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.

Novel jet-injection technology for nonviral intratumoral gene transfer in patients with melanoma and breast cancer.

PURPOSE: This phase I clinical trial evaluated safety, feasibility, and efficiency of nonviral intratumoral jet-injection gene transfer in patients with skin metastases from melanoma and breast cancer. EXPERIMENTAL DESIGN: Seventeen patients were enrolled. The patients received five jet injections with a total dose of 0.05 mg beta-galactosidase (LacZ)-expressing plasmid DNA (pCMVbeta) into a single cutaneous lesion. Clinical and laboratory safety monitoring were done. Systemic plasmid clearance was monitored by quantitative real-time PCR of blood samples throughout the study. All lesions were resected after 2 to 6 days. Intratumoral plasmid DNA load, DNA distribution, and LacZ expression was analyzed by quantitative real-time PCR, quantitative reverse transcription-PCR, Western blot, immunohistochemistry, and 5-bromo-4-chloro-3-indolyl-beta-D-galactoside staining. RESULTS: Jet injection of plasmid DNA was safely done in all patients. No serious side effects were observed. Thirty minutes after jet injection, peak plasmid DNA levels were detected in the blood followed by rapid decline and clearance. Plasmid DNA and LacZ mRNA and protein expression were detected in all treated lesions. Quantitative analysis revealed a correlation of plasmid DNA load and LacZ-mRNA expression confirmed by Western blot. Immunohistochemistry and 5-bromo-4-chloro-3-indolyl-beta-D-galactoside staining showed LacZ-protein throughout the tumor. Transfected tumor areas were found close and distant to the jet-injection site with varying levels of DNA load and transgene expression. CONCLUSION: Intratumoral jet injection of plasmid DNA led to efficient LacZ reporter gene expression in all patients. No side effects were experienced, supporting safety and applicability of this novel nonviral approach. A next step with a therapeutic gene product should determine antitumor efficacy of jet-injection gene transfer.

Technique and clinical consequences of sentinel lymph node biopsy in colorectal cancer.

Sentinel lymph node biopsy (SLNB) in colorectal cancer (CRC) is a controversial issue. Different detection techniques, various protocols for the histopathological work-up of the SLN and a greatly differing experience between the investigators make the comparison of the available studies problematic. Nevertheless, it is clear, that the successful clinical application of SLNB in breast cancer and melanoma cannot simply be transferred into colorectal cancer treatment. In this paper we try to define the current status of clinical application of this technique in CRC by means of a literature review and our own experience. Moreover, the background and the potential clinical implications of additionally small tumor deposits in the SLN (so-called "upstaging") is critically reviewed. Summarizing the results, it is clear, that the value of SLNB in CRC is still unclear. If current techniques are to be applied outside a study protocol and no patient selection is performed the correct identification of macrometastases needs further investigation. Although still under debate, there is otherwise growing evidence, that -at least if RT-PCR-techniques are used- the detection of small tumor deposits in the SLN may be of prognostic and therefore clinical value. Future studies should focus on two subjects: First, alternative detection techniques and careful patient selection may clarify, if an improvement of the sensitivity to detect macrometastases is feasible. Second, large prospective trials using a standardized histopathological lymph node assessment should compare SLN and Non-SLN for its incidence to bear small tumor deposits. If SLNB proves to be sensitive, the prognostic and predictive value of these additional findings should be clarified.

Long-term survival in stage IV melanoma after repetitive surgical therapy.

BACKGROUND: Surgical therapy in patients with stage IV melanoma is controversial and always an individual decision. CASE REPORT: We report the case of a young melanoma patient, who underwent resection of 5 distant metastases from 4 different organ systems. Thereby, the patient achieved a stable state of disease and a good quality of life for up to now 67 months without any evidence for further tumor manifestations at present. A systemic chemo- or immunotherapy was never applied. CONCLUSION: In selected patients with stage IV melanoma, surgery alone can provide long-term survival with good quality of life.

Sentinel lymph node biopsy in colon cancer: a prospective multicenter trial.

INTRODUCTION: The clinical impact of sentinel lymph node biopsy (SLNB) in colon cancer is still controversial. The purpose of this prospective multicenter trial was to evaluate its clinical value to predict the nodal status and identify factors that influence these results. METHODS: Colon cancer patients without prior colorectal surgery or irradiation were eligible. The sentinel lymph node (SLN) was identified intraoperatively by subserosal blue dye injection around the tumor. The SLN underwent step sections and immunohistochemistry (IHC), if classified free of metastases after routine hematoxylin and eosin examination. RESULTS: At least one SLN (median, n = 2) was identified in 268 of 315 enrolled patients (detection rate, 85%). Center experience, lymphovascular invasion, body mass index (BMI), and learning curve were positively associated with the detection rate. The false-negative rate to identify pN+ patients by SLNB was 46% (38 of 82). BMI showed a significant association to the false-negative rate (P < 0.0001), the number of tumor-involved lymph nodes was inversely associated. If only slim patients (BMI < or =24) were investigated in experienced centers (>22 patients enrolled), the sensitivity increased to 88% (14 of 16). Moreover, 21% (30 of 141) of the patients, classified as pN0 by routine histopathology, revealed micrometastases or isolated tumor cells (MM/ITC) in the SLN. CONCLUSIONS: The contribution of SLNB to conventional nodal staging of colon cancer patients is still unspecified. Technical problems have to be resolved before a definite conclusion can be drawn in this regard. However, SLNB identifies about one fourth of stage II patients to reveal MM/ITC in lymph nodes. Further studies must clarify the clinical impact of these findings in terms of prognosis and the indication of adjuvant therapy.

Efficacy of different technical procedures for sentinel lymph node biopsy in gastric cancer staging.

BACKGROUND: The clinical impact of sentinel lymph node biopsy (SLNB) in gastric cancer is controversial. We performed a prospective trial to compare different methods: radiocolloid method (RM), dye method (DM), and both methods simultaneously (dual method, or DUM) for reliability and therapeutic consequences. METHODS: RM and DM were applied in 35 gastric cancer patients. After endoscopic peritumoral injection of (99m)Tc-colloid and Patent Blue V, the positions of all blue sentinel lymph nodes (SLNs) were recorded, and the SLNs microscopically examined by hematoxylin and eosin, step sections, and immunohistochemistry. RESULTS: RM, DM, and DUM identified the SLNs in 34 (97%) of 35 patients. The sensitivity for the prediction of positive lymph node status for RM was 22 (92%) of 24, for DM 16 (66%) of 24, and for DUM 22 (92%) of 24. In 7 of 17 (RM), 5 of 15 (DM), and 7 of 17 (DUM) patients classified as N0 by routine hematoxylin and eosin staining, micrometastases or isolated tumor cells were found in the SLN (upstaging) after focused examination. If only a limited lymph node dissection of the SLN basins would have been performed in patients, residual lymph node metastases were left in 9 of 24 (RM), in 7 of 34 (DM), and in 5 of 24 (DUM) of patients with node-positive disease. CONCLUSIONS: Use of RM was superior. DUM did not further increase the sensitivity. A limited lymph node dissection-i.e., lymphatic basin in patients with SLN-positive disease-is associated with a high risk of residual metastases. Patients with negative SLNs may be selected for a limited surgical procedure if they meet certain criteria.

Prognostic value of cytokeratin-positive bone marrow cells of gastric cancer patients.

BACKGROUND: Epithelial cells in the bone marrow of patients with gastric cancer suggest tumor dissemination; however, their prognostic implications are controversial. We prospectively evaluated the correlation of bone marrow findings, recurrence rate, and disease-free survival after long-term follow-up. METHODS: Bone marrow were aspirated from both iliac crests and stained with monoclonal cytokeratin (CK)-18 antibody in 209 patients before their initial operation. Patients were followed up for a median of 56 months. RESULTS: Overall, 39 (19%) of 209 patients and 15 (14%) of 109 R0-resected patients had CK-positive cells. CK-positive patients had more local, regional, and distant recurrence than CK-negative patients (P < .05). We found a significantly shorter disease-free survival (P < .05) in the patients with >2 CK-positive cells per 2 x 10(6) bone marrow cells (mean, 35 months) than in patients with 2 CK-positive cells per 2 x 10(6) bone marrow cells was an independent prognostic factor for tumor-related death (P < .05). CONCLUSIONS: Not only the mere presence of CK-positive epithelial cells in bone marrow, but also the cell number, correlates with prognosis. Our findings suggest that classifying CK-positive bone marrow cells in these patients will facilitate future studies.

Long-term morbidity of patients with early breast cancer after sentinel lymph node biopsy compared to axillary lymph node dissection.

BACKGROUND AND OBJECTIVES: Sentinel lymph node biopsy (SLNB) is widely accepted as an excellent method in the management of early breast cancer in patients with clinically negative axillary lymph nodes. Since SLNB requires less traumatic surgery to the axilla than axillary lymph node dissection (ALND), it was assumed to result in reduced shoulder/arm morbidity. However, data on long-term morbidity after SNLB are sparse. The present study was set up to compare long-term arm/shoulder morbidity as well as oncological outcome after SLNB versus ALND in patients with early breast cancer. METHODS: Oncological outcome, objective shoulder/arm morbidity, and subjective complaints after SLNB or ALND for T1 breast cancer were assessed after a minimum follow-up of 20 months. RESULTS: One hundred thirty four patients were included in the study. Thirty-one patients underwent SNLB only, 103 patients had SLNB followed by ALND or ALND only. Loss of strength and hypaesthesia were less frequent after SLNB. No lymph oedema occurred after SNLB without adjuvant radiotherapy. Subjective complaints concerning pain, hypaesthesia, and paresthesia were more common in the ALND group. No axillary recurrence developed in either group. CONCLUSIONS: Isolated SLNB in node-negative pT1 breast cancer patients is a highly efficient tool to reduce postoperative long-term morbidity without compromising the local control of the disease. The reported ameliorations should favour SLNB as staging and treatment modality in patients suffering from early breast cancer.

Detection of lymph node micrometastases and isolated tumor cells in sentinel and nonsentinel lymph nodes of colon cancer patients.

About 20% to 30% of colon cancer patients classified as node negative by routine hematoxylin-eosin (H&E) staining are found to have micrometastases (MM) or isolated tumor cells (ITC) in sentinel lymph nodes (SLNs) if analyzed by step sections and immunohistochemistry (IHC). Whether SLNs are in this respect representative for all lymph nodes was addressed in this study. SLNs were identified using the intraoperative blue dye detection technique. If all lymph nodes (SLNs and non-SLNs) of a patient were negative by routine H&E staining, they were step-sectioned and analyzed by IHC using pancytokeratin antibodies. We identified at least one SLN in 47 of the 55 patients (85%) and examined a median of 26 lymph nodes per patient (range 10-59). By routine H&E staining, 14 of the 47 patients showed lymph node metastases (30%); the remaining 33 were classified as node-negative. In this group (33 patients), 1011 lymph nodes were analyzed by step sections and IHC: 14 of 70 SLNs. (20%) but only 37 of 941 non-SLNs (4%) had MM/ITC (p < 0.001). Furthermore, 13 of the 33 H&E-negative patients were found to have MM/ITC (39%). In 11 of the 13 patients, MM/ITC were identified in both SLNs and non-SLNs in 1 patient in the SLN only, and in 1 patient in a non-SLN only (sensitivity for the identification of MM/ITC: 92%; negative predictive value: 95%). The SLN biopsy is a valid tool to detect, as well as exclude, the presence of MM/ITC in colon cancer patients. Our results may be of prognostic relevance and influence patient stratification for adjuvant therapy trials.

A concept for the clinical implementation of sentinel lymph node biopsy in patients with breast carcinoma with special regard to quality assurance.

The development of standardized and reproducible clinical pathways is an important precondition for quality assurance in medicine, especially if a new method has not yet been ultimately validated. Sentinel lymph node biopsy (SLNB) is a widely accepted new surgical procedure in the treatment of early breast carcinoma. However, numerous steps of the method and details of the technique are not standardized and, thus, hamper quality assurance for SLNB. The German Society of Senology appointed an interdisciplinary consensus committee to work out guidelines for the standardized performance and quality-assured implementation of SLNB on a nationwide, homogeneous standard. The committee consisted of surgeons, gynecologists, radiooncologists, nuclear physicians, oncologists, and pathologists. Relevant questions related to patient selection, lymphatic mapping, surgery, histopathologic work-up, further local and systemic treatment decisions, patient information, training, and follow-up were evaluated with respect to clinical evidence, objectivity, and reproducibility. Clinical pathways were developed on the basis of this analysis. Requirements to the performing institutions and surgeons were defined.

Refined staging by sentinel lymph node biopsy to individualize therapy in anal cancer.

We evaluated the feasibility of the sentinel lymph node technique to refine staging and potentially individualize therapy for anal cancer. Seventeen patients with cancer of the anal canal underwent peritumoral injection of 99mTc-colloid, followed 17 hours later by lymphoscintigraphy. A selective lymph node biopsy (SLNB) was attempted in 12 of 13 cases with scintigraphically detected SLNs. Lymph node metastases were present in 5 of 12 cases (42%); in 2 of these 5 cases, micrometastases were detected only by immunohistochemical staining. Hence, SLNB refines the diagnostic workup for anal cancer and provides an accurate basis for individualized therapy.

Body mass index does not affect systematic D2 lymph node dissection and postoperative morbidity in gastric cancer patients.

BACKGROUND: The extent of standard lymph node dissection (D1, D2, or D3) in gastric cancer patients is still controversial. Several prospective European trials attained contradictory results. A generally increased body mass index (BMI) of the European patients was assumed to be one of the major causes for postoperative morbidity. METHODS: We evaluated the effect of BMI on the quality of routine D2 lymph node dissection and on postoperative morbidity in patients with gastric cancer who underwent a potentially curative total gastrectomy. A total of 199 consecutive gastric cancer patients who underwent a total gastrectomy and a routine D2 lymph node dissection between 1992 and 2001 were included in the study. According to BMI, they were assigned to three groups: group A, with BMI <25 kg/m(2) (normal body weight); group B, with BMI of 25 to 30 kg/m(2) (overweight); and group C, with BMI >30 kg/m(2) (obesity). Parameters such as complete histopathological staging, intraoperative blood loss, length of operation, and surgical and nonsurgical morbidity were recorded and correlated within the different groups. RESULTS: No significant differences were found with regard to the number of examined lymph nodes, blood loss, length of operation, surgical complications, or length of stay in the intensive care unit. CONCLUSIONS: In contrast to comparable Japanese studies, our analysis reveals that even for overweight patients, a standard D2 lymph node dissection is justified without significantly increased morbidity.