Role of Intra- and Peritumoral Budding in the Interdisciplinary Management of Rectal Cancer Patients

The presence of tumor budding (TuB) at the invasive front of rectal cancers is a valuable indicator of tumor aggressiveness. Tumor buds, typically identified as single cells or small tumor cell clusters detached from the main tumor body, are characterized by loss of cell adhesion, increased migratory, and invasion potential and have been referred to as malignant stem cells. The adverse clinical outcome of patients with a high-grade TuB phenotype has consistently been demonstrated. TuB is a category IIB prognostic factor; it has yet to be investigated in the prospective setting. The value of TuB in oncological and pathological practice goes beyond its use as a simple histomorphological marker of tumor aggressiveness. In this paper, we outline three situations in which the assessment of TuB may have direct implications on treatment within the multidisciplinary management of patients with rectal cancer: (a) patients with TNM stage II (i.e., T3/T4, N0) disease potentially benefitting from adjuvant therapy, (b) patients with early submucosally invasive (T1, sm1-sm3) carcinomas at a high risk of nodal positivity and (c) the role of intratumoral budding assessed in preoperative biopsies as a marker for lymph node and distant metastasis thus potentially aiding the identification of patients suitable for neoadjuvant therapy.

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Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

10.21203/rs.3.rs-257705/v2 ◽

2021 ◽

Author(s):

Inga-Maria Launonen ◽

Nuppu Lyytikäinen ◽

Julia Casado ◽

Ella Anttila ◽

Angéla Szabó ◽

...

Keyword(s):

Tumor Microenvironment ◽

Single Cell ◽

Single Cells ◽

High Grade ◽

Prognostic Role ◽

Immune Microenvironment ◽

Proteomic Data ◽

Tumor Immune Microenvironment ◽

Cellular Phenotypes

Abstract The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generated spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes (HRwt). We identified a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we found an opposing prognostic role of a proliferative tumor-cell phenotypic subpopulation in the HR-genotypes, which associated with enhanced spatial tumor-immune interactions by the CD8+ and CD4+T-cells in BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the premise to improve immunotherapeutic strategies and patient stratification in HGSC.

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Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

10.21203/rs.3.rs-257705/v1 ◽

2021 ◽

Author(s):

Inga-Maria Launonen ◽

Nuppu Lyytikäinen ◽

Julia Casado ◽

Ella Anttila ◽

Angéla Szabó ◽

...

Keyword(s):

Tumor Microenvironment ◽

Single Cell ◽

Spatial Data ◽

Single Cells ◽

High Grade ◽

Spatial Interactions ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Cellular Phenotypes

Abstract The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis on 112 tumor cores we generated single-cell spatial data for 21 markers in 124,623 single cells from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and 13 tumors without any alterations in HR genes (HRwt). We identified a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we found an opposing prognostic role of a proliferative tumor-cell phenotypic subpopulation in the HR-genotypes, which associated with enhanced spatial interactions in the tumor-immune cellular communities. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the premise to improve immunotherapeutic strategies and patient stratification in HGSC.

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The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.12.2640 ◽

1994 ◽

Vol 12 (12) ◽

pp. 2640-2647 ◽

Cited By ~ 277

Author(s):

P G Johnston ◽

E R Fisher ◽

H E Rockette ◽

B Fisher ◽

N Wolmark ◽

...

Keyword(s):

Rectal Cancer ◽

Thymidylate Synthase ◽

Disease Free Survival ◽

Free Survival ◽

Primary Rectal Cancer ◽

Bowel Project ◽

Rectal Cancers ◽

Prognostic Importance ◽

Disease Free

PURPOSE We assessed the prognostic importance of the level of thymidylate synthase (TS) expression in patients with primary rectal cancer and whether, for Dukes' B and C cancer patients, the benefit of chemotherapy was associated with TS expression. PATIENTS AND METHODS The level of TS expression in the primary rectal cancers of 294 of 801 patients enrolled on protocol R-01 of the National Surgical Adjuvant Breast and Bowel Project (NSABP) was immunohistochemically assessed with the monoclonal antibody TS 106. RESULTS Forty-nine percent of patients whose tumors had low TS levels (n = 91) were disease free at 5 years compared with 27% of patients with high levels of TS (n = 203; P < .01). Moreover, 60% of patients with low TS levels were alive after 5 years compared with 40% of patients with high TS levels (P < .01). The level of TS protein was significantly associated with Dukes' stage (P < .01); patients with a more advanced Dukes' stage had a significantly higher level of TS. The level of TS expression remained prognostic for both disease-free survival (P < .01) and survival (P < .05) independent of Dukes' stage and other pathologic characteristics evaluated. Thirty-eight percent and 54% of patients with high TS levels (n = 71) were disease free and alive, respectively, after 5 years when treated with chemotherapy, compared with 17% and 31%, respectively, of similar patients when treated with surgery alone (n = 64) (P < .01). No difference was noted in disease-free survival (P = .46) or survival (P = .43) in patients with low TS levels. CONCLUSION The expression of TS is an important independent prognosticator of disease-free survival and survival in patients with rectal cancer. Adjuvant fluorouracil (5-FU)-based chemotherapy demonstrated significant improvement in disease-free and overall survival for patients with high TS levels. Prospective studies measuring TS levels will be needed to understand further the role of TS as a prognosticator of survival and chemotherapeutic benefit.

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Multidisciplinary management of early rectal cancer – The role of surgical local excision in current and future clinical practice

Surgical Oncology ◽

10.1016/j.suronc.2021.101687 ◽

2021 ◽

pp. 101687

Author(s):

Lisanne J.H. Smits ◽

Annabel S. van Lieshout ◽

Alexander A.J. Grüter ◽

Karin Horsthuis ◽

Jurriaan B. Tuynman

Keyword(s):

Rectal Cancer ◽

Clinical Practice ◽

Local Excision ◽

Multidisciplinary Management ◽

Early Rectal Cancer ◽

Future Clinical Practice

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Lymph node metastasis in patients with early pathologic T-stage rectal cancers: What does local excision leave behind?

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.537 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 537-537

Author(s):

Maria C. Russell ◽

Yj Chiang ◽

Barry W. Feig ◽

George J. Chang ◽

Miguel A. Rodriguez-Bigas ◽

...

Keyword(s):

Rectal Cancer ◽

Local Excision ◽

Nodal Metastasis ◽

Nodal Metastases ◽

Nodal Disease ◽

Factors Associated ◽

T Stage ◽

Signet Ring ◽

Rectal Cancers

537 Background: As the interest in local excision (LE) for rectal cancer increases, the risk of residual nodal disease and local failure must be considered. We utilized a nationwide cancer registry to establish incidence and predictors of nodal metastasis in early pathologic T stage rectal cancers. Methods: Early path T stage rectal cancers (1998-2007) were identified from the National Cancer Database (NCDB), including pT1-2 tumors in patients not receiving neoadjuvant therapy (NT), or ypT0-2 tumors after NT. Proctectomy was performed in 22,416 (74.7%) and LE in 7,589 (25.3%) without NT. After NT, 7,481 (96.1%) underwent proctectomy and 300 (3.9%) LE. Nodal metastasis rates were calculated from proctectomy patients. Factors associated with nodal metastases were analyzed among those with ≥12 nodes assessed. Results: The incidence of nodal positivity was 12.5% for pT1 and 26.8% for pT2 tumors. Among those with ≥12 nodes examined, these rates increased to 16.9% and 28.6% respectively. After receiving NT, nodal positivity rates were 8.6% for ypT0, 12.9% for ypT1, and 21.4% for ypT2 tumors. These rates increased to 13.5%, 16.9% and 28.3% respectively when ≥12 nodes examined. In multivariate analysis, female sex, age <50, higher T stage, higher histologic grade, mucinous/signet-ring features, and more than 12 nodes examined were all significantly associated with nodal metastases in both groups ( Table ). Conclusions: Among rectal cancers of early path T stages, the risk of nodal metastasis increases with higher path T stage and with greater number of nodes examined, regardless of receipt of NT. These findings must be carefully deliberated, given the current interests in expanding the role of LE based on pathologic T stage of rectal cancer. [Table: see text]

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