Sidedness is not a prognostic factor in an unselected cohort of patients with colon cancer but prognosis for caecal carcinoma is worse - A multivariate analysis of a large single institution database.

PURPOSE: Sidedness has emerged as a prognostic factor for metastatic colorectal cancer treated with modern systemic therapies. This study investigates whether it is also relevant for an unselected patient cohort including all stages. METHODS: All consecutive patients admitted with colon cancer between 1995 and 2018 were retrieved from an institution-held database. Patients were divided into two cohorts. The first cohort included patients without distant metastases who were able to undergo curative resection. The second cohort presented with distant metastases (stage IV). Potentially prognostic factors were subjected to multivariate Cox Regression analysis. RESULTS: Overall, 1,606 patients met the inclusion and exclusion criteria. An R0-resection was achieved in 1,222 patients without distant metastases. Five-year cause-specific survival rate was 89.3% for this group. There was no difference between right- and left-sided cancers (88.2% vs. 90.1%, p = 0.220). However, prognosis of caecal carcinoma was significantly worse than that of all other sites combined (83.5% vs. 90.2%, p = 0.007). In multivariate analysis, pT-category, pN-category, grading, vascular invasion, emergency operation, adjuvant chemotherapy, and caecal carcinoma remained as independent prognostic factors. In the 384 patients with stage IV-disease, 3-year overall survival for right- vs. left-sided cancers differed only in univariate analysis (17.7% vs. 28.6%, p = 0.013). CONCLUSION: In non-metastatic colon cancer, location in the caecum is an independent prognostic factor. In unselected patients with stage IV colon cancer, sidedness was not found to be a prognostic factor. Differentiation into right- and left-sided tumors may be simplistic, and further studies on the biological behavior of different colonic sites are warranted.

Beyond Total Mesorectal Excision (TME)-Results of MRI-Guided Multivisceral Resections in T4 Rectal Carcinoma and Local Recurrence.

Rectal cancer invading adjacent organs (T4) and locally recurrent rectal cancer (LRRC) pose a special challenge for surgical resection. We investigate the diagnostic performance of MRI and the results that can be achieved with MRI-guided surgery. All consecutive patients who underwent MRI-based multivisceral resection for T4 rectal adenocarcinoma or LRRC between 2005 and 2019 were included. Pelvic MRI findings were reviewed according to a seven-compartment staging system and correlated with histopathology. Outcomes were investigated by comparing T4 tumors and LRRC with respect to cause-specific survival in uni- and multivariate analysis. We identified 48 patients with T4 tumors and 28 patients with LRRC. Overall, 529 compartments were assessed with an accuracy of 81.7%, a sensitivity of 88.6%, and a specificity of 79.2%. Understaging was as low as 3.0%, whereas overstaging was 15.3%. The median number of resected compartments was 3 (interquartile range 3-4) for T4 tumors and 4 (interquartile range 3-5) for LRRC (p = 0.017). In 93.8% of patients with T4 tumors, a histopathologically complete (R0(local)-) resection could be achieved compared to 57.1% in LRRC (p < 0.001). Five-year overall survival for patients with T4 tumors was 53.3% vs. 32.1% for LRRC (p = 0.085). R0-resection and M0-category emerged as independent prognostic factors, whereas the number of resected compartments was not associated with prognosis in multivariate analysis. MRI predicts compartment involvement with high accuracy and especially avoids understaging. Surgery based on MRI yields excellent loco-regional results for T4 tumors and good results for LRRC. The number of resected compartments is not independently associated with prognosis, but R0-resection remains the crucial surgical factor.

Significant decrease of the pathological stage I rectal carcinoma in the era of neoadjuvant therapy-A matter of concern.

BACKGROUND: Neoadjuvant treatment (nTx) for rectal cancer is commonly reserved for UICC stages II/III. Patients with stage I tumours (T1-2N0M0) are not candidates for nTx. The accuracy of treatment allocation depends on the precision of clinical staging, which is liable to understaging and overstaging. The study aimed at exploring changes in the proportion of stage pI patients with the introduction of nTx over a 26-year period. MATERIALS AND METHODS: All consecutive patients with histologically proven rectal cancer excluding carcinoma in situ were retrieved from a prospective database of our colorectal unit. Time periods were defined as per the use of nTx: baseline phase 1994-1997; implementation phase 1998-2005 and guideline phase 2006-2019. Trends over time regarding proportion of applied nTx and stage pI tumours were investigated. RESULTS: Overall, 1468 patients met the inclusion criteria. There were no major differences in patients' characteristics, especially proportion of synchronous metastases (stage IV) over time. nTx was applied to 1.2% of patients without metastases in the baseline phase, to 29.6% in the implementation phase, and to 59.6% in the guideline phase (p < 0.001). Corresponding proportions for patients with stage pI were 31.0%, 26.3% and 14.2%, respectively (p < 0.001). CONCLUSION: With a stable proportion of stage IV carcinomas indicating no major changes in the patient cohorts, we could document a significant decrease of stage pI patients with increasing use of nTx. This trend clearly signals overtreatment caused by clinical T- and N-staging. More precise criteria are needed to better select patients with rectal cancer for nTx.

Outcome for stage II and III rectal and colon cancer equally good after treatment improvement over three decades.

PURPOSE: This study aimed to investigate the outcome for stage II and III rectal cancer patients compared to stage II and III colonic cancer patients with regard to 5-year cause-specific survival (CSS), overall survival, and local and combined recurrence rates over time. METHODS: This prospective cohort study identified 3,355 consecutive patients with adenocarcinoma of the colon or rectum and treated in our colorectal unit between 1981 and 2011, for investigation. The study was restricted to International Union Against Cancer (UICC) stages II and III. Postoperative mortality and histological incomplete resection were excluded, which left 995 patients with colonic cancer and 726 patients with rectal cancer for further analysis. RESULTS: Five-year CSS rates improved for colonic cancer from 65.0% for patients treated between 1981 and 1986 to 88.1% for patients treated between 2007 and 2011. For rectal cancer patients, the respective 5-year CSS rates improved from 53.4% in the first observation period to 89.8% in the second one. The local recurrence rate for rectal cancer dropped from 34.2% in the years 1981-1986 to 2.1% in the years 2007-2011. In the last decade of observation, prognosis for rectal cancer was equal to that for colon cancer (CSS 88.6 vs. 86.7%, p = 0.409). CONCLUSION: Survival of patients with colon and rectal cancer has continued to improve over the last three decades. After major changes in treatment strategy including introduction of total mesorectal excision and neoadjuvant (radio)chemotherapy, prognosis for stage II and III rectal cancer is at least as good as for stage II and III colonic cancer.

Prognostic value of tumor response to neoadjuvant therapy in rectal carcinoma.

BACKGROUND: Neoadjuvant treatment in the multimodal therapy concept of rectal carcinoma has considerable effects on prognosis appraisal. OBJECTIVE: This study aimed to evaluate the tumor response specified as an improvement by at least one stage defined in terms of the International Union Against Cancer stages as a prognostic factor. DESIGN: This investigation was designed as a prospective cohort study. SETTING: This study was performed at a community-based hospital with a specialized colorectal unit. PATIENTS: One hundred seventy-four patients with locally advanced rectal carcinoma, treated in the Dresden-Friedrichstadt hospital from 1997 to 2009, who received long-term preoperative chemoradiotherapy and underwent curative resection, were included in this study. MAIN OUTCOME MEASURES: The main outcome measures were cause-specific and disease-free survival with respect to T and N category, International Union Against Cancer stage, venous and lymphatic invasions, grading, CEA level, complete pathologic response, tumor regression grading, International Union Against Cancer stage shift, T, N, and CEA shift, types of neoadjuvant therapy, adjuvant therapy, interval between completion of neoadjuvant chemoradiotherapy and surgery, and number of extracted lymph nodes in resected specimens. Univariate and multivariate analyses were performed. RESULTS: Median follow-up was 45 months. One hundred twenty-one patients (69.5%) showed a response to the treatment, whereas 53 (30.5%) did not. Five-year cause-specific and disease-free survival for responders (n = 121) vs nonresponders (n = 53) were 92.6% and 73.7% vs 84.9% and 47.9%. In the univariate analysis, ypN category, venous and lymphatic invasion, tumor regression grading, International Union Against Cancer stage shift, and T and N shift were significantly predictive for cause-specific and disease-free survival. Furthermore, ypUICC stage, ypT category, grading, and complete pathologic response had an impact on disease-free survival. In the multivariate analysis, only the International Union Against Cancer stage shift kept its independent explanatory power for cause-specific P = .012, HR 3.10 (95% CI 1.28-7.51) and disease-free survival P < .001, HR 3.85 (95% CI 1.98-7.51). LIMITATIONS: The determination of International Union Against Cancer stage shift depends on the pretreatment staging modalities. CONCLUSION: Our investigation demonstrates that the response of tumor to neoadjuvant therapy is an independent prognostic factor in patients with rectal carcinoma.

Short-term outcome of extra-levator abdominoperineal excision for rectal cancer.

BACKGROUND: Extra-levator abdominoperineal excision (ELAPE) has been introduced to avoid oncologic problems encountered with conventional abdominoperineal excision (APE) such as high rates of inadvertent bowel perforation and of positive circumferential resection margin. We compare our short-term results of this new approach with a historic patient cohort. PATIENTS AND METHODS: From 1997 until 2010, we performed 46 consecutive conventional APE and 28 ELAPE after neoadjuvant therapy with a macroscopically complete resection in the true pelvis. Patient data was prospectively collected in our colorectal tumor database. Patient and tumor characteristics were compared as were the rates of inadvertent bowel perforation, of circumferential margin involvement, and of wound abscesses. RESULTS: The rates of inadvertent bowel perforation, of circumferential margin involvement, and of wound abscesses were 15.2% vs. 0 (p = 0.04), 4.9% vs. 0 (p = 0.511), and 17.4% vs. 10.7% (p = 0.518), respectively, in the conventional APE vs. ELAPE group. CONCLUSION: With a significant reduction of the bowel perforation rate and a reduction of circumferential margin involvement and wound abscess formation, ELAPE improves important surrogate parameters for local recurrence rate and survival.

Practicability of quality goals for the treatment of rectal cancer.

PURPOSE: In 2007, the German Working Group "Workflow Rectal Cancer II" published 19 quality indicators with 36 quality goals for the treatment of rectal cancer. We investigate whether these parameters are practicable in a specialized coloproctologic unit. PATIENTS AND METHODS: We included 578 consecutive patients with rectal cancer who were treated in our institution from January 2000 to December 2008. Patient data were collected in a prospective database. Follow-up was conducted in a colorectal tumor clinic. Data were analyzed for the defined reference groups, and the results were compared with the quality goals. RESULTS: Median follow-up was 54.4 (range 1-116) months. We achieved 19 of the 36 defined quality goals. Among these were important parameters such as the rate of postoperative mortality (0.9%), the rate of intraoperative local tumor perforation (2.2% for anterior resection and 8.5% for abdominoperineal excision), the 5-year local recurrence rate (5.9% stages I-III), and the 5-year overall survival rates for stages yII and II (79.9%), and stages yIII and III (60.7%) for patients with microscopically negative resection margins. CONCLUSION: Most of the defined quality goals can be achieved in a specialized coloproctologic unit. The debate on quality goals has the potential to enable further improvement in the care of rectal cancer patients.

Sialylated multivalent antigens engage CD22 in trans and inhibit B cell activation.

CD22 is an inhibitory coreceptor on the surface of B cells that attenuates B cell antigen receptor (BCR) signaling and, therefore, B cell activation. Elucidating the molecular mechanisms underlying the inhibitory activity of CD22 is complicated by the ubiquity of CD22 ligands. Although antigens can display CD22 ligands, the receptor is known to bind to sialylated glycoproteins on the cell surface. The propinquity of CD22 and cell-surface glycoprotein ligands has led to the conclusion that the inhibitory properties of the receptor are due to cis interactions. Here, we examine the functional consequences of trans interactions by employing sialylated multivalent antigens that can engage both CD22 and the BCR. Exposure of B cells to sialylated antigens results in the inhibition of key steps in BCR signaling. These results reveal that antigens bearing CD22 ligands are powerful suppressors of B cell activation. The ability of sialylated antigens to inhibit BCR signaling through trans CD22 interactions reveals a previously unrecognized role for the Siglec-family of receptors as modulators of immune signaling.

Activating B cell signaling with defined multivalent ligands.

Depending on the stimuli they encounter, B lymphocytes engage in signaling events that lead to immunity or tolerance. Both responses are mediated through antigen interactions with the B cell antigen receptor (BCR). Antigen valency is thought to be an important parameter in B cell signaling, but systematic studies are lacking. To explore this issue, we synthesized multivalent ligands of defined valencies using the ring-opening metathesis polymerization (ROMP). When mice are injected with multivalent antigens generated by ROMP, only those of high valencies elicit antibody production. These results indicate that ligands synthesized by ROMP can activate immune responses in vivo. All of the multivalent antigens tested activate signaling through the BCR. The ability of antigens to cluster the BCR, promote its localization to membrane microdomains, and augment intracellular Ca2+ concentration increases as a function of antigen valency. In contrast, no differences in BCR internalization were detected. Our results indicate that differences in the antigenicity of BCR ligands are related to their ability to elicit increases in intracellular Ca2+ concentration. Finally, we observed that unligated BCRs cluster with BCRs engaged by multivalent ligands, a result that suggests that signals mediated by the BCR are amplified through receptor arrays. Our data suggest a link between the mechanisms underlying signal initiation by receptors that must respond with high sensitivity.

Synthesis of a multivalent display of a CD22-binding trisaccharide.

Multivalent interactions have been implicated in the binding of B-cell surface glycoprotein CD22 to its physiological ligands. Because CD22 can influence B-cell antigen receptor (BCR) signaling, multivalent ligands that cluster CD22 may influence B-cell responses. Here, we report an efficient synthesis of a fluorophore-labeled multivalent display of a CD22-binding trisaccharide, Neu5Acalpha2,6Galbeta1,4Glc, using the ring-opening metathesis polymerization (ROMP). Our synthetic strategy involves the modification of an N-hydroxysuccinimide (NHS) ester-substituted polymer generated by ROMP with the aminopropyl glycoside of the trisaccharide. The conjugation efficiency for the coupling is high; when 0.3 equiv of the trisaccharide derivative were used relative to NHS ester groups, the mole fraction (chi) of trisaccharide ligand incorporated onto the backbone was 0.3. A fluorescein-labeled version of the multivalent ligand binds to cells expressing CD22.