Background The American Joint Committee on Cancer (AJCC), which regularly reviews TNM staging systems, established a working party to develop recommendations for colorectal carcinoma. Methods A multidisciplinary consensus conference using published literature developed an arbitrary classification system of prognostic marker value (Category I, IIA, IIB, III, and IV), which forms the framework for this report. Results The working party concluded that several T categories should be subdivided: pTis into intraepithelial carcinoma (pTie) and intramucosal carcinoma (pTim); pT1 into pT1a and pT1b corresponding to the absence or presence of blood or lymphatic vessel invasion, respectively; and pT4 into pT4a and pT4b according to the absence or presence of tumor involving the surface of the specimen, respectively. The working party also recommended that TNM groups be stratified based on the presence or absence of elevated serum levels of carcinoembryonic antigen (CEA) (>/= 5 ng/mL) on preoperative clinical examination. In addition, the working party also concluded that carcinoma of the appendix should be excluded from the colorectal carcinoma staging system because of fundamental differences in natural history. Conclusions The TNM categories and stage groupings for colorectal carcinoma published in the current AJCC manual have clinical and academic value. However, a few categories require subdivision to provide increasing discrimination for individual patients. The serum marker CEA should be added to the staging system, whereas multiple other factors should be recorded as part of good clinical practice. Although many molecular and oncogenic markers show promise to supplement or modify the current staging systems eventually, to the authors' knowledge none have yet been evaluated sufficiently to recommend their inclusion in the TNM system.

American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group.

Mucins are high-molecular weight epithelial glycoproteins with a high content of clustered oligosaccharides O-glycosidically linked to tandem repeat peptides rich in threonine, serine, and proline. There are two structurally and functionally distinct classes of mucins: secreted gel-forming mucins (MUC2, MUC5AC, MUC5B, and MUC6) and transmembrane mucins (MUC1, MUC3A, MUC3B, MUC4, MUC12, MUC17), although the products of some MUC genes do not fit well into either class (MUC7, MUC8, MUC9, MUC13, MUC15, MUC16). MUC1 mucin, as detected immunologically, is increased in expression in colon cancers, which correlates with a worse prognosis. Expression of MUC2 secreted gel-forming mucin is generally decreased in colorectal adenocarcinoma, but preserved in mucinous carcinomas, a distinct subtype of colon cancer associated with microsatellite instability. Another secreted gel-forming mucin, MUC5AC, a product of normal gastric mucosa, is absent from normal colon, but frequently present in colorectal adenomas and colon cancers. The O-glycosidically linked oligosaccharides of mucins can be described in terms of core type, backbone type, and peripheral structures. Colon cancer mucins have differences in both core carbohydrates and in peripheral carbohydrate structures that are being investigated as diagnostic and prognostic markers, and also as targets for cancer vaccines. Colon cancer mucins typically have increases in three core structures: Tn antigen (GalNAcalphaThr/Ser), TF antigen (Galbeta3GalNAc) and sialyl Tn (NeuAcalpha6GalNAc). The type 3 core (GlcNAcbeta3Ga1NAc) predominant in normal colonic mucin is lacking in colon cancer mucins. There are cancer-associated alterations in the peripheral carbohydrates of colonic mucins including a decrease in O-acetyl-sialic acid and a decrease in sulfation. There are, however, cancer-associated increases in sialyl LeX and related structures on mucins and other glycoproteins that can serve as ligands for selectins, increasing the metastatic capacity of colon cancer cells. The endogenous galactoside-binding protein galectin-3, which is expressed at higher levels in colon cancers than normal colon, binds to colon cancer mucin as well as other glycoproteins. Interference of the binding of selectins and galectin-3 to mucin may show therapeutic or preventative promise for colon cancer.

Mucins and mucin binding proteins in colorectal cancer.

Importance Effective treatment options are limited for patients with advanced, metastatic esophageal cancer progressing after 2 or more lines of systemic therapy. Objective To evaluate the efficacy and safety of pembrolizumab for patients with advanced, metastatic esophageal squamous cell carcinoma (ESCC) or advanced, metastatic adenocarcinoma of the esophagus and gastroesophageal junction that progressed after 2 or more lines of systemic therapy. Design, Setting, and Participants This phase 2, open-label, interventional, single-arm study, KEYNOTE-180, enrolled 121 patients from January 12, 2016, to March 21, 2017, from 57 sites in 10 countries. Patients had advanced, metastatic esophageal cancer that progressed after 2 or more lines of therapy and had evaluable tumor samples for biomarkers. Interventions Pembrolizumab, 200 mg, was administered intravenously every 3 weeks until disease progression, unacceptable toxic effects, or study withdrawal, for up to 2 years. Main Outcomes and Measures Primary end point was objective response rate per the Response Evaluation Criteria in Solid Tumors by central imaging review for all patients. Results As of September 18, 2017, of 121 enrolled patients (100 men and 21 women; median age, 65 years [range, 33-87 years]), 18 (14.9%) had undergone 3 or more prior therapies, 63 (52.1%) had ESCC, and 58 (47.9%) had tumors positive for programmed death ligand-1 (PD-L1), defined as a combined positive score of 10 or higher assessed by immunohistochemistry. Median duration of follow-up was 5.8 months (range, 0.2-18.3 months). Objective response rate was 9.9% (95% CI, 5.2%-16.7%) among all patients (12 of 121), and median duration of response was not reached (range, 1.9-14.4 months). Objective response rate was 14.3% (95% CI, 6.7%-25.4%) among patients with ESCC (9 of 63), 5.2% (95% CI, 1.1%-14.4%) among patients with adenocarcinoma (3 of 58), 13.8% (95% CI, 6.1%-25.4%) among patients with PD-L1–positive tumors (8 of 58), and 6.3% (95% CI, 1.8%-15.5%) among patients with PD-L1–negative tumors (4 of 63). Overall, 15 patients (12.4%) had treatment-related grade 3 to 5 adverse events. Only 5 patients (4.1%) discontinued treatment because of adverse events. There was 1 treatment-related death from pneumonitis. Conclusions and Relevance Where effective treatment options are an unmet need, pembrolizumab provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer. Phase 3 studies evaluating pembrolizumab vs standard therapy for patients with esophageal cancer progressing after first-line therapy or in combination with chemotherapy as first-line therapy for patients with locally advanced unresectable or metastatic esophageal cancer are ongoing. Trial Registration ClinicalTrials.gov identifier:NCT02559687

/pdf/efficacy-and-safety-of-pembrolizumab-for-heavily-pretreated-1kzie41n7f.pdf

Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus: The Phase 2 KEYNOTE-180 Study.

Open or laparoscopic colorectal surgery comprises of many different types of procedures for various diseases. Depending upon the operation and modifiable and non-modifiable risk factors the intra- and postoperative morbidity and mortality rate vary. In general, surgical complications can be divided into intraoperative and postoperative complications and usually occur while the patient is still in the hospital. A literature search (1980-2009) was carried out, using MEDLINE, PubMed and the Cochrane library. This review provides an overview how to identify and minimize intra- and postoperative complications. The improvement of different treatment strategies and technical inventions in the recent decade has been enormous. This is mainly attributable to the increase in the laparoscopic approach, which is now well accepted for many procedures. Training of the surgeon, hospital volume and learning curves are becoming increasingly more important to maximize patient safety, surgeon expertise and cost effectiveness. In addition, standardization of perioperative care is essential to minimize postoperative complications. This review summarizes the main perioperative complications of colorectal surgery and influencable and non-influencable risk factors which are important to the general surgeon and the relevant specialist as well. In order to minimize or even avoid complications it is crucial to know these risk factors and strategies to prevent, treat or reduce intra- and postoperative complications.

/pdf/complications-in-colorectal-surgery-risk-factors-and-2l214u7uxs.pdf

Complications in colorectal surgery : risk factors and preventive strategies

Second-line treatment options for advanced head and neck squamous cell carcinoma (HNSCC) are limited. The phase Ib KEYNOTE-012 study evaluated the safety and the efficacy of pembrolizumab for the treatment of HNSCC after long-term follow-up. Multi-centre, non-randomised trial included two HNSCC cohorts (initial and expansion) in which 192 patients were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks (initial cohort; N = 60) or 200 mg every 3 weeks (expansion cohort; N = 132). Co-primary endpoints were safety and overall response rate (ORR; RECIST v1.1; central imaging vendor review). Median follow-up was 9 months (range, 0.2–32). Treatment-related adverse events (AEs) of any grade and grade 3/4 occurred in 123 (64%) and 24 (13%) patients, respectively. No deaths were attributed to treatment-related AEs. ORR was 18% (34/192; 95% CI, 13–24%). Median response duration was not reached (range, 2+ to 30+ months); 85% of responses lasted ≥6 months. Overall survival at 12 months was 38%. Some patients received 2 years of treatment and the responses were ongoing for more than 30 months; the durable anti-tumour activity and tolerable safety profile, observed with long-term follow-up, support the use of pembrolizumab as a treatment for recurrent/metastatic HNSCC.

/pdf/efficacy-and-safety-of-pembrolizumab-in-recurrent-metastatic-3pwwp1vab3.pdf

Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012.

OBJECTIVE To review the results of the analysis and quantification of the influence of medical factors on the morbidity and mortality associated with emergency surgery for colorectal cancer. PATIENTS AND METHODS We analyze retrospectively the data for 51 patients who underwent emergency surgery: 34 (67%) to treat acute obstruction and 17 (33%) for perforation. The median follow-up period was 18.5 months (3 to 62 months). RESULTS The main tumor was located in the right colon in 13 patients (25%), in the left colon in 35 (69%) and in, the rectum in 3 (6%). Primary resection was performed in 94% of the patients: without anastomosis in 35% (18 of 51) and with primary anastomosis in 59% (30 of 51); 6% of the tumors were not resectable. The postoperative morbidity was 41%: 29% (10 of 34) occurring in obstructions and 65% (11 of 17) in perforations. The mortality rate was 14% (9% and 23%, respectively). There were statistically significant associations between mortality and the American Society of Anesthesia grading (p < 0.01) and between both the mortality and morbidity and the score for the acute physiology component of APACHE II (p = 0.01, respectively) and the total APACHE II score (p < 0.01 in both cases). The rate of actuarial disease-free survival was 26% at 36 months. Overall survival was 15% at 62 months. A recurrence rate of 48% (14 of 29) has been recorded. CONCLUSIONS Emergency surgery for colorectal cancer is associated with a high postoperative morbidity and mortality rate, which correlate with the medical status and, particularly, with the acute physiology score of the APACHE II risk stratification system.

Medical factors in the morbidity and mortality associated with emergency colorectal cancer surgery.

OBJECTIVE To analyze the prognostic value of a set of pathological variables after curative resection for large bowel adenocarcinoma and to test a prognostic score derived from factors with independent effect. PATIENTS AND METHODS The study is based on data from 292 consecutive unselected patients (B-C Astler-Coller stages). Histopathological features were evaluated prospectively on the resected primary tumors. Relationship between these factors and risk of recurrence was assessed by a Cox's proportional regression analysis. RESULTS Four variables retained independent prognostic significance: extent of bowel wall invasion, peritumoral lymphocytic infiltration, number of positive nodes and vascular invasion. A prognostic score based on the regression coefficients attained by such variables was developed. This system revealed four prognostic groups. Group I included 14% of patients, with 94% 5-year disease-free survival. These figures were: 35% and 60% in group II; 43% and 46% in group III; and 7% and 24.4% in group IV. Histopathologic score applied to bearers of Astler-Coller B2 tumors permitted the identification of two populations, one characterized by a low risk of relapse and another with high risk (p = 0.002). CONCLUSION A prognostic score based in the evaluation of four histopathologic parameters concerning the tumor phenotype enables the identification of groups of patients at risk of relapse after curative resection for colorectal adenocarcinoma.

Histopathologic prognostic score in colorectal adenocarcinomas.

Objective To assess the clinical and biological significance of histological typing of colorectal carcinomas. Patients and methods The retrospective analysis of 142 consecutive patients who underwent surgical resection of a mucinous (MC; n = 27; 19%) or a nonmucinous (nMC; n = 115; 81%) colorectal adenocarcinoma was carried out. The two groups were compared in terms of the clinical features, p53 gene expression (antiserum CM1), proliferating cell nuclear antigen (PCNA) labeling index, DNA ploidy (by flow cytometry), histopathological features, prognosis and recurrence rate. Results The two types of tumors differed with respect to patient age, location, morphology, pattern of genetic lesions and type of tumor recurrences. Twenty-five percent of the patients with MC and 9% of those with nMC (p = 0.04) were under 50 years of age. The incidences of right MC and left MC were similar, while the majority of the nMC were located on the left side (p = 0.04). The MC were of higher grade and their margins more infiltrative than those of the nMC (p = 0.001 and p = 0.01, respectively), p53 nuclear staining was observed less frequently in the MC than in the nMC (30% vs 55%; p = 0.03). The PCNA labeling index was higher in the nMC (46% vs 21%; p = 0.05). We observed no significant differences with respect to tumor stage, incidence of vascular invasion or prevalence of lymphocytic infiltration. The prognosis was similar in both groups, although their recurrence patterns differed, with a tendency toward locoregional recurrence in the cases of MC. Conclusion These findings suggest that, despite their similar prognoses, these two types of lesions are epidemiologically, phenotypically and genotypically different and, thus, result from distinct carcinogenic pathways.

Clinical, histopathological, cytogenetic and prognostic differences between mucinous and nonmucinous colorectal adenocarcinomas.

PURPOSE The aim of this study was to assess the value of Hughes' pathogenic classification in the prognosis and management of perianal Crohn's disease (CD). PATIENTS AND METHODS This classification differentiates between purely inflammatory lesions and their mechanical or septic complications, and defines the presence of ulceration (U), fistula (F) and stricture (S), which are assigned a score of 0, 1 or 2 according to the severity and associated conditions, proximal intestinal involvement and disease activity (A, P and D). Of a series of 96 patients with CD, 12 underwent 16 procedures involving anesthesia to treat symptomatic anal lesions. Patients presenting with severe pain were explored and treated by surgical drainage or, in cases in which there was no demonstrable sepsis, by gentle dilation or infiltration with steroids. For superficial, non-specific fistulas, conventional fistulotomy was performed, and long-term seton drainage was implanted for complex fistulas. Strictures were treated by gentle dilation. Uncontrolled sepsis or proctocolitis was managed by proximal stoma creation or proctocolectomy. RESULTS The association of cavitating ulcers (U2) and contiguous active rectal involvement (P1) was a contraindication for rectal preservation, making proctectomy or stoma creation the most feasible therapeutic option. The etiology of most, but not all, complex fistulas (F2) was the progressive cavitation of U2, whilst F1 was either of cryptoglandular origin or the result of epithelialized fissures (U1). The treatment was also adjusted to this association, and it was confirmed that most of the severe lesions (F2) and S2) were secondary to U2. CONCLUSIONS Hughes' pathogenic classification: 1) makes it possible to set up an easily stored registry of anal and perianal Crohn's disease; 2) identifies predefined lesions, allowing the individualization of therapeutic procedures and the comparison of results, and 3) provides prognostic information.

The value of Hughes-Cardiff classification in the management of perianal Crohn's disease.

Valor de la clasificacion de hughes-cardiff en el manejo de la enfermedad anorrectal de crohn

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