Characterising the prognostic potential of HLA-DR during colorectal cancer development.

HLA-DR, an MHC class II molecule that mediates antigen presentation, is a favourable prognostic indicator in colorectal cancer (CRC). However, the dynamics and location of HLA-DR expression during CRC development are unclear. We aimed to define HLA-DR expression by immunohistochemistry in colorectal epithelium and stromal tissue at different stages of cancer development, assessing non-neoplastic colorectal adenocarcinoma-adjacent tissue, adenomas and carcinoma tissues, and to associate HLA-DR levels with clinical outcomes. Patients with higher than median HLA-DR expression survived at least twice as long as patients with lower expression. This association was significant for HLA-DR staining in the colorectal carcinoma epithelium (n = 152, p = 0.011, HR 1.9, 95% CI 1.15-3.15) and adjacent non-neoplastic epithelium (n = 152, p < 0.001, HR 2.7, 95% CI 1.59-4.66), but not stroma. In stage II cases, however, the prognostic value of HLA-DR expression was significant only in adjacent non-neoplastic tissues, for both epithelium (n = 63, p = 0.015, HR 3.6, 95% CI 1.279-10.25) and stroma (n = 63, p = 0.018, HR 5.07, 95% CI 1.32-19.49). HLA-DR was lower in carcinoma tissue compared to matched adenomas (n = 35), in epithelium (p < 0.01) and stroma (p < 0.001). HLA-DR was further reduced in late-stage carcinoma (n = 101) compared to early stage (n = 105), in epithelium (p < 0.001) and stroma (p < 0.01). HLA-DR expression was lower (p < 0.05) in the adjacent non-neoplastic epithelium of patients with cancer recurrence. We demonstrate a progressive loss of HLA-DR in epithelial and stromal tissue compartments during CRC development and show prognostic ability in carcinoma-adjacent non-neoplastic tissues, highlighting the importance of this molecule in the anti-cancer immune response. These findings may have wider implications for immunotherapeutic interventions.

KH-Type Splicing Regulatory Protein Controls Colorectal Cancer Cell Growth and Modulates the Tumor Microenvironment.

KH-type splicing regulatory protein (KHSRP) is a multifunctional nucleic acid binding protein implicated in key aspects of cancer cell biology: inflammation and cell-fate determination. However, the role KHSRP plays in colorectal cancer (CRC) tumorigenesis remains largely unknown. Using a combination of in silico analysis of large data sets, ex vivo analysis of protein expression in patients, and mechanistic studies using in vitro models of CRC, we investigated the oncogenic role of KHSRP. We demonstrated KHSRP expression in the epithelial and stromal compartments of both primary and metastatic tumors. Elevated expression was found in tumor versus matched normal tissue, and these findings were validated in larger independent cohorts in silico. KHSRP expression was a prognostic indicator of worse overall survival (hazard ratio, 3.74; 95% CI, 1.43-22.97; P = 0.0138). Mechanistic data in CRC cell line models supported a role of KHSRP in driving epithelial cell proliferation in both a primary and metastatic setting, through control of the G1/S transition. In addition, KHSRP promoted a proangiogenic extracellular environment by regulating the secretion of oncogenic proteins involved in diverse cellular processes, such as migration and response to cellular stress. Our study provides novel mechanistic insight into the tumor-promoting effects of KHSRP in CRC.

Impact of timing of trastuzumab initiation on long-term outcome of patients with early-stage HER2-positive breast cancer: the "one thousand HER2 patients" project.

BACKGROUND: The optimal timing of (neo)adjuvant trastuzumab initiation with respect to chemotherapy and surgery remains undefined. METHODS: Retrospective analysis of a large institutional database of HER2-positive patients who received anti-HER2 therapy. We included all Stage I to III patients treated with trastuzumab with a minimum follow up of 3 years. The date of first breast biopsy was recorded as initial diagnosis. RESULTS: A total of 506 patients [adjuvant: 386 (76%)-neo-adjuvant: 120 (24%)] were included. The median time-to-first-trastuzumab (TFT) from diagnosis was 12 weeks (range 1.9-122.3). Median follow-up is 73.3 months (range 1.4-176.3). TFT was significantly shorter in the neo-adjuvant than in the adjuvant cohort (median: 4.4 vs. 14 weeks, p < 0.00001). Despite the neo-adjuvant cohort having significantly more node-positive patients (75 vs. 53%, p < 0.0001), DFS rate (neo-adjuvant: 12.5 vs. adjuvant: 18%, p = 0.094) was numerically superior in neo-adjuvant patients. A TFT ≤ 12 weeks was associated with significantly superior DFS and OS over TFT > 12 weeks. Early concomitant regimens were associated with superior DFS over delayed-concomitant and sequential regimens. CONCLUSIONS: Initiating trastuzumab more than 12 weeks from diagnosis has a negative impact on clinical outcome. Neo-adjuvant anti-HER2 therapy could be the optimal strategy to treat early stage HER2-positive breast cancer.

Multivisceral Resection for Locally Invasive Colorectal Liver Metastases: Outcomes of a Matched Cohort Analysis.

Local invasion of adjacent viscera by colorectal liver metastases (CRLM) is no longer considered an absolute contraindication to curative hepatic resection. A growing number of observational analyses have illustrated the feasibility of such resections; however, the evidence base is at best heterogeneous with a lack of evidence comparing similar patient groups. We aimed to evaluate the outcomes of hepatectomy for CRLM when combined with other viscera and compare to a matched cohort of isolated hepatic resections. METHODS: From 2005 to 2015, 523 patients underwent hepatic resection for CRLM at our institution, 19 of whom underwent hepatectomy with extrahepatic resection. A 3: 1 matched cohort analysis was performed between those who underwent isolated hepatectomy (control group) and those who underwent hepatectomy with extrahepatic resection (combined group). Clinicopathological data were reviewed along with 30-day postoperative morbidity and mortality. Furthermore, overall survival for the multivisceral cohort was compared to all other isolated hepatectomies over the same time period. RESULTS: Nineteen patients underwent liver resection accompanied by either/or diaphragmatic resection (n = 13), major vein resection and reconstruction (n = 5), and visceral resection (n = 3). Maximum tumor size was significantly larger in the combined group (60.58 vs. 15.34 mm p < 0.0001). Postoperative morbidity was similar in both groups (p = 0.41). Following multivisceral resection, 1-, 3- and 5-year survival rates were 75, 56.6, and 25.7% respectively. Overall survival showed no significant difference between combined and control groups (p = 0.78). Similarly, when compared to the total cohort of isolated liver resections (n = 504), no significant difference in overall mortality was noted. CONCLUSION: In patients presenting with concomitant CRLM and extrahepatic extension where R0 margins can be achieved, this present study supports the rationale to proceed to -surgery with comparable morbidity and mortality rates to -isolated hepatectomy.

Predicting response to vascular endothelial growth factor inhibitor and chemotherapy in metastatic colorectal cancer.

BACKGROUND: Bevacizumab improves progression free survival (PFS) and overall survival (OS) in metastatic colorectal cancer patients however currently there are no biomarkers that predict response to this treatment. The aim of this study was to assess if differential protein expression can differentiate patients who respond to chemotherapy and bevacizumab, and to assess if select proteins correlate with patient survival. METHODS: Pre-treatment serum from patients with metastatic colorectal cancer (mCRC) treated with chemotherapy and bevacizumab were divided into responders and nonresponders based on their progression free survival (PFS). Serum samples underwent immunoaffinity depletion and protein expression was analysed using two-dimensional difference gel electrophoresis (2D-DIGE), followed by LC-MS/MS for protein identification. Validation on selected proteins was performed on serum and tissue samples from a larger cohort of patients using ELISA and immunohistochemistry, respectively (n = 68 and n = 95, respectively). RESULTS: 68 proteins were identified following LC-MS/MS analysis to be differentially expressed between the groups. Three proteins (apolipoprotein E (APOE), angiotensinogen (AGT) and vitamin D binding protein (DBP)) were selected for validation studies. Increasing APOE expression in the stroma was associated with shorter progression free survival (PFS) (p = 0.0001) and overall survival (OS) (p = 0.01), DBP expression (stroma) was associated with shorter OS (p = 0.037). Increasing APOE expression in the epithelium was associated with a longer PFS and OS, and AGT epithelial expression was associated with a longer PFS (all p < .05). Increasing serum AGT concentration was associated with shorter OS (p = 0.009). CONCLUSIONS: APOE, DBP and AGT identified were associated with survival outcomes in mCRC patients treated with chemotherapy and bevacizumab.

Neoadjuvant chemoradiotherapy followed by liver transplantation for unresectable cholangiocarcinoma: a single-centre national experience.

BACKGROUND: Unresectable cholangiocarcinoma (CCA) has a dismal prognosis. Initial studies of orthotopic liver transplantation (OLT) alone for CCA yielded disappointing outcomes. The Mayo Clinic demonstrated long-term survival using neoadjuvant chemoradiotherapy followed by OLT in selected patients with unresectable CCA. This study reports the Irish National Liver Transplant Programme experience of neoadjuvant therapy and OLT for unresectable CCA. MATERIALS AND METHODS: Twenty-seven patients with CCA were selected for neoadjuvant chemoradiotherapy in a single centre from October 2004 to September 2011. Patients were given brachytherapy, external beam radiotherapy and 5-fluorouracil (5-Fu), followed by liver transplantation if progression free (20 patients). RESULTS: Twenty progression-free patients after neoadjuvant therapy underwent OLT. Hospital mortality was 20%. Of the 16 patients who left hospital, survival rates were 94% and 61% at 1 and 4 years. Seven patients developed recurrent disease and died at intervals of 10-58 months after OLT, whereas 9 are disease free with a median follow-up of 37 months (18-76). Predictors of disease recurrence were a tumour in explant specimen and high CA 19.9 levels. DISCUSSION: In selected patients with unresectable CCA, long-term survival can be achieved using neoadjuvant chemoradiotherapy and OLT although short-term mortality is high. Prospective international registries may aid patient selection and refinement of neoadjuvant regimens.

Pilot study of the implementation of G8 screening tool, Cognitive screening assessment and Chemotherapy Toxicity assessment in older adults with cancer in a Tertiary University Hospital in Ireland.

BACKGROUND: Comprehensive geriatric assessment (CGA) is recommended by international guidelines prior to initiation of systemic anti-cancer treatment (SACT). In practice, CGA is limited by time constraints, lack of resources and expert interpretation. AIMS: The primary objective of this pilot study was to establish the prevalence of frailty (assessed by G8), cognitive impairment (assessed by Mini-Cog), and risk of chemotherapy toxicity (assessed by CARG Chemo-Toxicity Calculator) among patients (pts) ≥65 years commencing SACT. We selected these three screening tools due to the ease of conducting them in a busy outpatient setting. In addition, they have been validated to predict frailty and risk of toxicity from SACT among older adults with cancer. METHODS: Eligible participants were identified from medical oncology clinics. Assessments were conducted in an outpatient setting by treating physicians. Pt records were reviewed to gather demographic and cancer details. Statistical analyses were conducted using SPSS statistical software. RESULTS: Sixty-three participants were enrolled. The mean age of participants was 73yrs (range=65-88). Thirty-three (52.4%) were female and 30 (47.6%) were male. The majority (n=38, 60.3%) had metastatic cancer. The mean G8 score was 11.9 (range=6-19). Eighty-three percent had a G8 score ≤14. Mini-Cog was positive in 13 pts (21%). The mean CARG score was 7.5 (range=0-16), and 80% had a risk of at least 50% grade ≥3 toxicity. Of these, 48 (76.2%) received chemotherapy and 15 (23.8%) received non-cytotoxic SACT. In multi-variate analyses, age, cancer type, treatment type, and disease stage did not impact G8, Mini-Cog, or CARG scores. CONCLUSIONS: Our study has several limitations but suggests that the majority of older adults with cancer would qualify for formal CGA assessment. The risk of high-grade toxicity from SACT is substantial in this cohort. Chronological age was not found to negatively impact pts' frailty, cognition, or risk of toxicity.

A prospective analysis of patient outcome following treatment of T3 rectal cancer with neo-adjuvant chemoradiotherapy and transanal excision.

BACKGROUND: Local excision is an alternative to anterior or abdomino-perineal resection in patients with early rectal cancer. In more advanced disease, neo-adjuvant therapy (CRXT) can result in significant disease regression such that local excision may be considered. The primary aim was to assess oncological outcome in patients with T3 rectal cancer treated with CRXT and local excision due to unsuitability for or aversion to anterior resection and stoma. The secondary aim was to examine oncological outcomes in patients treated in a similar way in the published literature. METHODS: Between July 2006 and July 2009, patients with rectal cancer staged T3, N0/N1, M0 who were deemed unfit for or who refused anterior resection were offered long-course CRXT. Patients were restaged 8 weeks following completion. If there was a good response (regression grade 2 or 3 clinically and radiologically), full thickness transanal excision was performed. All patients were followed regularly (monthly CT abdomen/pelvis and annual endoscopy) to assess for recurrence of disease. A literature search of PubMed was performed to identify all prospective data available of T3 rectal cancers managed with CRXT and local excision. RESULTS: Ten patients were treated over 3 years. Six patients had complete pathological response, while four patients had a partial response. The resection margins following local excision were clear in all. There was no local recurrence (median follow-up 24 months, range 9-42 months). CONCLUSION: Neo-adjuvant chemoradiotherapy and local excision is an option in patients unfit for or averse to major surgical resection if there is a good response to CRXT.

Growing Teratoma Syndrome of the Liver in a 22-Year-Old Female.

Following a presentation with abdominal pain, a 22-year-old female was diagnosed with a massive primary liver immature teratoma with evidence of omental and pelvic metastases. Despite chemotherapy, the teratoma continued to rapidly increase in size. Significant treatment-associated myelosuppression was challenging as the patient did not want to receive any blood products (religious objections). The only feasible approach was surgical resection. Surgical resection of the primary tumor and abdominal metastases was undertaken despite unappealing perioperative risk with histological specimens demonstrating only mature teratoma. We report the first case of a liver teratoma suggestive of growing teratoma syndrome treated with myelosuppressive chemotherapy and major hepatectomy without the use of any blood products.

Tumour vasculature immaturity, oxidative damage and systemic inflammation stratify survival of colorectal cancer patients on bevacizumab treatment.

Despite treatment of patients with metastatic colorectal cancer (mCRC) with bevacizumab plus chemotherapy, response rates are modest and there are no biomarkers available that will predict response. The aim of this study was to assess if markers associated with three interconnected cancer-associated biological processes, specifically angiogenesis, inflammation and oxidative damage, could stratify the survival outcome of this cohort. Levels of angiogenesis, inflammation and oxidative damage markers were assessed in pre-bevacizumab resected tumour and serum samples of mCRC patients by dual immunofluorescence, immunohistochemistry and ELISA. This study identified that specific markers of angiogenesis, inflammation and oxidative damage stratify survival of patients on this anti-angiogenic treatment. Biomarkers of immature tumour vasculature (% IMM, p=0.026, n=80), high levels of oxidative damage in the tumour epithelium (intensity of 8-oxo-dG in nuclear and cytoplasmic compartments, p=0.042 and 0.038 respectively, n=75) and lower systemic pro-inflammatory cytokines (IL6 and IL8, p=0.053 and 0.049 respectively, n=61) significantly stratify with median overall survival (OS). In summary, screening for a panel of biomarkers for high levels of immature tumour vasculature, high levels of oxidative DNA damage and low levels of systemic pro-inflammatory cytokines may be beneficial in predicting enhanced survival outcome following bevacizumab treatment for mCRC.

Mutually exclusive promoter hypermethylation patterns of hMLH1 and O6-methylguanine DNA methyltransferase in colorectal cancer.

Hypermethylation of CpG islands in gene promoter regions is an important mechanism of gene inactivation in cancer. Many cellular pathways, including DNA repair, are inactivated by this type of epigenetic lesion, resulting in proposed mutator phenotypes. Promoter hypermethylation of hMLH1 has been implicated in a subset of colorectal cancers that show microsatellite instability (MSI). Transcriptional silencing of O6-methylguanine DNA methyltransferase (MGMT) has also been described in a variety of neoplasms and has been associated with a consequent mutational spectrum. We investigated the relationship between hMLH1 promoter hypermethylation and MGMT promoter hypermethylation in 110 colorectal cancers using methylation-specific polymerase chain reaction. Expression of hMLH1 and MGMT was assessed by immunohistochemistry. MSI testing was performed using the National Cancer Institute consensus panel of five microsatellite markers. Promoter hypermethylation of hMLH1 was detected in 12% of tumors. This was significantly associated with the MSI-high phenotype (P < 0.01) and loss of hMLH1 expression (P < 0.01). Methylation of the MGMT promoter was detected in 43% of tumors, which were mostly microsatellite stable or MSI-low (P = 0.041) and showed loss of MGMT expression (P < 0.01). We demonstrated an inverse relationship between hMLH1 promoter hypermethylation and MGMT promoter hypermethylation (P = 0.041), suggesting that a number of distinct hypermethylation-associated pathways may exist in colorectal cancer.

Multiple metastases to skeletal muscle from carcinoma of the esophagus detected by FDG PET-CT imaging.

A 67-year-old woman was treated with neoadjuvant chemotherapy, esophagectomy, and subsequent radiotherapy for T3N1 poorly differentiated adenocarcinoma of the esophagus. Five months after surgery, a routine follow-up CT demonstrated a 1.2-cm soft tissue mass in the posterior mediastinum suspicious for local recurrence. An FDG-PET/CT study confirmed tumor in the posterior mediastinum and also showed focal areas of increased tracer uptake within several muscles. Skeletal muscle is one of the most unusual sites of metastatic disease, although it is probable that the more frequent use of FDG-PET imaging will lead to an increase in the detection of such lesions.

Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer deaths. Molecularly targeted therapies (e.g. bevacizumab) have improved survival rates but drug resistance ultimately develops and newer therapies are required. We identified quininib as a small molecule drug with anti-angiogenic activity using in vitro, ex vivo and in vivo screening models. Quininib (2-[(E)-2-(Quinolin-2-yl) vinyl] phenol), is a small molecule drug (molecular weight 283.75 g/mol), which significantly inhibited blood vessel development in zebrafish embryos (p < 0.001). In vitro, quininib reduced endothelial tubule formation (p < 0.001), cell migration was unaffected by quininib and cell survival was reduced by quininib (p < 0.001). Using ex vivo human CRC explants, quininib significantly reduced the secretions of IL-6, IL-8, VEGF, ENA-78, GRO-α, TNF, IL-1ß and MCP-1 ex vivo (all values p < 0.01). Quininib is well tolerated in mice when administered at 50 mg/kg intraperitoneally every 3 days and significantly reduced tumour growth of HT-29-luc2 CRC tumour xenografts compared to vehicle control. In addition, quininib reduced the signal from a αvß3 integrin fluorescence probe in tumours 10 days after treatment initiation, indicative of angiogenic inhibition. Furthermore, quininib reduced the expression of angiogenic genes in xenografted tumours. Collectively, these findings support further development of quininib as a novel therapeutic agent for CRC.

Targeting EGFR in metastatic colorectal cancer beyond the limitations of KRAS status: alternative biomarkers and therapeutic strategies.

Patients with metastatic colorectal cancer have a very poor prognosis. Incorporation of targeted molecular therapies, such as the anti-EGFR receptor monoclonal antibodies cetuximab and panitumumab, into treatment regimens has improved outcomes for patients with wild-type RAS tumors. Yet, response rates remain low and overall survival times are short. Increased understanding of oncogenic signaling pathways within the tumor, and how these are regulated by the inflammatory tumor microenvironment, is a priority to facilitate the development of biomarkers to better guide the use of existing therapies and to develop new ones. Here, we review recent preclinical and clinical progress in the development of biomarkers for predicting response to anti-EGFR therapy in metastatic colorectal cancer.

Visceral Adiposity is a Risk Factor for Poor Prognosis in Colorectal Cancer Patients Receiving Adjuvant Chemotherapy.

BACKGROUND: Studies utilizing body mass index (BMI) have failed to show a consistent relationship between obesity and survival following treatment for colorectal cancer (CRC). Computerized tomography (CT) offers a reliable alternative approach to quantify body adiposity. We hypothesized that visceral obesity may negatively impact survival in CRC patients. AIMS AND METHODS: A retrospective review of CRC patients who received adjuvant chemotherapy at a single center during the period 2006-2009 identified from a prospectively maintained database. Visceral adiposity was determined by measuring visceral fat area (VFA) on preoperative staging CT. All patients were followed up to study completion or death. RESULTS: Sixty-two CRC patients with a mean age of 63.2 years received adjuvant chemotherapy and had imaging available for analysis. Thirty-five patients (56.5 %) had node positive disease. Thirty-one patients (50 %) were classified viscerally obese based on staging CT. 85.4 % of the patients completed adjuvant chemotherapy and visceral obesity was not associated with increased toxicity or failure to complete treatment. After a median follow-up of 65.2 months, patients with visceral obesity had a significantly lower overall survival (OS) (54.8 % vs 87.1 %, p = 0.004) and disease-free survival (DFS) (48.4 vs 77.4 %, p = 0.007) compared with patients without visceral obesity. There was no relationship between BMI and survival. Multivariate analysis using Cox proportional hazards model showed that visceral obesity was independently associated with reduced OS (Hazard ratio = 7.0; 95 % CI 2.0-24.6; p = 0.002). CONCLUSION: This study shows that visceral obesity increases the likelihood of a poor prognosis in CRC patients receiving adjuvant chemotherapy thus underlying the value of lifestyle interventions to minimize visceral obesity in this patient cohort.

Initial impact of a systematic multidisciplinary approach on the management of patients with gastroenteropancreatic neuroendocrine tumor.

According to the international guidelines, a multidisciplinary approach is currently advised for the optimal care of patients with a gastroenteropancreatic neuroendocrine tumor (GEP NET). In our institution (tertiary care center), a systematic multidisciplinary approach was established in May 2007. In this study, we have aimed to assess the initial impact of establishing a systematic multidisciplinary approach to the management of GEP NET patients. We have collected and compared the biochemical, imaging, and pathological data and the therapeutic strategies in GEP NET patients diagnosed, treated, or followed-up from January 1993 to April 2007 versus GEP NET patients attending our institution after the multidisciplinary approach starting, from May 2007 to October 2008. Data of 91 patients before and 42 patients after the establishment of the multidisciplinary approach (total: 133 consecutive GEP NET patients) have been finally collected and analyzed. Before the establishment of the multidisciplinary approach, a lack of consistency in the biochemical, imaging, and pathological findings before treatment initiation as well as during follow-up of GEP NET patients was identified. These inconsistencies have been reduced by the systematic multidisciplinary approach. In addition, the therapeutic management of GEP NET patients has been altered by the multidisciplinary approach and became more consistent with recommended guidelines. We think that a systematic multidisciplinary approach significantly impacts on GEP NET patient care and should be established in all centers dealing with these tumors.

Inhibition of dendritic cell maturation by the tumor microenvironment correlates with the survival of colorectal cancer patients following bevacizumab treatment.

Development of bevacizumab has improved survival in colorectal cancer, however, currently there are no biomarkers that predict response to bevacizumab and it is unknown how it influences the immune system in colorectal cancer patients. Dendritic cells are important for the induction of an antitumor immune response; however tumors are capable of disabling dendritic cells and escaping immune surveillance. The aim of this study was to assess the numbers of CD11c+ cells infiltrating tumor tissue and to examine the effects of tumor conditioned media (TCM) and bevacizumab conditioned media (BCM) on dendritic cell maturation and correlate our findings with patient survival. colorectal cancer explant tissues were cultured with or without bevacizumab, to generate BCM and TCM, which were used to treat dendritic cells. CD80, CD86, CD83, CD54, HLA-DR, and CD1d expression was measured by flow cytometry. Interleukin (IL)-10 and IL-12p70 were measured by ELISA. The Cox proportional hazards model was used to associate survival with dendritic cell inhibition. TCM and BCM inhibited lipopolysaccharide (LPS)-induced dendritic cell maturation and IL-12p70 secretion (P < 0.0001), while increasing IL-10 secretion (P = 0.0033 and 0.0220, respectively). Inhibition of LPS-induced CD1d (P = 0.021, HR = 1.096) and CD83 (P = 0.017, HR = 1.083) by TCM and inhibition of CD1d (P = 0.017, HR = 1.067), CD83 (P = 0.032, HR = 1.035), and IL-12p70 (P = 0.037, HR = 1.036) by BCM was associated with poor survival in colorectal cancer patients. CD11c expression was elevated in tumor tissue compared with normal tissue (P < 0.001), but this did not correlate with survival. In conclusion, TCM and BCM inhibit dendritic cells, and this inhibition correlates with survival of colorectal cancer patients receiving bevacizumab.

Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer.

BACKGROUND: Tumor budding along the advancing front of colorectal adenocarcinoma is an early event in the metastatic process. A reproducible, prognostic budding scoring system based on outcomes in early stage colorectal cancer has not been established. DESIGN: One hundred twenty-eight T3N0M0 colorectal carcinoma patients with known outcome were identified. Tumor budding was defined as isolated tumor cells or clusters of <5 cells at the invasive tumor front. Tumor bud counts were generated in 5 regions at 200x by 2 pathologists (conventional bud count method). The median bud count per case was used to divide cases into low (median=0) and high budding (median > or =1) groups. Forty cases were reevaluated to assess reproducibility using the conventional and a novel rapid bud count method. RESULTS: Fifty-seven (45%) carcinomas had high and 71 (55%) had low budding scores. High budding was associated with an infiltrative growth pattern (P<0.0001) and lymphovascular invasion (P=0.005). Five-year cancer-specific survival was significantly poorer in high compared with low budding groups: 63% versus 91%, respectively, P<0.0001. Multivariate analysis demonstrated tumor budding to be independently prognostic (hazard ratio=4.76, P<0.001). Interobserver agreement was at least equivalent comparing the conventional to the rapid bud count methods: 87.5% agreement (kappa=0.75) versus 92.5% agreement (kappa=0.85), respectively. CONCLUSIONS: Tumor budding is a strong, reproducible, and independent prognostic marker of outcome that is easily assessed on hematoxylin and eosin slides. This may be useful for identifying the subset of T3N0M0 patients at high risk of recurrence who may benefit from adjuvant therapy.

Common critical pathways in embryogenesis and cancer.

Cancer may arise because the developmental programs that create the dramatic alterations in form and structure in embryonic development are potentially corrupted. The cells in our bodies retain memories of these processes and cancer can occur later in life if imperfections occur in the fidelity of these pathways. This article is particularly interested in the phenomenon of epithelial to mesenchymal transition, which occurs in embryogenesis. Also reviewed are the small molecules and pathways that are involved both in homeostasis in adult epithelium and embryogenesis in utero. There are five such pathways in particular selected for review in this article: the Wnt pathway, Hedgehog, Notch, PAR and Bone morphogenetic peptide/TGF beta. These are usually conserved throughout mammalian evolution. Though they have been arbitrarily separated in this article they are not exclusive from one another. Their pathologically altered expression is found especially frequently in childhood tumours where they may recapitulate their developmental role, and in tumours that resemble primitive precursor cells. These pathways are important for selecting cell fates, cellular rearrangements, cytological context and morphologic design in embryology as well as participating in epithelial function in adults.