Pathological determinants of outcome following resection of locally advanced or locally recurrent rectal cancer.

INTRODUCTION: Pathological factors that influence and predict survival following pelvic exenteration (PE) for locally advanced (LARC) or locally recurrent rectal cancer (LRRC), especially LRRC, remain poorly understood. A clear resection margin has previously been demonstrated to be of most significance. MATERIALS AND METHODS: A retrospective cohort study was performed for all patients undergoing a curative PE for LARC or LRRC between 2008 and 2021 at a tertiary referral UK specialist colorectal hospital. Cox regression analysis was planned to identify pathological factors associated with overall (OS), disease free (DFS) and local recurrence free survival (LRFS). RESULTS: 388 patients were included in the analysis with 256 resections for LARC and 132 for LRRC. 62.4% of patients were male with a median age of 59 years (IQR 49-67). 247 (64%) partial pelvic exenterations and 141 (36%) total pelvic exenterations performed. Overall R0 rate 86.6%. Poorly differentiated tumours and a positive resection margin independently influenced OS, DFS and LRFS on multivariate analysis in LARC. On multivariate analysis venous invasion negatively influenced DFS and poorly differentiated lesions negatively influenced LRFS in LRRC. CONCLUSIONS: A positive resection margin and poorly differentiated tumours are significant negative prognostic markers for survival and recurrence in LARC. The results of this study support the need to look for alternative prognostic markers beyond that in the existing standard reporting dataset for rectal cancers. With increasing R0 rates, novel prognostic pathological markers are required to help guide treatment and surveillance for patients with LRRC.

A systematic review of the pathological determinants of outcome following resection by pelvic exenteration of locally advanced and locally recurrent rectal cancer.

BACKGROUND: Despite multimodal therapy 5-15% of patients who undergo resection for advanced rectal cancer (LARC) will develop local recurrence. Management of locally recurrent rectal cancer (LRRC) presents a significant therapeutic challenge and even with modern exenterative surgery, 5-year survival rates are poor at 25-50%. High rates of local and systemic recurrence in this cohort are reflective of the likely biological aggressiveness of these tumour types. This review aims to appraise the current literature identifying pathological factors associated with survival and tumour recurrence in patients undergoing exenterative surgery. METHODS: A systematic review was carried out searching MEDLINE, EMBASE and COCHRANE Trials database for all studies assessing pathological factors influencing survival following pelvic exenteration for LARC or LRRC from 2010 to July 2021 following PRISMA guidelines. Risk of bias was assessed using QUIPS tool. RESULTS: Nine cohort studies met inclusion criteria, reporting outcomes for 2864 patients. Meta-analysis was not possible due to significant heterogeneity of reported outcomes. Resection margin status and nodal disease were the most commonly reported factors. A positive resection margin was demonstrated to be a negative prognostic marker in six studies. Involved lymph nodes and lymphovascular invasion also appear to be negative prognostic markers with tumour stage to be of lesser importance. No studies assessed other adverse tumour features that would not otherwise be included in a standard histopathology report. CONCLUSION: Pathological resection margin status is widely demonstrated to influence disease free and overall survival following pelvic exenteration for rectal cancer. With increasing R0 rates, other adverse tumour features must be explored to help elucidate differences in survival and potentially guide tailored oncological treatment.

CXCL8 expression is associated with advanced stage, right sidedness, and distinct histological features of colorectal cancer.

CXCL8 is an inflammatory chemokine elevated in the colorectal cancer (CRC) tumour microenvironment. CXCR2, the major receptor for CXCL8, is predominantly expressed by neutrophils. In the cancer setting, CXCL8 plays important roles in neutrophil chemotaxis, facilitating angiogenesis, invasion, and metastasis. This study aimed to assess the spatial distribution of CXCL8 mRNA expression in CRC specimens, explore associations with clinical characteristics, and investigate the underlying biology of aberrant CXCL8 levels. CXCR2 expression was also assessed in a second cohort of unique CRC primary tumours and synchronously resected matched liver metastases. A previously constructed tissue microarray consisting of a cohort of stage I-IV CRC patients undergoing surgical resection with curative intent (n = 438) was probed for CXCL8 via RNAscope®. Analysis was performed using HALO® digital pathology software to quantify expression in the tumour and stromal compartments. Scores were assessed for association with clinical characteristics. Mutational analyses were performed on a subset of these patients to determine genomic differences in patients with high CXCL8 expression. A second cohort of stage IV CRC patients with primary and matched metastatic liver tumours was stained via immunohistochemistry for CXCR2, and scores were assessed for clinical significance. CXCL8 expression within the stromal compartment was associated with reduced cancer-specific survival in the first cohort (p = 0.035), and this relationship was potentiated in right-sided colon cancer cases (p = 0.009). High CXCL8 within the stroma was associated with driving a more stromal-rich phenotype and the presence of metastases. When stromal CXCL8 scores were combined with tumour-infiltrating macrophage counts or systemic neutrophil counts, patients classified as high for both markers had significantly poorer prognosis. CXCR2+ immune cell infiltration was associated with increased stromal invasion in liver metastases (p = 0.037). These data indicate a role for CXCL8 in driving unfavourable tumour histological features and promoting metastases. This study suggests that inhibiting CXCL8/CXCR2 should be investigated in patients with right-sided colonic disease and stroma-rich tumours.

Relationship between immune checkpoint proteins, tumour microenvironment characteristics, and prognosis in primary operable colorectal cancer.

The tumour microenvironment is an important factor for colorectal cancer prognosis, affecting the patient's immune response. Immune checkpoints, which regulate the immune functions of lymphocytes, may provide prognostic power. This study aimed to investigate the prognostic value of the immune checkpoints TIM-3, LAG-3 and PD-1 in patients with stage I-III colorectal cancer. Immunohistochemistry was employed to detect TIM-3, LAG-3, PD-1 and PD-L1 in 773 patients with stage I-III colorectal cancer. Immune checkpoint protein expression was assessed in tumour cells using the weighted histoscore, and in immune cells within the stroma using point counting. Scores were analysed for associations with survival and clinical factors. High tumoural LAG-3 (hazard ratio [HR] 1.45 95% confidence interval [CI] 1.00-2.09, p = 0.049) and PD-1 (HR 1.34 95% CI 1.00-1.78, p = 0.047) associated with poor survival, whereas high TIM-3 (HR 0.60 95% CI 0.42-0.84, p = 0.003), LAG-3 (HR 0.58 95% CI 0.40-0.87, p = 0.006) and PD-1 (HR 0.65 95% CI 0.49-0.86, p = 0.002) on immune cells within the stroma associated with improved survival, while PD-L1 in the tumour (p = 0.487) or the immune cells within the stroma (p = 0.298) was not associated with survival. Furthermore, immune cell LAG-3 was independently associated with survival (p = 0.017). Checkpoint expression scores on stromal immune cells were combined into a Combined Immune Checkpoint Stromal Score (CICSS), where CICSS 3 denoted all high, CICSS 2 denoted any two high, and CICSS 1 denoted other combinations. CICSS 3 was associated with improved patient survival (HR 0.57 95% CI 0.42-0.78, p = 0.001). The results suggest that individual and combined high expression of TIM-3, LAG-3, and PD-1 on stromal immune cells are associated with better colorectal cancer prognosis, suggesting there is added value to investigating multiple immune checkpoints simultaneously.

Multidisciplinary management of anal intraepithelial neoplasia and rate of progression to cancer: A retrospective cohort study.

PURPOSE: To describe the regional burden of AIN and rate of progression to cancer in patients managed in specialist and non-specialist clinic settings. METHODS: Patients with a histopathological diagnosis of AIN between 1994 and 2018 were retrospectively identified. Clinicopathological characteristics including high-risk status (chronic immunosuppressant use or HIV positive), number and type of biopsy (punch/excision) and histopathological findings were recorded. The relationship between clinicopathological characteristics and progression to cancer was assessed using logistic regression. RESULTS: Of 250 patients identified, 207 were eligible for inclusion: 144 from the specialist and 63 from the non-specialist clinic. Patients in the specialist clinic were younger (<40 years 31% vs 19%, p = 0.007), more likely to be male (34% vs 16%, p = 0.008) and HIV positive (15% vs 2%, p = 0.012). Patients in the non-specialist clinic were less likely to have AIN3 on initial pathology (68% vs 79%, p = 0.074) and were more often followed up for less than 36 months (46% vs 28%, p = 0.134). The rate of progression to cancer was 17% in the whole cohort (20% vs 10%, p = 0.061). On multivariate analysis, increasing age (OR 3.02, 95%CI 1.58-5.78, p < 0.001), high risk status (OR 3.53, 95% CI 1.43-8.74, p = 0.006) and increasing number of excisions (OR 4.88, 95%CI 2.15-11.07, p < 0.001) were related to progression to cancer. CONCLUSION: The specialist clinic provides a structured approach to the follow up of high-risk status patients with AIN. Frequent monitoring with specialist assessments including high resolution anoscopy in a higher volume clinic are required due to the increased risk of progression to anal cancer.

Histological phenotypic subtypes predict recurrence risk and response to adjuvant chemotherapy in patients with stage III colorectal cancer.

Histological 'phenotypic subtypes' that classify patients into four groups (immune, canonical, latent and stromal) have previously been demonstrated to stratify survival in a stage I-III colorectal cancer (CRC) pilot cohort. However, clinical utility has not yet been validated. Therefore, this study assessed prognostic value of these subtypes in additional patient cohorts along with associations with risk of recurrence and response to chemotherapy. Two independent stage I-III CRC patient cohorts (internal and external cohort) were utilised to investigate phenotypic subtypes. The primary endpoint was disease-free survival (DFS) and the secondary endpoint was recurrence risk (RR). Stage II-III patients, from the SCOT adjuvant chemotherapy trial, were utilised to further validate prognostic value and for exploratory analysis assessing associations with adjuvant chemotherapy. In an 893-patient internal cohort, phenotypic subtype independently associated with DFS (p = 0.025) and this was attenuated in stage III patients (p = 0.020). Phenotypic subtype also independently associated with RR (p < 0.001) in these patients. In a 146-patient external cohort, phenotypic subtype independently stratified patients by DFS (p = 0.028), validating their prognostic value. In 1343 SCOT trial patients, the effect of treatment type significantly depended on phenotypic subtype (pinteraction = 0.011). Phenotypic subtype independently associated with DFS in stage III patients receiving FOLFOX (p = 0.028). Furthermore, the immune subtype significantly associated with better response to FOLFOX compared to CAPOX adjuvant chemotherapy in stage III patients (p = 0.013). In conclusion, histological phenotypic subtypes are an effective prognostic classification in patients with stage III CRC that associates with risk of recurrence and response to FOLFOX adjuvant chemotherapy.

Preoperative, biopsy-based assessment of the tumour microenvironment in patients with primary operable colorectal cancer.

The tumour microenvironment (TME) is recognised as an important prognostic characteristic and therapeutic target in patients with colorectal cancer (CRC). However, assessment generally utilises surgically resected specimens, precluding neoadjuvant targeting. The present study investigated the feasibility of intra-epithelial CD3+ T-lymphocyte density and tumour stroma percentage (TSP) assessment using preoperative colonoscopic biopsies from 115 patients who had undergone resection of stages I-III CRC, examining the relationship between biopsy and surgically resected specimen-based assessment, and the relationship with cancer-specific survival (CSS). High biopsy CD3+ density was associated with high CD3+ density in the invasive margin, cancer stroma and intra-epithelial compartments of surgically resected specimens (area under the curve > 0.62, p < 0.05 for all) and with high Immunoscore. High biopsy TSP predicted high TSP in resected specimens (p = 0.001). Intra-class correlation coefficient for both measures was >0.7 (p < 0.001), indicating excellent concordance between individuals. Biopsy CD3+ density (hazard ratio [HR] 0.23, p = 0.002) and TSP (HR 2.23, p = 0.029) were independently associated with CSS; this was comparable to the prognostic value of full section assessment (HR 0.21, p = 0.004, and HR 2.25, p = 0.033 respectively). These results suggest that assessment of the TME is comparable in biopsy and surgically resected specimens from patients with CRC, and biopsy-based assessment could allow for stratification prior to surgery or commencement of therapy targeting the TME.

Possible dose dependent effect of perioperative dexamethasone and laparoscopic surgery on the postoperative systemic inflammatory response and complications following surgery for colon cancer.

BACKGROUND: Perioperative dexamethasone is associated with attenuation of the postoperative systemic inflammatory response and fewer postoperative complications following elective surgery for colorectal cancer. This study examined the impact of different doses of dexamethasone, given to reduce postoperative nausea and vomiting (PONV) after elective colonic resection for cancer, on the postoperative Glasgow Prognostic Score (poGPS) and morbidity. METHODS: Patients from a single centre were included if they underwent potentially curative resection of colonic cancer from 2008 to 2017 (n = 480). Patients received no dexamethasone (209, 44%), or either 4 mg (166, 35%), or 8 mg (105, 21%), intravenously during anaesthesia, at the discretion of the anaesthetist. The postoperative Glasgow Prognostic Score (poGPS) on day 3 and 4, and complication rate at discharge were recorded. RESULTS: When patients were grouped by surgical approach (open or laparoscopic) and dexamethasone dose (0 mg, 4 mg or 8 mg), there was a statistically significant linear trend toward a lower postoperative systemic inflammatory response (day 3 poGPS) with the use of minimally invasive surgery and higher doses of dexamethasone (p < 0.001). Furthermore, this combination of laparoscopic surgery and higher doses of dexamethasone was significantly associated with a lower proportion of postoperative complications (p < 0.001). At multivariate Cox regression, dexamethasone was not significantly associated with either improved or poorer cancer specific or overall survival. CONCLUSIONS: Higher doses of perioperative dexamethasone are associated with greater reduction in postoperative systemic inflammation and complications following surgery for colonic cancer without negative impact on survival.

Quantitative data on red cell measures of iron status and their relation to the magnitude of the systemic inflammatory response and survival in patients with colorectal cancer.

BACKGROUND: Inflammation is recognised to be associated with perturbation of serum measures of iron status. However, the impact of colorectal cancer associated host inflammation on red cell measures of iron status has not been previously quantified. METHODS: Patients undergoing elective surgery with curative intent, for colorectal cancer, at a single centre between 2008 and 2017 were included (n = 824). Blood samples taken for C-reactive protein (CRP), albumin, and full blood count (FBC) allowed patients to be grouped by modified Glasgow Prognostic Score (mGPS), and anaemia subtype (haemoglobin (Hb) M < 130 mg/L and F < 120 mg/L, with microcytic anaemia being mean corpuscular volume (MCV) < 80 f/L, and normocytic anaemia with MCV 80-100 f/L). Relationships between these groupings and red cell measures iron status including Hb, MCV, mean corpuscular haemoglobin (MCH) and red cell distribution width (RDW) were examined. RESULTS: The combination of increasing T stage and increasing mGPS was associated with lower Hb, lower MCV, lower MCH, higher RDW, and higher prevalence of both microcytic and normocytic anaemia (all p < 0.001). The combination of CRP >10 mg/L and albumin <35  g/L was associated with lower Hb, lower MCV, lower MCH, higher RDW, and higher prevalence of both microcytic and normocytic anaemia (all p < 0.010). At multivariate Cox regression only Hb remained significantly associated with cancer specific (HR 0.98, 95% CI 0.97-0.99, p < 0.001), and overall survival (HR 0.98, 95% CI 0.97-0.99, p = 0.001). CONCLUSIONS: The presence of a host systemic inflammatory response to colorectal cancer was associated with significant perturbation of red cell measure of iron status.