Ann M. Hanly

Multicenter evaluation of rectal cancer reimaging post neoadjuvant (MERRION) therapy.

Objective:The aim of this study was to evaluate the utility of reimaging rectal cancer post-CRT (chemoradiotherapy) with magnetic resonance (MR) imaging of the pelvis for local staging and computed tomography of thorax, abdomen, and pelvis (CT TAP) to identify distant metastases. Background:The success of neoadjuvant CRT for locally advanced rectal cancer has changed an already complex management algorithm. There is no consensus whether patients should be restaged before surgery. Methods:Data from 5 institutions with prospectively maintained databases including patients who received neoadjuvant CRT for locally advanced rectal cancer were acquired. Only patients who had been staged pre- and post-CRT with MR imaging and CT TAP were included. MR findings were correlated with histopathological stage using weighted &kgr; (kappa) statistics to test agreement, where a &kgr; value of less than 0.5 was deemed unacceptable. Results:A total of 285 patients fulfilled the criteria for the study; 84% had American Joint Committee for Cancer stage 3 disease pre-CRT, and the remainder had stage 2 disease. Fourteen patients did not proceed to surgery post-CRT—2 were observed as “complete responders,” and the remainder either had unresectable disease or were unfit for surgery. MR imaging could not predict T stage (&kgr; = 0.212) or nodal involvement (&kgr; = 0.336). Most pertinently, MR imaging was unable to detect a complete pathological response (&kgr; = 0.021), nor could it discriminate T4 disease (&kgr; = 0.445). CT TAP restaging altered management in 6.7% of patients, who had metastatic disease. Conclusions:MR reimaging using standard protocols is of limited value in determining surgical approaches; a better modality of local restaging is required.

Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy

Tumor budding is an increasingly important prognostic feature for pathologists to recognize. The aim of this study was to correlate intra-tumoral budding in pre-treatment rectal cancer biopsies with pathological response to neoadjuvant chemoradiotherapy and with long-term outcome. Data from a prospectively maintained database were acquired from patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy. Pre-treatment rectal biopsies were retrospectively reviewed for evidence of intra-tumoral budding. Multivariate logistic regression was used to identify factors contributing to cancer-specific death, expressed as hazard ratios with 95% confidence intervals. Of the 185 patients with locally advanced rectal cancer, 89 patients met the eligibility criteria, of whom 18 (20%) exhibited budding in a pre-treatment tumor biopsy. Intra-tumoral budding predicted a poor pathological response to neoadjuvant chemoradiotherapy (higher ypT stage, P=0.032; lymph node involvement, P=0.018; lymphovascular invasion, P=0.004; and residual poorly differentiated tumors, P=0.005). No patient with intra-tumoral budding exhibited a tumor regression grade 1 or complete pathological response, providing a 100% specificity and positive predictive value for non-response to neoadjuvant chemoradiotherapy. Intra-tumoral budding was associated with a lower disease-free 5-year survival rate (33 vs 78%, P<0.001), cancer-specific 5-year survival rate (61 vs 87%, P=0.021) and predicted cancer-specific death (hazard ratio 3.51, 95% confidence interval 1.03–11.93, P=0.040). Intra-tumoral budding at diagnosis of rectal cancer identifies those who will poorly respond to neoadjuvant chemoradiotherapy and those with a poor prognosis.

Review Article: Loss of the Calcium-Sensing Receptor in Colonic Epithelium is a Key Event in the Pathogenesis of Colon Cancer

The calcium-sensing receptor (CaSR) is expressed abundantly in normal colonic epithelium and lost in colon cancer, but its exact role on a molecular level and within the carcinogenesis pathway is yet to be described. Epidemiologic studies show that inadequate dietary calcium predisposes to colon cancer; this may be due to the ability of calcium to bind and upregulate the CaSR. Loss of CaSR expression does not seem to be an early event in carcinogenesis; indeed it is associated with late stage, poorly differentiated, chemo-resistant tumors. Induction of CaSR expression in neoplastic colonocytes arrests tumor progression and deems tumors more sensitive to chemotherapy; hence CaSR may be an important target in colon cancer treatment. The CaSR has a complex role in colon cancer; however, more investigation is required on a molecular level to clarify its exact function in carcinogenesis. This review describes the mechanisms by which the CaSR is currently implicated in colon cancer and identifies areas where further study is needed.

Organ preservation with local excision or active surveillance following chemoradiotherapy for rectal cancer.

Background:Organ preservation has been proposed as an alternative to radical surgery for rectal cancer to reduce morbidity and mortality, and to improve functional outcome.Methods:Locally advanced non-metastatic rectal cancers were identified from a prospective database. Patients staged ⩾T3 or any stage N+ were referred for neoadjuvant chemoradiotherapy (CRT) (50–54 Gy and 5-fluorouracil), and were reassessed 6–8 weeks post treatment. An active surveillance programme (‘watch and wait’) was offered to patients who were found to have a complete endoluminal response. Transanal excision was performed in patients who were found to have an objective clinical response and in whom a residual ulcer measured ⩽3 cm. Patients were followed up clinically, endoscopically and radiologically to assess for local recurrence or disease progression.Results:Of 785 patients with rectal cancer between 2005 and 2015, 362 had non-metastatic locally advanced tumours treated with neoadjuvant CRT. Sixty out of three hundred and sixty-two (16.5%) patients were treated with organ-preserving strategies – 10 with ‘watch and wait’ and 50 by transanal excision. Fifteen patients were referred for salvage total mesorectal excision post local excision owing to adverse pathological findings. There was no significant difference in overall survival (85.6% vs 93.3%, P=0.414) or disease-free survival rate (78.3% vs 80%, P=0.846) when the outcomes of radical surgery were compared with organ preservation. Tumour regrowth occurred in 4 out of 45 (8.9%) patients who had organ preservation.Conclusions:Organ preservation for locally advanced rectal cancer is feasible for selected patients who achieve an objective endoluminal response to neoadjuvant CRT. Transanal excision defines the pathological response and refines decision-making.

Adenocarcinoma of the rectum in patients under age 40 is increasing: impact of signet-ring cell histology.

BACKGROUND: Overall, the incidence of colorectal cancer appears to be stable or diminishing. However, based on our practice pattern, we observed that the incidence of rectal cancer in patients under 40 is increasing and may be associated with a prominence of signet-ring cell histology. OBJECTIVE: The aim of this study was to verify the rising trend in rectal cancer in patients under 40 and describe the histology prominent in that cohort. DESIGN: This is a retrospective cohort study. SETTING AND PATIENTS: We performed a retrospective cohort study of all patients diagnosed with rectal adenocarcinoma from 1980 to 2010 using the Surveillance, Epidemiology, and End Results cancer registry. MAIN OUTCOME MEASURES: Rectal cancer incidence, histology, and associated staging characteristics were the primary outcomes measured. RESULTS: Although the incidence of rectal cancer for all ages remained stable from 1980 to 2010, we observed an annual percent change of +3.6% in the incidence of rectal cancer in patients under 40. The prevalence of signet cell histology in patients under 40 was significantly greater than in patients over 40 (3% vs 0.87%, p < 0.01). A multivariate regression analysis revealed an adjusted odds ratio of 3.6 (95% CI, 2.6–5.1) for signet cell histology in rectal adenocarcinoma under age 40. Signet cell histology was also significantly associated with a more advanced stage at presentation, poorly differentiated tumor grade, and worse prognosis compared with mucinous and nonmucinous rectal adenocarcinoma. LIMITATIONS: The study was limited by its retrospective nature and the information available in the Surveillance, Epidemiology, and End Results database. CONCLUSIONS: Despite a stable incidence of rectal cancer for all ages, the incidence in patients under 40 has quadrupled since 1980, and cancers in this group are 3.6 times more likely to have signet cell histology. Given the worse outcomes associated with signet cell histology, these data highlight a need for thorough evaluation of young patients with rectal symptoms.

Torsion of monofilament and polyfilament sutures under tension decreases suture strength and increases risk of suture fracture.

BACKGROUND A continuous running suture is the preferential method for abdominal closure. In this technique the suture is secured with an initial knot and successive tissue bites are taken. At each tissue bite, the needle is rotated through the tissue; in doing so, the suture can twist around the knot which acts as an anchor. OBJECTIVE To determine the effect of axial torsional forces on sutures used in abdominal closure. METHODS The effect of axial twisting on polydioxanone (PDS*II), polyglactin (Vicryl), polypropylene (Prolene) and nylon (Ethilon) sutures was investigated using a uniaxial testing device. RESULTS The maximum tensile force withstood for untwisted sutures was determined: polydioxanone failed at a tensile force of 116.4±0.84 N, polyglactin failed at 113.9±2.4 N, polypropylene failed at 71.1±1.5 N and nylon failed at 61.8±0.5 N. Twisting decreased the maximum tensile force of all sutures; one complete twist per 10 mm (i.e., 15 twists) decreased the tensile strength of polydioxanone by 21%, polyglactin by 23%, polypropylene by 16% and nylon by 13%, p<0.001. Excessive twisting caused a nonlinear decrease in suture strength, with one twist per 75 mm (i.e., 20 twists) of polydioxanone decreasing strength by 39%, P<0.001. CONCLUSION The effect of excessive twisting on the mechanical properties of sutures is a previously unrecognised phenomenon. Surgeons should be aware that this can result in a decrease in suture strength and reduce the elasticity of the material, and therefore need to adapt their practice to reduce the torsional force placed on sutures.

Prophylactic colectomy for hyperplastic polyposis.

BackgroundHyperplastic polyposis (HP) is important to recognise as it increases the risk of adenomata which may develop dysplastic change or frank adenocarcinoma. We present the case of a 58-year-old woman with HP.CaseFollowing a diagnosis of HP in this patient, it was noted that the number of polyps were progressively increasing over time, becoming pancolic and extending into the rectum. Genetic testing for a familial polypotic syndrome was negative. Histological analysis demonstrated that the majority of polyps were hyperplastic, but there were also serrated and tubular adenomata with foci of low-grade dysplasia. Whilst there was no evidence of frank malignancy or high-grade dysplasia, following a risk–benefit discussion the patient underwent a laparoscopic total colectomy with an ileal pouch formation.ConclusionThis case highlights the complexity in the management of HP and that even in the absence of confirmed invasive disease, patients may elect to undergo prophylactic colonic resection.

Blind J limb syndrome: Recurrent enterocutaneous fistulae from an ileal pouch

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Tumor Budding and PDC Grade are Stage Independent Predictors of Clinical Outcome in Mismatch Repair Deficient Colorectal Cancer

Mismatch repair deficient (dMMR) colorectal cancer (CRC) despite its association with poor histologic grade often has improved prognosis compared with MMR proficient CRC. Tumor budding and poorly differentiated clusters (PDCs) may predict metastatic potential of colorectal adenocarcinoma (CRC). In addition, their assessment may be more reproducible than the evaluation of other histopathologic parameters. Therefore, we wished to determine their potential as prognostic indicators in a cohort of dMMR CRC patients relative to histologic grade. We investigated the predictive value of conventional WHO grade, budding, PDC grade and other histopathologic parameters on the presence of lymph node metastasis (LNM) and clinical outcome in 238 dMMR CRCs. MMR status was determined by immunohistochemistry for the mismatch repair proteins hMLH1, hMSH2, hMSH6, and hPMS2. Tumor budding and PDCs were highly correlated (r=0.701; P<0.000). Both budding and PDC grade were associated with WHO grade, perineural invasion, lympho-vascular invasion, and extramural vascular invasion, and the presence of LNM in dMMR CRC (P<0.009). Independent predictors of LNM were PDC grade (odds ratio, 4.12; 95% confidence interval [CI], 1.69-10.04; P=0.011) and EMVI (odds ratio, 3.81; 95% CI, 1.56-9.19; P<0.000). Only pTstage (hazard ratio [HR], 4.11; 95% CI, 1.48-11.36; P=0.007) and tumor budding (HR, 2.99; 95% CI, 1.72-5.19; P<0.000) were independently associated with worse disease-free survival (DFS). If tumor budding was excluded from the model, PDC grade became significant for DFS (HR, 2.34; 95% CI, 1.34-4.09; P=0.003). WHO Grade does not independently correlate with clinical outcome in dMMR CRC. PDC grade and extramural vascular invasion are independent predictors of LNM. Tumor budding and pTstage are the best predictors of DFS. If tumor budding cannot be assessed, PDC grade may be used as a prognostic surrogate.

Lymph node ratio does not provide additional prognostic information compared with the N1/N2 classification in stage III colon cancer.

The ratio of positive nodes to total nodes, the lymph node ratio (LNR), is a proposed alternative to the current N1/N2 classification of nodal disease. The true clinical benefit of adopting the LNR, however, has not been definitively demonstrated. This study compared the LNR with the current N1/N2 classification of Stage III colon cancer.