Progressive plasticity during colorectal cancer metastasis.

Metastasis is the principal cause of cancer death, yet we lack an understanding of metastatic cell states, their relationship to primary tumor states, and the mechanisms by which they transition. In a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that while primary tumors largely adopt LGR5 + intestinal stem-like states, metastases display progressive plasticity. Loss of intestinal cell states is accompanied by reprogramming into a highly conserved fetal progenitor state, followed by non-canonical differentiation into divergent squamous and neuroendocrine-like states, which is exacerbated by chemotherapy and associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cancer cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues than their intestinal lineage-restricted primary tumor counterparts. We identify PROX1 as a stabilizer of intestinal lineage in the fetal progenitor state, whose downregulation licenses non-canonical reprogramming.

Changes in the multidisciplinary management of rectal cancer from 2009 to 2015 and associated improvements in short-term outcomes.

AIM: Significant recent changes in management of locally advanced rectal cancer (LARC) include preoperative staging, use of extended neoadjuvant therapies and minimally invasive surgery (MIS). This study was aimed at characterizing these changes and associated short-term outcomes. METHOD: We retrospectively analysed treatment and outcome data from patients with T3/4 or N+ LARC ≤ 15 cm from the anal verge who were evaluated at a comprehensive cancer centre in 2009-2015. RESULTS: In total, 798 patients were identified and grouped into five cohorts based on treatment year: 2009-2010, 2011, 2012, 2013 and 2014-2015. Temporal changes included increased reliance on MRI staging, from 57% in 2009-2010 to 98% in 2014-2015 (P < 0.001); increased use of total neoadjuvant therapy, from 17% to 76% (P < 0.001); and increased use of MIS, from 33% to 70% (P < 0.001). Concurrently, median hospital stay decreased (from 7 to 5 days; P < 0.001), as did the rates of Grade III-V complications (from 13% to 7%; P < 0.05), surgical site infections (from 24% to 8%; P < 0.001), anastomotic leak (from 11% to 3%; P < 0.05) and positive circumferential resection margin (from 9% to 4%; P < 0.05). TNM downstaging increased from 62% to 74% (P = 0.002). CONCLUSION: Shifts toward MRI-based staging, total neoadjuvant therapy and MIS occurred between 2009 and 2015. Over the same period, treatment responses improved, and lengths of stay and the incidence of complications decreased.

Value of adding dynamic contrast-enhanced MRI visual assessment to conventional MRI and clinical assessment in the diagnosis of complete tumour response to chemoradiotherapy for rectal cancer.

PURPOSE: To determine if DCE-MRI adds diagnostic value to the combined use of T2WI and DWI-MRI in the determination of clinical complete response (cCR) after neoadjuvant treatment (NAT) in patients with locally advanced rectal cancer. METHODS AND MATERIALS: In this IRB-approved, HIPAA-compliant retrospective study, response was assessed using a 5-point confidence score by T2WI and DWI-MRI only ('standard MRI'), then with addition of DCE-MRI. Review of digital rectal exams and endoscopy notes produced a clinical overall response score. The reference standard was CR by histopathology or cCR determined after a minimum of 18 months' follow-up. Diagnostic accuracy and ROC curves were calculated for standard MRI and added DCE-MRI (to detect complete or good response), for clinical evaluation (to detect CR) and for MRI and clinical methods combined. RESULTS: Of 65 patients undergoing NAT, 20 had cCR (31%). Sensitivity, specificity and area under the ROC (AUC) were 0.55, 0.87 and 0.69 for clinical evaluation; 0.42, 0.77 and 0.66 for standard MRI, and 0.53, 0.76 and 0.68 for added DCE-MRI, respectively. Combined clinical evaluation and standard MRI with DCE-MRI resulted in the highest specificity of 0.96 and highest AUC of 0.72. CONCLUSION: For the assessment of cCR after neoadjuvant therapy using clinical and multi-sequence MRI reading strategies, the addition of DCE-MRI increased specificity and PPV, but not significantly. KEY POINTS: • The addition of dynamic contrast-enhanced MRI to standard MRI, including DWI-MRI, may not significantly improve accuracy of response assessment in rectal cancer treatment. • Clinical assessment consisting of digital rectal examination and endoscopy is the most accurate standalone test to assess response to chemoradiotherapy in rectal cancer. • Combining MRI using DWI and DCE with the clinical assessment may potentially improve the accuracy for response assessment in rectal cancer.

Effectiveness of a multidisciplinary patient care bundle for reducing surgical-site infections.

BACKGROUND: Surgical-site infection (SSI) is associated with significant healthcare costs. To reduce the high rate of SSI among patients undergoing colorectal surgery at a cancer centre, a comprehensive care bundle was implemented and its efficacy tested. METHODS: A pragmatic study involving three phases (baseline, implementation and sustainability) was conducted on patients treated consecutively between 2013 and 2016. The intervention included 13 components related to: bowel preparation; oral and intravenous antibiotic selection and administration; skin preparation, disinfection and hygiene; maintenance of normothermia during surgery; and use of clean instruments for closure. SSI risk was evaluated by means of a preoperative calculator, and effectiveness was assessed using interrupted time-series regression. RESULTS: In a population with a mean BMI of 30 kg/m2 , diabetes mellitus in 17·5 per cent, and smoking history in 49·3 per cent, SSI rates declined from 11·0 to 4·1 per cent following implementation of the intervention bundle (P = 0·001). The greatest reductions in SSI rates occurred in patients at intermediate or high risk of SSI: from 10·3 to 4·7 per cent (P = 0·006) and from 19 to 2 per cent (P < 0·001) respectively. Wound care modifications were very different in the implementation phase (43·2 versus 24·9 per cent baseline), including use of an overlying surface vacuum dressing (17·2 from 1·4 per cent baseline) or leaving wounds partially open (13·2 from 6·7 per cent baseline). As a result, the biggest difference was in wound-related rather than organ-space SSI. The median length of hospital stay decreased from 7 (i.q.r. 5-10) to 6 (5-9) days (P = 0·002). The greatest reduction in hospital stay was seen in patients at high risk of SSI: from 8 to 6 days (P < 0·001). SSI rates remained low (4·5 per cent) in the sustainability phase. CONCLUSION: Meaningful reductions in SSI can be achieved by implementing a multidisciplinary care bundle at a hospital-wide level.

Incisional hernias after laparoscopic and robotic right colectomy.

PURPOSE: Incisional hernia (IH) is a common complication after colectomy, with impacts on both health care utilization and quality of life. The true incidence of IH after minimally invasive colectomy is not well described. The purpose of this study was to examine IH incidence after minimally invasive right colectomies (RC) and to compare the IH rates after laparoscopic (L-RC) and robotic (R-RC) colectomies. METHODS: This is a retrospective review of patients undergoing minimally invasive RC at a single institution from 2009 to 2014. Only patients undergoing RC for colonic neoplasia were included. Patients with previous colectomy or intraperitoneal chemotherapy were excluded. Three L-RC patients were included for each R-RC patient. The primary outcome was IH rate based on clinical examination or computed tomography (CT). Univariate and multivariate time-to-event analyses were used to assess predictors of IH. RESULTS: 276 patients where included, of which 69 had undergone R-RC and 207 L-RC. Patient and tumor characteristics were similar between the groups, except for higher tumor stage in L-RC patients. Both the median time to diagnosis (9.2 months) and the overall IH rate were similar between the groups (17.4 % for R-RC and 22.2 % for L-RC), as were all other postoperative complications. In multivariable analyses, the only significant predictor of IH was former or current tobacco use (hazard raio 3.0, p = 0.03). CONCLUSIONS: This study suggests that the incidence of IH is high after minimally invasive colectomy and that this rate is equivalent after R-RC and L-RC. Reducing the IH rate represents an important opportunity for improving quality of life and reducing health care utilization after minimally invasive colectomy.

Prognostic aspects of DCE-MRI in recurrent rectal cancer.

OBJECTIVE: To explore whether pre-reoperative dynamic contrast-enhanced (DCE)-MRI findings correlate with clinical outcome in patients who undergo surgical treatment for recurrent rectal carcinoma. METHODS: A retrospective study of DCE-MRI in patients with recurrent rectal cancer was performed after obtaining an IRB waiver. We queried our PACS from 1998 to 2012 for examinations performed for recurrent disease. Two radiologists in consensus outlined tumour regions of interest on perfusion images. We explored the correlation between K(trans), Kep, Ve, AUC90 and AUC180 with time to re-recurrence of tumour, overall survival and resection margin status. Univariate Cox PH models were used for survival, while univariate logistic regression was used for margin status. RESULTS: Among 58 patients with pre-treatment DCE-MRI who underwent resection, 36 went directly to surgery and 18 had positive margins. K(trans) (0.55, P = 0.012) and Kep (0.93, P = 0.04) were inversely correlated with positive margins. No significant correlations were noted between K(trans), Kep, Ve, AUC90 and AUC180 and overall survival or time to re-recurrence of tumour. CONCLUSION: K(trans) and Kep were significantly associated with clear resection margins; however overall survival and time to re-recurrence were not predicted. Such information might be helpful for treatment individualisation and deserves further investigation.

Goblet cell carcinoid neoplasm of the appendix: clinical and CT features.

PURPOSE: To describe the clinical and CT imaging features of goblet cell carcinoid (GCC) neoplasm of the appendix. METHODS AND MATERIALS: A computer search of pathology and radiology records over a 19-year period at our two institutions was performed using the search string "goblet". In the patients with appendiceal GCC neoplasms who had abdominopelvic CT, imaging findings were categorized, blinded to gross and surgical description, as: "Appendicitis", "Prominent appendix without peri-appendiceal infiltration", "Mass" or "Normal appendix". The CT appearance was correlated with an accepted pathological classification of: low grade GCC, signet ring cell adenocarcinoma ex, and poorly differentiated adenocarcinoma ex GCC group. RESULTS: Twenty-seven patients (age range, 28-80 years; mean age, 52 years; 15 female, 12 male) with pathology-proven appendiceal GCC neoplasm had CT scans that were reviewed. Patients presented with acute appendicitis (n=12), abdominal pain not typical for appendicitis (n=14) and incidental finding (n=1). CT imaging showed 9 Appendicitis, 9 Prominent appendices without peri-appendiceal infiltration, 7 Masses and 2 Normal appendices. Appendicitis (8/9) usually correlated with typical low grade GCC on pathology. In contrast, the majority of Masses and Prominent Appendices without peri-appendiceal infiltration were pathologically confirmed to be signet ring cell adenocarcinoma ex GCC. Poorly differentiated adenocarcinoma ex GCC was seen in only a small minority of patients. Hyperattenuation of the appendiceal neoplasm was seen in a majority of cases. CONCLUSIONS: GCC neoplasm of the appendix should be considered in the differential diagnosis in patients with primary appendiceal malignancy. Our cases demonstrated close correlation between our predefined CT pattern and the pathological classification.

Multivisceral resections for rectal cancer.

BACKGROUND: En bloc resection of adjacent pelvic organ(s) may be needed to achieve clear surgical margins in rectal cancer surgery. An institutional experience is reported with perioperative morbidity and oncological outcomes. METHODS: Patients were identified retrospectively from a prospectively collected institutional database (1992-2010). Outcomes, and clinical and pathological factors were determined from medical records. Estimated overall survival, overall recurrence and local recurrence were compared using the log rank method and Cox regression analysis. RESULTS: Among 1831 patients with rectal cancer, 124 (6·8 per cent) underwent en bloc resection of part or all of an adjacent organ (vagina/uterus/ovary 90, prostate/seminal vesicle 23, bladder/ureter 15, small bowel/appendix 7). Five-year overall survival and local recurrence rates were 53·3 and 18·8 per cent respectively. There was one postoperative death, from multiple organ failure in a patient with liver cirrhosis. Fifty-two patients underwent sphincter-preserving surgery and three (6 per cent) developed an anastomotic leak. On univariable analysis, the only factor associated with local recurrence was completeness of resection (local recurrence rate 15 per cent versus 69 per cent for R0 versus R1 resection; P < 0·001). On multivariable analysis, factors associated with overall survival were sphincter-preserving surgery, absence of metastatic disease and R0 resection. CONCLUSION: Multiple organ resection for locally advanced primary rectal cancer had good oncological outcomes when clear resection margins were achieved.

Dynamic contrast enhanced-MRI for the detection of pathological complete response to neoadjuvant chemotherapy for locally advanced rectal cancer.

OBJECTIVE: To determine the ability of dynamic contrast enhanced (DCE-MRI) to predict pathological complete response (pCR) after preoperative chemotherapy for rectal cancer. METHODS: In a prospective clinical trial, 23/34 enrolled patients underwent pre- and post-treatment DCE-MRI performed at 1.5T. Gadolinium 0.1 mmol/kg was injected at a rate of 2 mL/s. Using a two-compartmental model of vascular space and extravascular extracellular space, K(trans), k(ep), v(e), AUC90, and AUC180 were calculated. Surgical specimens were the gold standard. Baseline, post-treatment and changes in these quantities were compared with clinico-pathological outcomes. For quantitative variable comparison, Spearman's Rank correlation was used. For categorical variable comparison, the Kruskal-Wallis test was used. P ≤ 0.05 was considered significant. RESULTS: Percentage of histological tumour response ranged from 10 to 100%. Six patients showed pCR. Post chemotherapy K(trans) (mean 0.5 min(-1) vs. 0.2 min(-1), P = 0.04) differed significantly between non-pCR and pCR outcomes, respectively and also correlated with percent tumour response and pathological size. Post-treatment residual abnormal soft tissue noted in some cases of pCR prevented an MR impression of complete response based on morphology alone. CONCLUSION: After neoadjuvant chemotherapy in rectal cancer, MR perfusional characteristics have been identified that can aid in the distinction between incomplete response and pCR. KEY POINTS: Dynamic contrast enhanced (DCE) MRI provides perfusion characteristics of tumours. These objective quantitative measures may be more helpful than subjective imaging alone Some parameters differed markedly between completely responding and incompletely responding rectal cancers. Thus DCE-MRI can potentially offer treatment-altering imaging biomarkers.

Extended surgery and pelvic exenteration for locally advanced rectal cancer. What are the limits?

Historically, locally advanced rectal cancers with invasion of tumor into adjacent organs (T4 N1, 2 tumors) have been considered poor prognosis cancers treated with palliative intent. However with the advent of multi-modality therapy and improvement in surgical reconstructive techniques, extended resections for rectal tumors are possible with acceptable patient morbidity and excellent oncological outcomes.

Long term outcome for extra-anatomic arch reconstruction. An analysis of 143 procedures.

PURPOSE: With the FDA approval of thoracic endografts, extra-anatomic reconstruction of the aortic arch has allowed for more suitable proximal landing zones and increased applicability of thoracic endovascular procedures. We evaluated our short term and long term results of extra-anatomic reconstruction of the carotid and subclavian vessels. METHODS: One hundred and forty three (143) procedures were performed for extra-anatomic carotid and subclavian reconstruction. Of these 143 operations: 85 were carotid subclavian reconstructions, 22 were carotid crossover bypasses, 30 were subclavian carotid reconstructions and 6 were carotid subclavian transpositions. Sixty (42%) were male, 20 (14%) were diabetic, and 63 (44%) were current smokers. Mean age was 63 (SD +/- 12.3). Indication for surgery was primarily for occlusive or embolic disease (97%). In those patients undergoing bypass graft, prosthetic (ePTFE) was used in 93%. Follow-up was performed at 3 and 6 month intervals by ultrasound and pulse volume recordings where indicated. Life table analyses were used to analyze patency. RESULTS: Of the 143 reconstructions operative mortality was 1 (0.7%). Non-fatal complications included 3 (2.1%) for bleeding, 1 (0.7%) wound infection, 2 (1.4%) TIA, 1 (0.7%) suffered a non-fatal stroke, 2 (1.4%) had postoperative myocardial infarctions, and 6 (4.3%) late (>30-day) occlusions. Follow-up was 1 to 124 months (mean: 39 months). Primary patency at 1 year was 98%, 3 years 96%, and 5 years was 92%. CONCLUSION: Extra-anatomic arch reconstruction can be performed safely and appears to be durable over long term follow-up. Its use with endovascular grafting should provide a durable reconstruction for patients who require aortic "debranching" prior endovascular thoracic aortic aneurysm repair.

Young age influences treatment but not outcome of colon cancer.

BACKGROUND: Early age at onset is often considered a poor prognostic factor for colon cancer. The aim of this study was to determine the association between age, clinicopathologic features, adjuvant therapy, and outcomes following colon cancer resection. METHODS: A prospective database of 1,327 surgical stage I-III colon cancer patients operated on from 1990-2001 was evaluated, and patients grouped by age. RESULTS: Sixty-eight patients (5%) were diagnosed at age 40 (older). Younger patients were more likely to have left-sided tumors (66% vs 51%, P = .02), but no more likely to present with symptomatic lesions, more advanced tumors, or have worse pathologic features. Younger patients were noted to have more nodes retrieved in their surgical specimens than older patients (median 18 vs 14, P = .001), although the numbers of total colectomies were similar in both groups. Younger patients were also more likely to receive adjuvant chemotherapy, and this was most pronounced in the stage II cohort: 39% vs 14%, P = .003. With a median follow-up of 55 months, 5-year disease-specific survival (DSS) was similar in both study groups: 86% vs 87%, but 5-year overall survival (OS) was significantly higher in the younger patient cohort (84% vs 73%, P = .001). CONCLUSION: Younger patients undergoing complete resection of stage I-III colon cancer had DSS similar to older patients. However, younger patients had more nodes retrieved from their specimens and were more likely to receive adjuvant therapy, especially for node-negative disease. These factors may have contributed to their overall favorable outcome.

Relationship of proximal fixation to renal dysfunction in patients undergoing endovascular aneurysm repair.

Technological advancements have lead to dramatic improvements in stentgraft device design resulting in more trackable delivery systems and transrenal uncovered stents and barbs for better fixation. Transrenal bare-stents may limit stentgraft migration, particularly in patients with short or flared proximal aortic necks. However, potential disadvantages might be in worsening renal function, particularly in patients with preexisting renal insufficiency. We retrospectively analyzed our recent 7 year experience of patients undergoing endovascular aneurysm repair (EVAR) using a variety of stentgrafts with and without transrenal bare-stent fixation. Patients were divided into 2 groups; infrarenal fixation (IRF) vs transrenal fixation (TRF), or patients with preoperative serum Cr values that were normal (= or <1.5 mg/dl) vs slightly elevated (1.6-2 mg/dl), vs markedly elevated (2.1- 3.5 mg/dl). The exclusion criteria included patients with chronic renal insufficiency (CRI) on hemodialysis, and preoperative high-grade renal artery stenoses requiring angioplasty and stenting. Of 705 patients that underwent EVAR, 496 (IRF: 385 [78%], and TRF: 111 [22%]) were available with routine evaluations of serum Cr and CT scans. Preexisting comorbidities, mean procedure contrast volume, and postprocedure follow-up were similar in both groups. In the immediate postoperative period, mean serum Cr did not change significantly in either the IRF group (1.3+/-0.7 mg/dl to 1.2+/-0.9 mg/dl) or the TRF group (1.3+/-0.5 mg/dl to 1.3+/-0.6 mg/dl). Mean serum Cr did, however, significantly increase over longer follow-up in both groups: 1.4+/-0.8 mg/dl for IRF (P<0.03), and 1.5 +/- 0.8 mg/dl for TRF (P<0.01). Cr clearance was similarly unchanged in the immediate postoperative period (58+/-23 to 61+/-25 ml/min/1.73 m2 for IRF group, 53+/-17 to 55+/-17 ml/min/1.73 m2 for TRF group), but was significantly decreased in longer follow-up (53+/-23 ml/min/1.73 m2 for IRF, p<0.02: and 48+/-16 ml/min/1.73 m2 for TRF, P<0.01). There were no significant differences in serum Cr increase (p=0.19) or Cr clearance decrease (p=0.68) between the IRF and TRF groups. Small renal infarcts were noted in 6 patients (1.6%) in the IRF group, and in 8 patients (7%) in the TRF group (p=0.37). Of patients with normal preoperative renal function, renal dysfunction developed in 7.7% of IRF group and 6.1% of TRF group (p=0.76). In patients with preexisting CRI, renal dysfunction developed in 18.2% of IRF group, and 17.1% of TRF group (p=0.95). Eight patients with postoperative renal dysfunction, 5 (1.3%) from IRF group and 3 (2.7%) from TRF group subsequently required hemodialysis, and this difference was not statistically significant (p=0.91). We also analyzed 200 consecutive patients undergoing EVAR with intra-arterial contrast agents with and without preexisting CRI not on dialysis. The groups were identified on the basis of preprocedure serum Cr: group 1 (n=108), Cr less than 1.5 mg/dL (normal range); group 2 (n=65), Cr 1.5 to 2.0 mg/dL; group 3 (n=27), Cr 2.1 to 3.5 mg/dL. Routine precautions in patients with CRI included preoperative intravenous hydration with 2 L of normal saline solution, discontinuation of all nephrotoxic drugs, intraoperative administration of mannitol (0.5 g/kg intravenously), and use of nonionic, low osmolar intra-arterial contrast agent (Omnipaque 350). One-hundred and eight patients had normal renal function (group 1), and 92 patients had preexisting CRI with baseline Cr 1.5 to 2.0 mg/dL (group 2, n=65) or 2.1 to 3.5 mg/dL (group 3, n=27). Comorbid conditions included coronary artery disease (group 1, 51%; group 2, 49%; group 3, 59%), hypertension (group 1, 39%; group 2, 46%; group 3, 52%), and diabetes mellitus (group 1, 25%; group 2, 35%; group 3, 48%). In groups 1, 2, and 3, the mean volume of low osmolar contrast agent used was 210 cc, 160 cc, 130 cc, respectively; hemodynamic instability developed in 3, 1, and 1 patient, respectively. The incidence of postoperative complications between the 3 study groups was not statistically different. In grications between the 3 study groups was not statistically different. In group 1 a transient increase in serum Cr (>30% over baseline and >1.4 mg/dL) was noted in 3 patients (2.7%), 2 of whom (1.9%) required temporary hemodialysis and 1 (0.9%) who died of renal failure. In group 2 a transient increase in serum Cr was noted in 2 patients (3.1%); both patients (3.1%) required temporary hemodialysis, and 1 patient (1.5%) died of renal failure. In group 3 a transient increase in serum Cr was noted in 2 patients (7.4%); 1 patient (3.7%) required temporary hemodialysis, and 1 patient (3.7%) died of renal failure. Perioperative hypotension significantly increased the risk for elevated serum Cr and death (p<0.05), and larger contrast volume was associated with an increase in serum Cr (p<0.05) during the postoperative period. Following EVAR renal function declines slightly with both IRF and TRF. Our data show no overall difference between patients with IRF and TRF with respect to infarcts, decline in renal function, or onset of dialysis. There were a slightly greater number of renal infarcts in the TRF group, but these infarcts were clinically inconsequential. In patients with CRI, EVAR with intra-arterial radiographic contrast agents is believed to impair renal function, and CRI is considered a relative contraindication to the procedure. Results of our investigation indicate that risk for worsening renal insufficiency, dialysis, and death is only slightly and not significantly greater in patients with CRI compared with patients with normal renal function. With appropriate precautions of avoiding perioperative hypotension and limiting the volume of nonionic contrast agents, CRI need not be a contraindication for EVAR with intra-arterial contrast agents.

Neuroendocrine carcinomas of the colon and rectum.

PURPOSE: This study was designed to review experience with neuroendocrine carcinomas of the colon and rectum at a single institution, with emphasis on the pathology and clinical characteristics of this uncommon malignancy. METHODS: A study group of patients was identified from a prospective colorectal service database. Pathology was reviewed and neuroendocrine tumors were classified by a single pathologist. Medical records were retrospectively reviewed. RESULTS: From March 1975 to September 1998, 38 patients with neuroendocrine carcinomas were identified from the colorectal service database comprising 6495 patients (0.6 percent). These neuroendocrine carcinomas did not include carcinoid tumors. Average patient age was 57 years (range, 29-86 years). There were 17 males (44.7 percent) and 21 females (55.3 percent). Tumors were located as follows: 17 colon, 14 rectum, 6 anal canal, and 1 appendix. The diagnosis of neuroendocrine carcinoma was suggested preoperatively from tissue biopsy in 59.3 percent (16/27) of patients evaluable. Pathology was reviewed and tumors were categorized as small cell carcinoma (n = 22) or large cell neuroendocrine carcinoma (n = 16). Most tumors (20/25 evaluable, 80 percent) stained positive by means of immunohistochemistry for neuroendocrine markers, including chromogranin (18/19), synaptophysin (10/15), and/or neuron-specific enolase (14/15). Metastatic disease was detected at the time of diagnosis in 69.4 percent of the patients (25/36). Tumors were advanced at the time of diagnosis, with American Joint Committee on Cancer (AJCC) Stage I (n = 6), Stage III (n = 7), and Stage IV (n = 25) tumors. As a group, these tumors had a poor prognosis, with a median survival of 10.4 months. One-year, two-year, and three-year survival was 46 percent, 26 percent, and 13 percent, respectively. There was no significant difference in survival based on pathologic subtypes. Median follow-up time was 9.4 months (range, 0.6-263.7 months). CONCLUSIONS: Neuroendocrine carcinomas of the colon and rectum are uncommon, comprising less than 1 percent of colon and rectal cancers. Pathologically, these tumors are poorly differentiated carcinomas with distinctive cytoarchitectural features and are often immunoreactive for markers of neuroendocrine differentiation. The prognosis for high-grade neuroendocrine carcinomas is poor, as most patients have metastatic disease at the time of diagnosis.

Preoperative evaluation and postoperative follow-up for patients with rectal cancer.

Rectal cancer has a wide variety of presentations. In most cases, it is the surgeon who is faced with the challenge of determining the extent of disease and advising the patient how to proceed with treatment. Utilizing diagnostic tests of the highest accuracy and relevance will help in the selection of the best initial therapy, which is critical for achieving the highest cure rate while also avoiding over-treatment and unnecessary morbidity. Following curative treatment, surveillance testing for detection of recurrence is traditionally done, but the efficacy of this practice has been questioned. Surveillance will detect a number of asymptomatic recurrences that are treatable by potentially curative salvage surgery, but to what extent early detection improves salvage therapy is not well established. In this brief review, the goals, methods, and expected benefits of rectal cancer staging and surveillance are assessed.

Surgical resection and high dose rate intraoperative radiation therapy for locally recurrent rectal cancer.

For intra-pelvic recurrence of rectal cancer, surgical resection is technically difficult and must be aggressive to achieve a high rate of negative resection margins. Resection with clear margins can be curative, particularly for those patients with true anastomotic recurrence. HDR-IORT is a safe, feasible, versatile, logistically sound modality that is highly reliable in delivering radiation to at-risk surgical margins in the pelvis. Despite surgery and IORT, overall local failure rates in this population are 33 to 50 percent. The most important prognostic variable is the state of surgical resection margins. At our institution, in patients with negative and positive resection margins the 2-year actuarial local recurrence rates are 33 percent versus 73 percent and 5-year survival rates are 51 percent versus 16 percent, respectively. On subset analysis, the most favorable outcome was seen in patients with true anastomotic recurrences (78 percent 5-year survival).

Automated, multiplex assay for high-frequency microsatellite instability in colorectal cancer.

PURPOSE: In a series of hereditary nonpolyposis colorectal cancer (HNPCC) patients, we evaluated the sensitivities of the individual microsatellites recommended by the National Cancer Institute (NCI) consensus workshop for detection of high-frequency microsatellite instability (MSI-H). On the basis of this evaluation, we developed a three-marker assay that assigns microsatellite instability (MSI) in a multiplex polymerase chain reaction. METHODS: Individual marker sensitivity was assessed in 18 HNPCC tumors. Multiplex and NCI assays were then assessed in a series of 120 patients with early-onset colon cancer. RESULTS: The sensitivity of microsatellite markers BAT25, BAT26, D2S123, D5S346, and D17S250 for ASI in HNPCC cancers was 100%, 94%, 72%, 50%, and 50%, respectively. The three most accurate markers were combined and optimized in a multiplex assay that assigned MSI-H whenever at least two of three markers revealed ASI. In early-onset colon cancers, the prevalence of MSI-H determined by the multiplex assay and by the NCI assay was 16% and 23%, respectively. The additional MSI-H tumors and patients with MSI-H identified by the NCI assay lacked the traits characteristic of MSI-H seen in tumors and patients identified by the multiplex assay: retention of heterozygosity (NCI additional 22% v multiplex 84%; P =.003), characteristic tumor morphology (0% v 64%; P =.006), and 5-year cancer survival rate (44% v 100%; P =.0003). CONCLUSION: The multiplex assay identifies colon cancers with MSI-H by assessing three highly accurate microsatellite markers. This assay identifies a smaller MSI-H cohort with more homogeneous clinical features and is superior as a marker of favorable prognosis. It merits prospective evaluation as a marker of prognosis and as a screening test for HNPCC.

Results after rectal cancer resection with in-continuity partial vaginectomy and total mesorectal excision.

BACKGROUND: Although sharp mesorectal excision reduces circumferential margin involvement and local recurrence, a concomitant partial vaginectomy may be required in women with locally advanced rectal cancer. METHODS: Sixty-four patients requiring a partial vaginectomy during resection of primary rectal cancer were identified. Survival was determined by the Kaplan-Meier method, and distributions were compared by the log-rank test. RESULTS: Locally advanced disease was reflected by presentation with malignant rectovaginal fistulae (n = 6) or cancers described as bulky or adherent/tethered to the rectovaginal septum (n = 32). Thirty-five patients received adjuvant radiation with or without chemotherapy. At a median follow-up of 22 months, 27 (42%) patients developed recurrent disease, with most of these occurring at distant sites. The 5-year overall survival was 46%, with a median survival of 44 months. The 2-year local recurrence-free survival was 84%. The crude local failure rate was 16% (10 of 64), and local recurrence was more common in patients with a positive as opposed to a negative microscopic margin (2 [50%] of 4 vs. 8 [13%] of 60, respectively). Positive nodal status had a significant effect on overall survival (P <.001). CONCLUSIONS: Partial vaginectomy is indicated for locally advanced rectal cancers involving the vagina. The results are most favorable in patients with negative surgical margins and node-negative disease.

Resection of locally recurrent colorectal cancer in the presence of distant metastases: can it be justified?

BACKGROUND: We aimed to determine the outcome of resections for local recurrence of colorectal carcinoma in the presence of distant (M1) disease. METHODS: Patients who underwent resection of local recurrence in the presence of potentially resectable M1 disease were identified from the colorectal database. Outcome was determined by chart review. RESULTS: Forty-two patients (23 men) of mean age 60 years (range, 34-88 years) underwent complete gross resection of their local recurrence in the presence of M1 disease. Thirteen of the 42 underwent synchronous M1 resections to render them free of gross disease (R0). Nine of the 29 patients who left with residual disease (R1) subsequently underwent staged M1 resection, so that 22 of 42 were rendered R0 by surgery. The median survival of all patients was 14.5 months (interquartile range, 6-30 months), and that of patients rendered R0 was 23 months (interquartile range, 10-37 months), in comparison with 7 months (interquartile range, 3-25 months) for those of R1 status (P =.006; log-rank method). Ability to achieve R0 status by synchronous or staged resection was the only factor predictive of survival. CONCLUSIONS: The presence of M1 disease per se should not preclude resection of local recurrence, although case selection is problematic.

Preoperative radiation with or without chemotherapy and full-thickness transanal excision for selected T2 and T3 distal rectal cancers.

BACKGROUND AND AIMS: To evaluate the clinical outcome of selected patients with distal rectal cancer treated by preoperative radiation with or without chemotherapy and full-thickness local excision (FTLE). PATIENTS AND METHODS: Ten patients with invasive distal rectal cancer (six T2, four T3) were treated with preoperative radiotherapy (3600-5040 cGy) with or without 5-fluorouracil based chemotherapy. FTLE was performed 4-6 weeks after completion of radiotherapy, primarily because of comorbid diseases or patient refusal of a permanent colostomy. Median follow-up was 28.5 months. RESULTS: There were no prolonged wound complications, and only one positive microscopic margin was detected. Among three cases of complete pathological response, two remain without evidence of disease. All patients retained sphincter function and avoided creation of a stoma. Two patients developed recurrence, one with widespread disease including pelvic recurrence 26 months after surgery and the other with distant disease only at 23 months. There were four deaths: two unrelated to cancer, one of undetermined cause after 7 years, and one after widespread recurrence at 26 months, with death 4 months later. Two-year actuarial survival was 78%. CONCLUSIONS: This pilot study demonstrates that preoperative radiotherapy and FTLE avoids major abdominal surgery yet facilitates sphincter preservation, excision with negative margins, and short-term local control in selected patients with distal rectal cancer.