Daniel Oertli

Morbidity of Sentinel Lymph Node Biopsy (SLN) Alone Versus SLN and Completion Axillary Lymph Node Dissection After Breast Cancer Surgery A Prospective Swiss Multicenter Study on 659 Patients

Objective:To assess the morbidity after sentinel lymph node (SLN) biopsy compared with SLN and completion level I and II axillary lymph node dissection (ALND) in a prospective multicenter study. Summary Background Data:ALND after breast cancer surgery is associated with considerable morbidity. We hypothesized: 1) that the morbidity in patients undergoing SLN biopsy only is significantly lower compared with those after SLN and completion ALND level I and II; and 2) that SLN biopsy can be performed with similar intermediate term morbidity in academic and nonacademic centers. Methods:Patients with early stage breast cancer (pT1 and pT2 ≤ 3 cm, cN0) were included between January 2000 and December 2003 in this prospective Swiss multicenter study. All patients underwent SLN biopsy. In all patients with SLN macrometastases and most patients with SLN micrometastases (43 of 68) or isolated tumor cells (11 of 19), a completion ALND was performed. Postoperative morbidity was assessed based on a standardized protocol. Results:SLN biopsy alone was performed in 449 patients, whereas 210 patients underwent SLN and completion ALND. The median follow-ups were 31.0 and 29.5 months for the SLN and SLN and completion ALND groups, respectively. Intermediate-term follow-up information was available from 635 of 659 patients (96.4%) of enrolled patients. The following results were found in the SLN versus SLN and completion ALND group: presence of lymphedema (3.5% vs. 19.1%, P < 0.0001), impaired shoulder range of motion (3.5% vs. 11.3%, P < 0.0001), shoulder/arm pain (8.1% vs. 21.1%, P < 0.0001), and numbness (10.9% vs. 37.7%, P < 0.0001). No significant differences regarding postoperative morbidity after SLN biopsy were noticed between academic and nonacademic hospitals (P = 0.921). Conclusions:The morbidity after SLN biopsy alone is not negligible but significantly lower compared with level I and II ALND. SLN biopsy can be performed with similar short- and intermediate-term morbidity in academic and nonacademic centers.

High frequency of tumor-infiltrating FOXP3+ regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients†

Regulatory T cells (Treg) inhibit the generation of host‐versus‐tumor immunity via suppression of tumor‐specific effector T‐cell responses and development of immune tolerance to neoplastic cells. The transcription factor forkhead box P3 (FOXP3) is an intracellular key molecule for Treg development and function and is considered to represent the most specific Treg cell marker. The aim of this study was to analyze the frequency and prognostic impact of tumor‐infiltrating FOXP3+ Treg in colorectal cancer (CRC) stratified by mismatch‐repair (MMR) status. Using the tissue microarray technique, 1,420 tumor samples were immunohistochemically stained for FOXP3 and stratified into 1,197 MMR‐proficient and 223 MMR‐deficient CRCs. Additionally, the 1,197 MMR‐proficient CRCs were randomized into 2 subgroups (Test Groups 1 and 2; n = 613 and 584, respectively). In both MMR‐proficient CRC subgroups high frequency tumor‐infiltrating FOXP3+ Treg was associated with early T stage (p = 0.001 and <0.001), tumor location (p = 0.01 and 0.045) and increased 5‐year survival rate (p = 0.004 and <0.001), whereas in MMR‐deficient CRCs an association between FOXP3+ Treg and absence of lymph node involvement (p = 0.023), absence of vascular invasion (p = 0.023) and improved 5‐year survival rate (p = 0.029) could be detected. In a multivariable analysis including age, gender, T stage, N stage, tumor grade, vascular invasion, and tumor border configuration, a high FOXP3+ Treg frequency was an independent prognostic factor in both MMR‐proficient CRC subsets (p = 0.019 and p = 0.007), but not in the MMR‐deficient CRCs (p = 0.13). Therefore, high frequency of tumor‐infiltrating FOXP3+ Treg is associated with early T stage and independently predicts improved disease‐specific survival in MMR‐proficient CRC patients.

The timing of surgical antimicrobial prophylaxis.

Objective:To obtain precise information on the optimal time window for surgical antimicrobial prophylaxis. Summary Background Data:Although perioperative antimicrobial prophylaxis is a well-established strategy for reducing the risk of surgical site infections (SSI), the optimal timing for this procedure has yet to be precisely determined. Under todays recommendations, antibiotics may be administered within the final 2 hours before skin incision, ideally as close to incision time as possible. Methods:In this prospective observational cohort study at Basel University Hospital we analyzed the incidence of SSI by the timing of antimicrobial prophylaxis in a consecutive series of 3836 surgical procedures. Surgical wounds and resulting infections were assessed to Centers for Disease Control and Prevention standards. Antimicrobial prophylaxis consisted in single-shot administration of 1.5 g of cefuroxime (plus 500 mg of metronidazole in colorectal surgery). Results:The overall SSI rate was 4.7% (180 of 3836). In 49% of all procedures antimicrobial prophylaxis was administered within the final half hour. Multivariable logistic regression analyses showed a significant increase in the odds of SSI when antimicrobial prophylaxis was administered less than 30 minutes (crude odds ratio = 2.01; adjusted odds ratio = 1.95; 95% confidence interval, 1.4–2.8; P < 0.001) and 120 to 60 minutes (crude odds ratio = 1.75; adjusted odds ratio = 1.74; 95% confidence interval, 1.0–2.9; P = 0.035) as compared with the reference interval of 59 to 30 minutes before incision. Conclusions:When cefuroxime is used as a prophylactic antibiotic, administration 59 to 30 minutes before incision is more effective than administration during the last half hour.

Clinical impact of programmed cell death ligand 1 expression in colorectal cancer.

BACKGROUND Programmed cell death 1 (PD-1) receptor triggering by PD ligand 1 (PD-L1) inhibits T cell activation. PD-L1 expression was detected in different malignancies and associated with poor prognosis. Therapeutic antibodies inhibiting PD-1/PD-L1 interaction have been developed. MATERIALS AND METHODS A tissue microarray (n=1491) including healthy colon mucosa and clinically annotated colorectal cancer (CRC) specimens was stained with two PD-L1 specific antibody preparations. Surgically excised CRC specimens were enzymatically digested and analysed for cluster of differentiation 8 (CD8) and PD-1 expression. RESULTS Strong PD-L1 expression was observed in 37% of mismatch repair (MMR)-proficient and in 29% of MMR-deficient CRC. In MMR-proficient CRC strong PD-L1 expression correlated with infiltration by CD8(+) lymphocytes (P = 0.0001) which did not express PD-1. In univariate analysis, strong PD-L1 expression in MMR-proficient CRC was significantly associated with early T stage, absence of lymph node metastases, lower tumour grade, absence of vascular invasion and significantly improved survival in training (P = 0.0001) and validation (P = 0.03) sets. A similar trend (P = 0.052) was also detectable in multivariate analysis including age, sex, T stage, N stage, tumour grade, vascular invasion, invasive margin and MMR status. Interestingly, programmed death receptor ligand 1 (PDL-1) and interferon (IFN)-γ gene expression, as detected by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in fresh frozen CRC specimens (n = 42) were found to be significantly associated (r = 0.33, P = 0.03). CONCLUSION PD-L1 expression is paradoxically associated with improved survival in MMR-proficient CRC.

Axillary recurrence rate in breast cancer patients with negative sentinel lymph node (SLN) or SLN micrometastases: prospective analysis of 150 patients after SLN biopsy.

Objective:To assess the axillary recurrence rate in breast cancer patients with negative sentinel lymph node (SLN) or SLN micrometastases (>0.2 mm to ≤2.0 mm) after breast surgery and SLN procedure without formal axillary lymph node dissection (ALND). Summary Background Data:Under controlled study conditions, the SLN procedure proved to be a reliable method for the evaluation of the axillary nodal status in patients with early-stage invasive breast cancer. Axillary dissection of levels I and II can thus be omitted if the SLN is free of macrometastases. The prognostic value and potential therapeutic consequences of SLN micrometastases, however, remain a matter of great debate. We present the follow-up data of our prospective SLN study, particularly focusing on the axillary recurrence rate in patients with negative SLN and SLN micrometastases. Methods:In this prospective study, 236 SLN procedures were performed in 234 patients with early-stage breast cancer between April 1998 and September 2002. The SLN were marked and identified with 99m technetium-labeled colloid and blue dye (Isosulfanblue 1%). The excised SLNs were examined by step sectioning and stained with hematoxylin and eosin and immunohistochemistry (cytokeratin antibodies Lu-5 or CK 22). Only patients with SLN macrometastases received formal ALND of levels I and II, while patients with negative SLN or SLN micrometastases did not undergo further axillary surgery. Results:The SLN identification rate was 95% (224/236). SLN macrometastases were found in 33% (74/224) and micrometastases (>0.2 mm to ≤2 mm) in 12% (27/224) of patients. Adjuvant therapy did not differ between the group of SLN-negative patients and those with SLN micrometastases. After a median follow-up of 42 months (range 12–64 months), 99% (222/224) of evaluable patients were reassessed. While 1 patient with a negative SLN developed axillary recurrence (0.7%, 1/122), all 27 patients with SLN micrometastases were disease-free at the last follow-up control. Conclusions:Axillary recurrences in patients with negative SLN or SLN micrometastases did not occur more frequently after SLN biopsy alone compared with results from the recent literature regarding breast cancer patients undergoing formal ALND. Based on a median follow-up of 42 months—one of the longest so far in the literature—the present investigation does not provide evidence that the presence of SLN micrometastases leads to axillary recurrence or distant disease and supports the theory that formal ALND may be omitted in these patients.

Surgical Glove Perforation and the Risk of Surgical Site Infection

HYPOTHESIS Clinically apparent surgical glove perforation increases the risk of surgical site infection (SSI). DESIGN Prospective observational cohort study. SETTING University Hospital Basel, with an average of 28,000 surgical interventions per year. PARTICIPANTS Consecutive series of 4147 surgical procedures performed in the Visceral Surgery, Vascular Surgery, and Traumatology divisions of the Department of General Surgery. MAIN OUTCOME MEASURES The outcome of interest was SSI occurrence as assessed pursuant to the Centers of Disease Control and Prevention standards. The primary predictor variable was compromised asepsis due to glove perforation. RESULTS The overall SSI rate was 4.5% (188 of 4147 procedures). Univariate logistic regression analysis showed a higher likelihood of SSI in procedures in which gloves were perforated compared with interventions with maintained asepsis (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.4-2.8; P < .001). However, multivariate logistic regression analyses showed that the increase in SSI risk with perforated gloves was different for procedures with vs those without surgical antimicrobial prophylaxis (test for effect modification, P = .005). Without antimicrobial prophylaxis, glove perforation entailed significantly higher odds of SSI compared with the reference group with no breach of asepsis (adjusted OR, 4.2; 95% CI, 1.7-10.8; P = .003). On the contrary, when surgical antimicrobial prophylaxis was applied, the likelihood of SSI was not significantly higher for operations in which gloves were punctured (adjusted OR, 1.3; 95% CI, 0.9-1.9; P = .26). CONCLUSION Without surgical antimicrobial prophylaxis, glove perforation increases the risk of SSI.

Response to [90Yttrium-DOTA]-TOC Treatment is Associated with Long-term Survival Benefit in Metastasized Medullary Thyroid Cancer: A Phase II Clinical Trial

Purpose: We aimed to explore the efficacy of 90Yttrium–1,4,7,10-tetra-azacyclododecane N,N′,N″,N-‴-tetraacetic acid (90Y-DOTA)–Tyr3-octreotide (TOC) therapy in advanced medullary thyroid cancer. Experimental Design: In a phase II trial, we investigated the response, survival, and long-term safety profile of systemic [90Y-DOTA]-TOC treatment in metastasized medullary thyroid cancer. Adverse events were assessed according to the criteria of the National Cancer Institute. Survival analyses were done using multiple regression models. Results: Thirty-one patients were enrolled. A median cumulative activity of 12.6 GBq (range, 1.7-29.6 GBq) of [90Y-DOTA]-TOC was administered. Response was found in nine patients (29.0%). Four patients (12.9%) developed hematologic toxicities and seven patients (22.6%) developed renal toxicities. Response to treatment was associated with longer survival from time of diagnosis (hazard ratio, 0.20; 95% confidence interval, 0.05-0.81; P = 0.02) and from time of first [90Y-DOTA]-TOC therapy (hazard ratio, 0.16; 95% confidence interval, 0.04-0.63; P = 0.009). The visual grade of scintigraphic tumor uptake was not associated with treatment response or survival. Conclusions: Response to [90Y-DOTA]-TOC therapy in metastasized medullary thyroid cancer is associated with a long-term survival benefit. Treatment should be considered independently from the result of the pretherapeutic scintigraphy.

Phase I/II clinical trial of a nonreplicative vaccinia virus expressing multiple HLA-A0201-restricted tumor-associated epitopes and costimulatory molecules in metastatic melanoma patients.

We performed a phase I/II clinical trial in metastatic melanoma patients with an ultraviolet (UV)-inactivated nonreplicating recombinant vaccinia virus enabling the expression, from a single construct, of endoplasmic reticulum-targeted HLA-A0201-restricted Melan-A/MART-1(27-35), gp100(280-288), and tyrosinase(1-9) epitopes, together with CD80 and CD86 costimulatory proteins. Corresponding soluble peptides were used to boost responses and granulocyte-macrophage colony-stimulating factor was used as systemic adjuvant. Safety and immunogenicity, as monitored with in vitro-restimulated peripheral blood mononuclear cells by cytotoxic T lymphocyte precursor (CTLp) frequency analysis and tetramer staining, were specifically addressed. Of 20 patients entering the protocol, 2 had to withdraw because of rapidly progressing disease. Immune responses were evaluated in 18 patients (stage III, n = 5; stage IV, n = 13) and increases in specific CTLp frequencies were observed in 15. In 16 patients responsiveness against all 3 antigens could be analyzed: 7 (43%), including all stage III cases, showed evidence of induction of CTLs specific for the three epitopes, and 2 (12%) and 4 (25%), respectively, showed reactivity against two or one tumor-associated antigen. In three stage IV patients no specific CTL reactivity could be induced. Increases in CTLp frequency were detected mostly after viral vaccine injections. However, in a majority of patients final CTLp levels were comparable to initial levels. Tetramer characterization of Melan-A/MART-1(27-35)-specific CTLs during the protocol also suggested preferential expansion after recombinant virus administration. Vector-specific humoral responses, frequently undetectable in stage IV patients, did not appear to prevent tumor-associated antigen-specific CTL induction. Aside from a single occurrence of transient grade 3 leukopenia, no major clinical toxicity was reported. Seventeen of 18 patients completed the 3-month trial (one patient died before the last delayed-type hypersensitivity test). Three displayed regression of individual metastases, seven had stable disease, and progressive disease was observed in seven patients. This is the first report on the administration of a UV-inactivated recombinant vaccinia virus coexpressing five transgenes in cancer patients. The results described here, in terms of safety and immunogenicity, support the use of this reagent in active specific immunotherapy.

Detecting pheochromocytoma: defining the most sensitive test.

Objective:To define the most sensitive biochemical test to establish the diagnosis of pheochromocytoma and also to assess the potential role of iodine 131-labeled metaiodobenzylguanidine scintigraphy (131I-MIBG) in the diagnosis of this tumor. Summary Background Data:Pheochromocytoma is a rare, catecholamine-producing tumor with preferential localization in the adrenal gland. Despite its importance, the most sensitive test to establish the diagnosis remains to be defined. Methods:Prospective data collection was done on patients with pheochromocytoma treated at the Duke University Medical Center and the Durham Veterans Affairs Medical Center, Durham, NC. All urinary, plasma, and platelet analyses were highly standardized and supervised by one investigator (J.M.F.). 131I-MIBG scans were independently reviewed by 2 nuclear medicine physicians. Results:A total of 152 patients (55.3% female) were enrolled in the present analysis. Patients were predominantly white (73.7%). Spells (defined as profuse sweating, tachycardia, and headache) and hypertension at diagnosis were present in 51.4% and 66.6%, respectively. Bilateral disease was found in 12.5%, malignant pheochromocytoma in 29.6%, and hereditary forms in 23.0%. The most sensitive tests were total urinary normetanephrine (96.9%), platelet norepinephrine (93.8%), and 131I-MIBG scintigraphy (83.7%). In combination with 131I-MIBG scintigraphy, platelet norepinephrine had a sensitivity of 100%, plasma norepinephrine/MIBG of 97.1%, total urine normetanephrine/MIBG of 96.6%, and urine norepinephrine/MIBG of 95.3%. Conclusions:The tests of choice to establish the diagnosis of pheochromocytoma are urinary normetanephrine and platelet norepinephrine. A combination of 131I-MIBG scintigraphy and diagnostic tests in urine, blood, or platelets does further improve the sensitivity. We thus advocate performing an MIBG scan if the diagnosis of pheochromocytoma is clinically suspected and catecholamine measurements are within the normal range.

Selective axillary surgery in breast cancer patients based on positron emission tomography with 18F-fluoro-2-deoxy-D-glucose: not yet!

We prospectively evaluated 31 patients with invasive breast cancer. Preoperative positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) for detection of axillary lymph node metastases was compared with the histopathologic status of the sentinel lymph node (SLN). Sensitivity of PET imaging was 43%, specificity and negative predictive value were 94 and 67%, respectively. The smallest metastasis detected by PET measured 3 mm in diameter. The results of this study suggest that detection of small axillary lymph node metastases is limited by the currently achievable spatial resolution of PET imaging. Selective axillary surgery in breast cancer patients based on 18F-FDG PET is yet not possible.