lymphocytic infiltration (P = 0.0077). Cytoplasmic pseudo-fragments had a stronger association with infiltrating growth pattern (P = 0.0014) than extent of tumour budding (P = 0.014). There was no association between extent of budding and cytoplasmic pseudo-fragments (P = 0.12). CONCLUSIONS: Cytoplasmic pseudo-fragments may be a marker for an activated budding phenotype that is associated with cell motility and increased invasiveness in CRC and is independent of the extent of budding.