Systematic development of an abbreviated protocol for screening breast magnetic resonance imaging.

RATIONALE & OBJECTIVES: We sought to develop an abbreviated protocol (AP) for breast MRI that maximizes lesion detection by assessing each lesion not seen on mammography by each acquisition from a full diagnostic protocol (FDP). MATERIALS & METHODS: 671 asymptomatic women (mean 55.7 years, range 40-80) with a negative mammogram were prospectively enrolled in this IRB approved study. All lesions on MRI not visualized on mammography were analyzed, reported, and suspicious lesions biopsied. In parallel, all FDP MRI acquisitions were scored by lesion to eventually create a high-yield AP. RESULTS: FDP breast MRI detected 452 findings not visible on mammography, including 17 suspicious lesions recommended for biopsy of which seven (PPV 41.2%) were malignant in six women. Mean size of the four invasive malignancies was 1.9 cm (range 0.7-4.1), all node negative; three lesions in two women were ductal carcinoma in situ. Nine biopsied lesions were benign, mean size 1.2 cm (range 0.6-2.0). All biopsied lesions were in women with dense breasts (heterogeneously or extremely dense on mammography, n = 367), for a cancer detection rate of 16.3/1000 examinations in this subpopulation. These data were used to identify four high-yield acquisitions: T2, T1-pre-contrast, T11.5, and T16 to create the AP with a scan time of 7.5 min compared to 24 min for the FDP. CONCLUSIONS: Our analysis of a FDP MRI in a mammographically negative group identified four high-yield acquisitions that could be used for rapid screening of women for breast cancer that retains critical information on morphology, histopathology, and kinetic activity to facilitate detection of suspicious lesions.

Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial.

Importance: The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary because the majority of the patients had estrogen receptor-positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology). Objective: To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection. Design, Setting, and Participants: The ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases. Interventions: All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. Main Outcomes and Measures: The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival. Results: Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 [1-sided 95% CI, 0-1.16]; noninferiority P = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 [95% CI, 0.62-1.17]; P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups. Conclusions and Relevance: Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT00003855.

Locoregional Recurrence After Sentinel Lymph Node Dissection With or Without Axillary Dissection in Patients With Sentinel Lymph Node Metastases: Long-term Follow-up From the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 Randomized Trial.

BACKGROUND AND OBJECTIVE: The early results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in locoregional recurrence for patients with positive sentinel lymph nodes (SLNs) randomized either to axillary lymph node dissection (ALND) or sentinel lymph node dissection (SLND) alone. We now report long-term locoregional recurrence results. METHODS: ACOSOG Z0011 prospectively examined overall survival of patients with SLN metastases undergoing breast-conserving therapy randomized to undergo ALND after SLND or no further axillary specific treatment. Locoregional recurrence was prospectively evaluated and compared between the groups. RESULTS: Four hundred forty-six patients were randomized to SLND alone and 445 to SLND and ALND. Both groups were similar with respect to age, Bloom-Richardson score, Estrogen Receptor status, adjuvant systemic therapy, histology, and tumor size. Patients randomized to ALND had a median of 17 axillary nodes removed compared with a median of only 2 SLNs removed with SLND alone (P < 0.001). ALND, as expected, also removed more positive lymph nodes (P < 0.001). At a median follow-up of 9.25 years, there was no statistically significant difference in local recurrence-free survival (P = 0.13). The cumulative incidence of nodal recurrences at 10 years was 0.5% in the ALND arm and 1.5% in the SLND alone arm (P = 0.28). Ten-year cumulative locoregional recurrence was 6.2% with ALND and 5.3% with SLND alone (P = 0.36). CONCLUSION: Despite the potential for residual axillary disease after SLND, SLND without ALND offers excellent regional control for selected patients with early metastatic breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.

The role of sentinel lymph node mapping in colon cancer: detection of micro-metastasis, effect on survival, and driver of a paradigm shift in extent of colon resection.

Unlike in breast cancer and melanoma, sentinel lymph node mapping in colon cancer is primarily used as an aid to the pathologist for accurate nodal staging. The study was undertaken to review the incidence of micro-metastasis and its impact on survival when treated with chemotherapy. The study was also undertaken to see if SLNM could guide limited colon resection in early T stage tumor as a paradigm shift. SLNM was done by subserosal injection of a blue dye. SLNs were ultra-staged by multilevel sectioning and remaining Specimen was then examined by conventional method. For the last 245 patients the specimen was divied ex vivo into two segments as segment A containing the tumor bearing portion of the colon and SLNs with attached mesentery, while segment B include distal part of the colon with attached mesentery. Nodal staging was separately examined. Of the 354 Pts, SLNM was successful in 99.9% of Pts with an average no of SLN/ Pt = 2.8 and total nodes 17.8/pt. Survival was directly related negatively with stage and nodal status. Pts with +ve LN did much better with chemotherapy than without chemotherapy. With 245 Pts, specimen A Vs B, no Pts had +ve node in specimen B with -ve LN in specimen A. SLNM results in more node/Pt, more positive node/Pt ,and more micro-metastasis who when treated with chemotherapy survive longer. Limited segmental resection in early T stage is possible when done with guidance by SLNM without compromising biology.

Impact of nodal status and tumor burden in sentinel lymph nodes on the clinical outcomes of cancer patients.

The validation of sentinel lymph node (SLN) concept in melanoma and breast cancer has established a new paradigm in cancer metastasis that, in general, cancer cells spread in a orderly fashion from the primary site to the SLNs in the regional nodal basin and then to the distant sites. In this review article, we examine the development of SLN concept in penile carcinoma, melanoma and breast carcinoma and its application to other solid cancers with emphasis of the relationship between micrometastasis in SLNs and clinical outcomes.

Detection and prognostic impact of micrometastasis in colorectal cancer.

Review of literature was performed on studies with prognostic impact of micrometastasis in colorectal cancer. Among 16 studies included, micrometastasis was detected in 26.5% of patients. Most analysis revealed that micrometastasis carries a poorer prognosis compared to node negative disease (NND). The results of those studies were compared with our pilot study of 109 patients with colon cancer, showing improved prognosis of micrometastasis after being upstaged and treated with chemotherapy when compared with NND.

Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial.

CONTEXT: Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast cancer, but it is not clear whether further nodal dissection affects survival. OBJECTIVE: To determine the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer. DESIGN, SETTING, AND PATIENTS: The American College of Surgeons Oncology Group Z0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patients from May 1999 to December 2004. Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. Targeted enrollment was 1900 women with final analysis after 500 deaths, but the trial closed early because mortality rate was lower than expected. INTERVENTIONS: All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Systemic therapy was at the discretion of the treating physician. MAIN OUTCOME MEASURES: Overall survival was the primary end point, with a noninferiority margin of a 1-sided hazard ratio of less than 1.3 indicating that SLND alone is noninferior to ALND. Disease-free survival was a secondary end point. RESULTS: Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy. CONCLUSION: Among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003855.

Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial.

BACKGROUND AND OBJECTIVE: Sentinel lymph node dissection (SLND) has eliminated the need for axillary dissection (ALND) in patients whose sentinel node (SN) is tumor-free. However, completion ALND for patients with tumor-involved SNs remains the standard to achieve locoregional control. Few studies have examined the outcome of patients who do not undergo ALND for positive SNs. We now report local and regional recurrence information from the American College of Surgeons Oncology Group Z0011 trial. METHODS: American College of Surgeons Oncology Group Z0011 was a prospective trial examining survival of patients with SN metastases detected by standard H and E, who were randomized to undergo ALND after SLND versus SLND alone without specific axillary treatment. Locoregional recurrence was evaluated. RESULTS: There were 446 patients randomized to SLND alone and 445 to SLND + ALND. Patients in the 2 groups were similar with respect to age, Bloom-Richardson score, estrogen receptor status, use of adjuvant systemic therapy, tumor type, T stage, and tumor size. Patients randomized to SLND + ALND had a median of 17 axillary nodes removed compared with a median of only 2 SN removed with SLND alone (P < 0.001). ALND also removed more positive lymph nodes (P < 0.001). At a median follow-up time of 6.3 years, there were no statistically significant differences in local recurrence (P = 0.11) or regional recurrence (P = 0.45) between the 2 groups. CONCLUSIONS: Despite the potential for residual axillary disease after SLND, SLND without ALND can offer excellent regional control and may be reasonable management for selected patients with early-stage breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.

Comparative analysis of bone marrow micrometastases with sentinel lymph node status in early-stage breast cancer.

Bone marrow micrometastases (BMM) and sentinel lymph node (SLN) status are both prognostic factors in breast cancer (BRCa) patients (pts). A definitive relationship between the two has not yet been proven and the data available is controversial. Thus, a retrospective study was conducted to determine the relationship of BM status and SLN status in pts with early BRCa (T1/T2). All female pts with early BRCa (T1/T2) operated upon by a single surgeon were included in the study. Prior to surgery, all pts underwent bone marrow aspiration from the posterior superior iliac spine bilaterally. Subsequently, pts underwent SLN biopsy and definitive primary breast surgery. BM samples were examined by using a Cytokeratin Detection Kit using CAM 5.2 monoclonal antibody. All pts with BMM underwent repeat BM analysis 6 months after completing all treatments. Data was collected for SLN, BM, estrogen receptor/progesterone receptor (ER/PR), and human epidermal growth factor receptor 2 (Her-2/neu) status and analyzed using chi-square (chi (2)) analysis or Fischer's exact test. A total of 270 consecutive pts with early BRCa were studied. SLN mapping was successful in all pts. SLN metastases (mets) were detected in 28.9% (78/270) pts. Of the 270 pts, 77.0% (208/270) had T1 disease. BMM were detected in 9.6% (26/270) pts, of whom 69.2% (18/26) were found to have BMM unilaterally. BMM were detected in 11.5% (9/78) pts with SLN mets versus 8.9% (17/192) in pts with node-negative disease (p = 0.65). Of the pts with T1 BRCa, BMM were observed in 9.1% (19/208) pts versus 11.3% (7/62) in pts with T2 BRCa (p = 0.6). In pts with ER/PR-negative (-ve) BRCa, BMM were found in 7.7% (2/26) pts versus 9.9% (24/242) in pts with ER/PR-positive (+ve) BRCa (p = 0.27). BMM were detected in 12.3% (9/73) pts with Her-2/neu +ve BRCa and in 8.6% (16/187) pts with Her-2/neu -ve BRCa (p = 0.11). After completion of adjuvant therapy all pts with BMM (n = 26) converted to BM negative status. We conclude that BM status did not correlate with SLN status and occurs independently of lymphatic metastasis possibly through a different mechanism. BMM occur in node-negative pts and may assist in identifying pts at high risk for disease recurrence. Obtaining bone marrow aspirate from two locations resulted in a significant increase in detection of micrometastases.

A prospective trial comparing 1% lymphazurin vs 1% methylene blue in sentinel lymph node mapping of gastrointestinal tumors.

BACKGROUND: Methylene blue (M), as a dye in sentinel lymph node mapping (SLNM), has been introduced as an alternative to lymphazurin (L) after the recent shortage of L. M has been evaluated in breast cancer in multiple studies with favorable results. Our study compares L with M in the SLNM of gastrointestinal (GI) tumors. METHODS: Between Jan 2005 and Aug 2008, 122 consecutive patients with GI tumors were enrolled. All patients (pts) underwent SLNM with either L or M by subserosal injection of 2-5 mL of dye. Efficacy and rates of adverse reactions were compared between the two dyes. Patients were prospectively monitored for adverse reactions including anaphylaxis, development of blue hives, and tissue necrosis. RESULTS: Of 122 pts, 60 (49.2%) underwent SLNM using L and 62 (50.8%) underwent SLNM using M. Colon cancer (CrCa) was the most common site in both groups. The success rate of L and M in SLNM was 96.6% and 96.7%, respectively, with similar numbers of total number of lymph nodes per pt, SLNs per pt (<3), nodal positivity, skip metastasis, and accuracy. The only adverse reaction in the L group was oxygen desaturation >5% in 5% (3/60) of pts, compared with none in the M group. Cost per vial of L was $210 vs $7 for M. CONCLUSION: The success rate, nodal positivity, average SLNs per patient, and overall accuracy were similar between L and M. Absence of anaphylaxis and lower cost make M more desirable than L in SLNM of GI tumors.

Sentinel node biopsy for the individualization of surgical strategy for cure of early-stage colon cancer.

INTRODUCTION: The requirement for nodal analysis currently confounds the oncological propriety of focused purely endoscopic resection for early-stage colon cancer and complicates the evolution of innovative alternatives such as natural orifice transluminal endoscopic surgery (NOTES) and its hybrids. Adjunctive sentinel node biopsy (SNB) deserves consideration as a means of addressing this shortfall. METHODS: Data from two prospectively maintained databases established for multicentric studies of SNB in colon cancer that employed similar methodologies were pooled to establish technique potency selectively in T1/T2 disease (both overall and under optimized conditions) and to project potential clinical impact. RESULTS: Of 891 patients with T1-4, M0 intraperitoneal colon cancer, 225 had T1/T2 disease. Sentinel nodes were either not found or were falsely negative in 18 patients with T1/T2 cancers (8%) as compared with 17% (112/646) in those with T3/T4 disease (P = 0.001). Negative predictive value (NPV) in the former exceeded 95%, while sensitivity [including immunohistochemistry (IHC)] was 81%. In the 193 patients with T1/T2 disease recruited from those centers contributing >22 patients, sensitivity was 89% and NPV 97%. Thus, in this cohort, SNB could have correctly prompted localized resection (obviating en bloc mesenteric dissection) in 75% (144) of patients, including 59 with T1 lesions potentially amenable to intraluminal resection alone as their definitive treatment. Forty-four patients (23.4%) would still have conventional resection, leaving three patients (1.6% overall) understaged (11% false-negative rate). CONCLUSION: These findings support the further investigation of SNB as oncological augment for localized resective techniques. Specific prospective study should pursue this goal.

Prognostic relevance of occult nodal micrometastases and circulating tumor cells in colorectal cancer in a prospective multicenter trial.

PURPOSE: Nodal micrometastasis and circulating tumor cells detected by multimarker quantitative real-time reverse transcription-PCR (qRT-PCR) may have prognostic importance in patients with colorectal cancer. EXPERIMENTAL DESIGN: Paraffin-embedded sentinel lymph nodes from 67 patients and blood from 34 of these patients were evaluated in a prospective multicenter trial of sentinel lymph node mapping in colorectal cancer. Sentinel lymph nodes were examined by H&E staining and cytokeratin immunohistochemistry. Sentinel lymph nodes and blood were examined by a four-marker qRT-PCR assay (c-MET, melanoma antigen gene-A3 family, beta1-->4-N-acetylgalactosaminyltransferase, and cytokeratin-20); qRT-PCR results were correlated with disease stage and outcome. RESULTS: In H&E-negative sentinel lymph node patients that recurred, cytokeratin immunohistochemistry and qRT-PCR detected metastasis in 30% and 60% of patients, respectively. Disease-free survival differed significantly by multimarker qRT-PCR upstaged sentinel lymph node (P = 0.014). qRT-PCR analysis of blood for circulating tumor cells correlated with overall survival (P = 0.040). CONCLUSION: Molecular assessment for micrometastasis in sentinel lymph node and blood specimens may help identify patients at high risk for recurrent colorectal cancer, who could benefit from adjuvant therapy.

Challenging the conventional treatment of colon cancer by sentinel lymph node mapping and its role of detecting micrometastases for adjuvant chemotherapy.

All colon cancer patients with lymph node (LN) positive disease are treated with chemotherapy. Patients with node negative disease are usually cured by surgery alone. Yet about 20% of patients develop recurrence within 5 years despite node negative status. This may often be the result of missed micrometastases by conventional examination. Sentinel lymph node (SLN) mapping was developed to find those nodes detected by blue dye which was ultrastaged to detect micrometastases. Consecutive patients, underwent SLN mapping with the blue dye with success rate of 99.2%. Average number of LN was 18.3, average number of SLN was 3/patient and overall nodal positivity was 45%. Ten patients had skip metastases. Overall survival of 235 patients was 84 months with survival of node negative patients 97 months versus 68 months for node positive patients. For stage I-IV patients, overall survival was as follows: stage I-115 months, stage II-90 months, stage III-84 months and stage IV-24 months respectively. Patients with micrometastases after chemotherapy had average survival of 108 months versus those without chemotherapy was 50 months. Thus, SLN mapping techniques is highly successful, easily reproducible and finds micrmoetastases in over 15% of patients which could have been missed by conventional pathological examination. These patients when treated with adjuvant chemotherapy have similar survival as those of node negative disease. Similarly, patients without any nodal metastases after SLN mapping and ultrastaging, may be considered as true node negative disease and may avoid further adjuvant chemotherapy.

Association of angiogenesis markers with lymph node metastasis in early colorectal cancer.

HYPOTHESIS: We hypothesized that p53 mutations (mp53) are associated with decreased expression of thrombospondin 1 (TSP-1) and that decreased TSP-1 expression is associated with lymph node metastases. DESIGN: A retrospective study of lymphatic mapping and pathologic determination of angiogenesis markers in primary colorectal cancer. SETTING: Tertiary care cancer institute. PATIENTS: Sixty-one patients with colorectal cancer underwent lymphatic mapping. Lymph nodes that stained negative by hematoxylin-eosin were examined with immunohistochemistry for micrometastases. Primary tumors were analyzed by immunohistochemistry for mp53 and TSP-1 expression. The t test and the Mann-Whitney U test were used to examine the mean difference in TSP-1 expression between tumors. MAIN OUTCOME MEASURES: Mutant p53 expression, TSP-1 expression, and metastatic progression. RESULTS: Thirty-six of the 61 patients (59%) had nodal metastases shown by hematoxylin-eosin or immunohistochemistry in the sentinel node (N2, N1, N1mi, or N0[i+]). Patients with a truly negative sentinel node (pN0[i-][sn]) had significantly higher TSP-1 expression compared with those with some degree of nodal metastases (57.7 vs 30.1; P < .001). Acquisition of mp53 was associated with a decreased mean TSP-1 expression. Tumors without mp53 expression had a mean TSP-1 optical density value of 51.3 while tumors with elevated mp53 had a mean TSP-1 optical density value of 31.8 (P < .03). CONCLUSIONS: Patients with primary colorectal cancer with low TSP-1 expression, with or without detection of mp53 gene product, are more likely to harbor lymph node metastasis than patients with higher expression. Patients with a truly negative sentinel node (pN0[i-][sn]) frequently have higher expression of TSP-1 that may have inhibited metastatic progression. Further studies will investigate the relationship between mp53, TSP expression, and disease progression.

Sentinel node for gastrointestinal malignancies.

Sentinel node (SN) concept is valid in gastrointestinal (GI) malignancies. The dual tracer method with radio-guided and dye-guided SN mapping is feasible in GI malignancies and is useful in detecting unexpected aberrant drainage routes from GI cancers. SN mapping enabled us to perform individualized and step-wise lymphadenectomy in patients with GI cancer. A combination of SN mapping and endoscopic surgery will contribute to the improvement in quality of life after surgical treatment of GI cancer.

Comparative analysis of mesenteric and peripheral blood circulating tumor DNA in colorectal cancer patients.

An increasing number of reports have demonstrated the presence of tumor-specific DNA in cancer patients' plasma/serum. These findings offer the prospective of serologic tumor markers that may aide in early disease detection, predict subclinical disease progression, and monitor treatment responses. However, for patients with colorectal cancer (CRC), there are few reports using this approach, with most revealing poor sensitivity. In contrast to tumors of other organ systems, CRCs drain predominantly via the mesenteric/portal veins (MV) to the liver. We hypothesize that because of this unique relation, tumor DNA may be less abundant in CRC patients' systemic circulation as compared to the mesenteric/portal system. At the time of surgery, paired blood was collected from both the peripheral vein (PV) and MV from 33 CRC patients. DNA was isolated from serum, quantified and assessed for loss of heterozygosity (LOH) using a panel of 11 microsatellite markers corresponding to regions on six chromosomes frequent for LOH in CRC. In addition, 16 samples were assessed for the presence of hypermethylated DNA for tumor suppressor genes: MGMT, P16, RAR-beta2, RASSF1A, and APC. Circulating tumor DNA associated with LOH or methylation was more frequently detected in the MV of patients, 11 (33%) and 6 (38%), as compared to PV, 9 (27%) and 1 (6%), respectively. This study is the first to identify the presence of increased tumor DNA in the direct efferent venous drainage system of CRC and its variation as compared to systemic circulation. The findings provide important evidence supporting the origin of tumor-associated DNA in circulation, which merits consideration when devising blood-based nucleic acid assays for the assessment of CRC.

Prospective multicenter trial of staging adequacy in colon cancer: preliminary results.

HYPOTHESIS: Lymph node evaluation is an important prognostic factor in colorectal cancer (CRC). A 25% recurrence rate in patients with node-negative CRC suggests that current staging practices are inadequate. Focused analysis of the sentinel node (SN) by multiple sectioning and immunohistochemistry improves staging accuracy. DESIGN: Prospective phase 2 multicenter trial. SETTING: Tertiary referral cancer centers. PATIENTS: Between March 2001 and June 2005, 132 patients were enrolled with clinical stage I and II CRC in a prospective multicenter trial (R01-CA90484). INTERVENTION: During a standard oncologic resection, lymphatic mapping was performed and the SN identified either by the surgeon or the pathologist. Hematoxylin-eosin staining was performed on all lymph nodes and immunohistochemistry, on lymph nodes negative by hematoxylin-eosin staining. MAIN OUTCOME MEASURES: Micrometastases greater than 0.2 mm but less than 2 mm and isolated tumor cells less than 0.2 mm were defined according to the sixth edition of the American Joint Committee on Cancer Cancer Staging Manual. RESULTS: The 63 men and 69 women had a median age of 74 years. Sixty-eight patients (52%) underwent a right hemicolectomy; 3 (2.3%), a transverse colectomy; 9 (7%), a left colectomy; 15 (11%), a sigmoid colectomy; 34 (26%), a low anterior resection; 1 (1%), an abdominal perineal resection; and 2 (2%), a total colectomy. Of the 111 evaluable primary tumors, 19 (17%) were T1 lesions; 17 (15%), T2; 72 (65%), T3; and 3 (2.7%), T4 tumors. Thirty-three patients (30%) were classified as stage I; 46 (41%), stage II, and 32 (29%), stage III. The SN was identified by the surgeon in 127 patients (96%) and by the pathologist in 5 patients (4%). The median number of SNs and total lymph nodes examined were 3 and 14.5, respectively. The sensitivity of lymphatic mapping and SN analysis was 88.2% and the false-negative rate, 7.4% (6/81). Of the 6 false-negative results, 4 were attributed to lymphatic channels obliterated by tumor. Upstaging occurred in 28 patients (23.6%). CONCLUSIONS: In a multicenter trial, ultrastaging of colon cancer is feasible and accurate. In stage II CRC, 24% of patients had nodal carcinoma cells not detected by conventional staging methods. Surgical technique (adequate lymph node retrieval) and focused pathological analysis may improve staging accuracy and the selection of patients for chemotherapy. The unnecessary toxicity and expense of chemotherapy may be avoided in those patients who are truly node negative.

A multicenter trial of sentinel lymph node mapping in colorectal cancer: prognostic implications for nodal staging and recurrence.

BACKGROUND: Sentinel lymph node (SLN) mapping (M) for staging in colorectal cancer (CRCa) remains controversial and needs to be validated. This study analyzes results of SLNM at a multi-institutional level for CRCa. METHODS: Group A patients underwent SLNM with 1 to 3 mL of 1% lymphazurin. First 1 to 4 blue lymph nodes were designated as SLNs and had focused analysis. Group B had standard resection and nodal staging. Patients with a minimum of 2 years of follow-up were analyzed for recurrence. RESULTS: Overall nodal metastasis were 50% for 500 group A patients versus 35% for 368 group B patients. In SLNM patients success, accuracy, sensitivity, and negative predictability values were 98%, 96%, 90%, and 93%, respectively. With a 2-year minimum follow-up, 153 group A patients had 7% recurrences compared with 25% in 162 group B patients. CONCLUSION: SLNM is highly feasible and accurate for staging CRCa with higher detection of nodal metastasis and lower recurrences.

Sentinel lymph node mapping in colon and rectal cancer: its impact on staging, limitations, and pitfalls.

Sentinel lymph node (SLN) mapping has been widely applied in the staging of solid neoplasms including colon and rectal cancer. Since the first reported feasibility study in 1997, there have been numerous publications validating SLN mapping as a highly accurate and powerful upstaging technique for colon and rectal cancer. In addition to refining the technical aspects of this procedure, these studies have investigated the use of other tracers and operative techniques, while determining the indications, limitations, and pitfalls of SLN mapping in patients with colorectal cancers. This chapter reviews the rationale for performing SLN mapping for the accurate staging of colon and rectal cancers, and provides a brief review of the historical background of the development of the procedure. Landmark publications, which have contributed to the current status of the technique, are discussed. We will focus on the technical details of the procedure, and on the pathological evaluation of the specimen and the SLNs. The various tracers and techniques of SLN mapping in colon and rectal cancer will be discussed. We have performed SLN mapping in more than 240 consecutive patients over the past 7 years. The success rates for identifying at least one SLN for colon and rectal cancer were 100% and 90.6%, respectively. The accuracy rates were 95.8% and 100%, respectively. In terms of upstaging, 32.3% of colon cancer patients with nodal metastases and 16.7% of rectal patients with nodal metastases were upstaged by the detection of micrometastases found in the SLNs only. Finally, we will also discuss the current role as well as the future research directions for SLN mapping in colon and rectal cancer.

c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases.

PURPOSE: Both c-MET and vascular endothelial growth factor (VEGF)-C expression are important factors in primary carcinoma progression. We hypothesized that overexpression of c-MET and/or VEGF-C mRNA in primary colorectal cancer (CRC) can predict tumor invasion and regional metastasis. EXPERIMENTAL DESIGN: The level of c-MET and VEGF-C mRNA expression was assessed using a quantitative RT-RealTime PCR assay on early stage primary CRC tumors (n = 36). RESULTS: The c-MET mRNA copy number ranged from 1.18 x 10(2) to 1.11 x 10(6) copies (median 5.17 x 10(4)) per 250 ng of RNA from CRC specimens. c-MET mRNA copies in CRC specimens was significantly higher than that from normal colon mucosal epithelium (P = 0.0001). c-MET mRNA copies significantly correlated with the depth of invasion: T(1) versus T(2), P = 0.007; T(1) versus T(3)/T(4), P = 0.0001; T(1) versus T(2) versus T(3)/T(4), P = 0.0005; and T(1)/T(2) versus T(3)/T(4), P = 0.011. c-MET copy number in primary CRC of N(1)/N(2) staged patients was significantly higher than N(0) cases (P < 0.03). Expression levels of c-MET mRNA were verified with immunohistochemistry analysis of c-MET protein expression in CRC specimens and normal mucosal epithelium. The VEGF-C mRNA copies of primary CRC assessed ranged from 0 to 1.65 x 10(5) copies (median 580). Although VEGF-C mRNA copies in CRC primary tumors were significantly higher than normal colon mucosal epithelium (P = 0.0008), it did not correlate with any major clinicopathological parameters of CRC. CONCLUSIONS: This study indicates c-MET mRNA overexpression in primary CRC may be an important prognostic marker for early stage invasion and regional disease metastasis.