Hot dots - which nodes should be removed in sentinel lymph node biopsy for melanoma?

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a critical staging tool for melanoma patients. The optimal number of lymph nodes removed in SLNB remains unclear. In this study, we retrospectively analysed and tested different criteria for selecting sentinel lymph nodes (SLNs) by radiotracer uptake and blue dye, and their impact on nodal staging. We also evaluated the association between SLN tumour burden and radiotracer uptake. METHODS: The study population consisted of melanoma patients undergoing SLNB. During the operation all radioactive and blue nodes were removed and sent for histopathological analysis. The ex vivo radioactive count and presence of blue dye of each node were recorded, and these were correlated with presence and size of metastasis in each SLN. RESULTS: Altogether 175 patients with clinically occult metastasis presented with one or more positive, i.e. metastatic, SLNs. The mean number of lymph nodes removed was 4.5, and the mean number of positive lymph nodes was 1.5 per patient. The most radioactive or hottest node was negative in 38 patients (22%). By removing the hottest node and all nodes with radioactivity >10% of the hottest node, 97% of patients would have been staged correctly. In five patients, metastasis was found solely in a SLN with radioactivity <10% of the hottest node. Of all 267 positive nodes removed, 125 (47%) contained blue dye. Patients with a negative hottest node were associated with lower SLN tumour burden. CONCLUSIONS: By removing the hottest node and all nodes with radioactivity >10% of the hottest node, 97% of patients with SLN metastases are correctly staged with or without using blue dye.

Breast Reconstruction-Prospective Follow up on Breast Cancer Patients' Health-Related Quality of Life.

BACKGROUND: Analysing the results of breast reconstruction is important both in terms of oncological safety and health-related quality of life (HRQoL). Immediate breast reconstruction (IBR) is thought to be prone to complications and heavy for patients with no time to adapt to having cancer. Delayed reconstruction (DR) is an option after primary surgery and oncological treatments, but requires patients to go through two recovery periods after surgery. METHODS: A prospective study of 1065 breast cancer patients with repeated measurement of HRQoL with both generic (15D) and disease specific (EORTC QLQ C-30 BR23) measuring tools included 51 IBR patients and 41 DR patients. These patients' HRQoL and reconstruction methods were studied in more detail alongside with clinical data to determine HRQoL levels for patients with IBR and those with mastectomy and DR during a 24-month follow-up. Measuring points were baseline, 3, 6, 12 and 24 months. RESULTS: Most frequent techniques used were abdominal flaps (IBR n = 16, DR n = 14), latissimus dorsi flaps (LD) (IBR n = 19, DR n = 10), implants (IBR n = 12) and fat grafting (DR n = 6). Smaller groups were excluded from group comparisons. Approximately one third of the patients encountered complications. Symptom scores did not differ between reconstruction methods. DR patients had better overall HRQoL at 12 months, but at 24 months the situation had changed in favour of IBR. Both approaches of reconstructive surgery produced good HRQoL with no significant differences between the approaches studied.

Health-Related Quality of Life After Breast Reconstruction: Comparing Outcomes Between Reconstruction Techniques Using the BREAST-Q.

BACKGROUND: Reconstruction of the breast following mastectomy can improve patients' health-related quality of life (HRQL). We aimed to assess HRQL in women after mastectomy and breast reconstruction and to identify differences in HRQL related to the reconstruction method used. METHODS: A cross-sectional study was performed on patients who had undergone breast reconstruction in Helsinki University Hospital between 08/2017 and 7/2019. The postoperative HRQL was assessed using the BREAST-Q (2.0) Reconstruction Module. The results were compared between patients with different reconstruction methods using the Kruskal-Wallis test. RESULTS: A total of 146 patients were identified. Microvascular flaps (n = 77) were the most common method for primary breast reconstruction, followed by latissimus dorsi (LD) flaps (n = 45), fat grafting (n = 18) and implant reconstruction (n = 6). The satisfaction with breasts was high in all groups (median 61, IQR 49-71). The physical well-being of the chest was high regardless of the reconstructive method (median 100, IQR 80-100). However, women with fat grafting reported more adverse effects of radiation (median 17, IQR 14-17 vs. 18, IQR 17-18 for other groups, p = 0.02). Donor site morbidity was low, and patients reported high satisfaction with the back (median 66/100, IQR57-90) and abdomen (median 9/12, IQR 8-10), and physical well-being of the back (median 61/100, IQR 53-70) and abdomen (median 65/100, IQR 60-86). CONCLUSIONS: The patient-reported HRQL after breast reconstruction is high. Most women report being satisfied with the reconstruction, irrespective of the reconstruction method used. The reconstruction method can thus be chosen individually in cooperation between the patient and the surgeon.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

Health-related quality of life in different states of breast cancer - comparing different instruments.

BACKGROUND: The prognosis of breast cancer has improved significantly during the last few decades increasing the interest in health-related quality of life (HRQoL). The aim of this study was to compare the HRQoL scores produced by different instruments and to shed light on their validity in various states of breast cancer by studying the association of cancer-related symptoms with HRQoL. MATERIAL AND METHODS: An observational, cross-sectional study of breast cancer patients treated in the Helsinki and Uusimaa Hospital District from September 2009 to April 2011. A total of 840 patients completed three HRQoL questionnaires: the EQ-5D-3L (including VAS), 15D and EORTC QLQ-30 and a questionnaire concerning sociodemographic factors. Patients were divided into five mutually exclusive groups: primary treatment (n = 118), recovery (6-18 months from diagnosis) (n = 150), remission (>18 months) (n = 382), metastatic disease (n = 176) and palliative care (n = 14). The association of HRQoL with sociodemographic and clinical factors and cancer-related symptoms, screened by the EORTC QLQ-30, was studied by multivariate modeling using stepwise linear regression analysis. RESULTS: HRQoL scores were the best at the time closest to diagnosis and deteriorated with disease progression. The EQ-5D had a pronounced ceiling effect with 40.8% of the respondents scoring 1 (perfect health) compared to 6% for the 15D and 5.6% for VAS. In regression analyses, pain, fatigue and financial difficulties were the most important predictors of lower HRQoL. The 15D showed better discriminatory power and content validity. The EORTC QLQ-C30 functioning deteriorated in advanced states of the disease with physical, social and role functioning being the most affected. Insomnia, fatigue and pain were the most commonly reported symptoms in all groups. CONCLUSIONS: Different HRQoL instruments produce notably different HRQoL scores. The EQ-5D has a pronounced ceiling effect. Pain and fatigue are the most common symptoms associated with poor HRQoL in all disease states.

Breast Cancer Detection by Preoperative Imaging in Reduction Mammaplasty Patients: A Single Center Study of 918 Patients.

BACKGROUND: The role of preoperative imaging and the usability of different imaging modalities is highly variable and controversial in reduction mammaplasty patients. Our study describes the imaging process in a single center in regard to modality selection, age and timing, and of the association between imaging and histopathological findings in reduction mammaplasty specimens. METHODS: Nine hundred eighteen women, who underwent reduction mammaplasty during 1.1.2007-31.12.2011, were retrospectively reviewed for demographics, preoperative imaging, further preoperative examinations, and pathology reports. RESULTS: Preoperative imaging had been conducted for 89.2% (n = 819) of the patients. In 49 (6.0%) patients, suspicious preoperative imaging led to further examinations revealing 2 high-risk lesions (atypical ductal hyperplasia (ADH), lobular carcinoma in situ (LCIS)), and 2 cancers preoperatively. Postoperatively abnormal histopathology specimens were revealed in 88 (10.4%) patients. The incidence of high-risk lesions was 5.5% (n = 47), and the incidence of cancer was 1.2% (n = 10). Preoperative imaging was normal (BI-RADS 1 and BI-RADS 2) in 80.8% of these patients. The sensitivity of the preoperative imaging for cancer detection was 20.0%, and the specificity was 100.0%. CONCLUSIONS: Preoperative imaging and further examinations do not sufficiently detect malignant or cancer risk-increasing findings. Therefore, histopathological analysis of reduction mammaplasty specimens seems mandatory.

Osteopontin promotes the invasive growth of melanoma cells by activating integrin αvß3 and down-regulating tetraspanin CD9.

Overexpression of osteopontin (OPN) is strongly associated with the invasiveness/metastasis of many cancers, including melanomas. However, the molecular mechanisms of OPN in these processes remain poorly understood. We found that forced expression of OPN in early vertical-growth-phase melanoma cells dramatically increased their migration/invasion and growth/survival in a three-dimensional collagen I gel. Neutralizing antibodies to OPN, integrin ß1, and integrin αvß3, but not to CD44, negated the effects of OPN. Conversely, knocking down OPN in metastatic melanoma cells abrogated the invasive growth. OPN overexpression activated and OPN knockdown inactivated αvß3 and αvß5 integrins, negligibly affecting their expression. We further found OPN expression to inversely correlate with tetraspanin CD9 expression. Early-stage melanoma cells displayed low OPN and high CD9 expression, and conversely, metastatic cells displayed high OPN and low CD9 expression. Overexpression of OPN in vertical-growth-phase melanoma cells induced down-regulation of CD9, and knockdown of OPN in metastatic melanoma cells up-regulated CD9. Reversion of these CD9 changes abolished the effects of OPN. Furthermore, knockdown of CD9 in early-stage melanoma cells stimulated their invasive capacity in three-dimensional collagen. Similarly, microarray analyses of benign nevi and primary melanomas from different stages revealed an inverse correlation between OPN and CD9. These data suggest that OPN promotes melanoma cell invasion by activating integrin αvß3 and down-regulating CD9, a putative metastasis suppressor.

Immediate versus delayed breast reconstruction: Long-term follow-up on health-related quality of life and satisfaction with breasts.

INTRODUCTION: Health-related quality of life (HRQL) can be improved by breast reconstruction following mastectomy. The optimal timing of the reconstruction remains unclear. METHODS: A cross-sectional study on 338 women who had undergone immediate or delayed breast reconstruction between 08/2017 and 07/2019 was performed. The postoperative HRQL was assessed using the BREAST-Q Reconstruction Module and the 36-Item Short Form Survey (SF-36). Regression analysis was performed for group-wise comparison. RESULTS: A total of 146 (43%) patients participated. Seventy-seven patients (53%) had undergone immediate, and 69 patients (47%) had delayed reconstruction. The median age was 55 years (interquartile ratio [IQR] 50-62) for the Immeda group te, and 60 years (IQR 54-65) for the delayed reconstruction group. The median follow-up time was 2.3 years (IQR 1.8-2.9). No difference between the groups was detected in satisfaction with breasts (median 61, IQR 53-71 vs. 62, IQR 46-71, p = 0.62), physical well-being of the chest (median 100, IQR 80-100 vs. 100, IQR 80-100, p = 0.95) or psychosocial well-being (median 69, IQR 54-83 vs. 62, IQR 54-74, p = 0.19). No difference was detected in the SF-36 domains either. CONCLUSIONS: The timing of the breast reconstruction does not affect the postoperative HRQL. Patients with both immediate and delayed breast reconstruction reported high satisfaction with the breast and psychosocial well-being.

Truncating NFKB1 variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis.

In monogenic autoinflammatory diseases, mutations in genes regulating innate immune responses often lead to uncontrolled activation of inflammasome pathways or the type I interferon (IFN-I) response. We describe a mechanism of autoinflammation potentially predisposing patients to life-threatening necrotizing soft tissue inflammation. Six unrelated families are identified in which affected members present with necrotizing fasciitis or severe soft tissue inflammations. Exome sequencing reveals truncating monoallelic loss-of-function variants of nuclear factor κ light-chain enhancer of activated B cells (NFKB1) in affected patients. In patients' macrophages and in NFKB1-variant-bearing THP-1 cells, activation increases both interleukin (IL)-1ß secretion and IFN-I signaling. Truncation of NF-κB1 impairs autophagy, accompanied by the accumulation of reactive oxygen species and reduced degradation of inflammasome receptor nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3), and Toll/IL-1 receptor domain-containing adaptor protein inducing IFN-ß (TRIF), thus leading to combined excessive inflammasome and IFN-I activity. Many of the patients respond to anti-inflammatory treatment, and targeting IL-1ß and/or IFN-I signaling could represent a therapeutic approach for these patients.

TGF-ß signaling, activated stromal fibroblasts, and cysteine cathepsins B and L drive the invasive growth of human melanoma cells.

Accumulating evidence indicates that interactions between cancer cells and stromal cells are important for the development/progression of many cancers. Herein, we found that the invasive growth of melanoma cells in three-dimensional-Matrigel/collagen-I matrices is dramatically increased on their co-culture with embryonic or adult skin fibroblasts. Studies with fluorescent-labeled cells revealed that the melanoma cells first activate the fibroblasts, which then take the lead in invasion. To identify the physiologically relevant invasion-related proteases involved, we performed genome-wide microarray analyses of invasive human melanomas and benign nevi; we found up-regulation of cysteine cathepsins B and L, matrix metalloproteinase (MMP)-1 and -9, and urokinase- and tissue-type plasminogen activators. The mRNA levels of cathepsins B/L and plasminogen activators, but not MMPs, correlated with metastasis. The invasiveness/growth of the melanoma cells with fibroblasts was inhibited by cell membrane-permeable inhibitors of cathepsins B/L, but not by wide-spectrum inhibitors of MMPs. The IHC analysis of primary melanomas and benign nevi revealed cathepsin B to be predominantly expressed by melanoma cells and cathepsin L to be predominantly expressed by the tumor-associated fibroblasts surrounding the invading melanoma cells. Finally, cathepsin B regulated TGF-ß production/signaling, which was required for the activation of fibroblasts and their promotion of the invasive growth of melanoma cells. These data provide a basis for testing inhibitors of TGF-ß signaling and cathepsins B/L in the therapy of invasive/metastatic melanomas.

Effect of delayed autologous breast reconstruction on breast cancer recurrence and survival.

BACKGROUND: The goal of the present study was to evaluate the impact of delayed autologous breast reconstruction on disease relapse in breast cancer patients treated with mastectomy. MATERIAL AND METHODS: The study was based on 503 consecutive patients younger than 70 years of age who underwent mastectomy between January 2000 and December 2003. Overall, 391 (78 %) received mastectomy alone and 112 (22 %) underwent a delayed breast reconstruction. The median time from mastectomy to delayed breast reconstruction was 34 months. The median duration of follow-up was 102 months. RESULTS: There were no locoregional recurrences (LRR) in patients who underwent delayed reconstruction (0.0 %); 21 LRR developed in patients treated with mastectomy only (5.4 %), P = 0.011. Distant metastases occurred less frequently in the reconstruction group (12.5 %) than in the patients who underwent mastectomy alone (21.5 %); P = 0.0343. The 8-year breast cancer specific survival in the reconstruction group was 98.2 and 85.7 % for the mastectomy only group, P = 0.000. CONCLUSIONS: Delayed autologous breast reconstruction does not appear to adversely influence disease progression when compared to patients treated with mastectomy only.

"An abdominoplasty modification for post-pregnancy abdomen with rectus diastasis and midline hernia: the technique and results".

SUMMARY: Few women recover from pregnancy abnormally and end up having severe post-pregnancy rectus diastasis (RD) with body control dysfunction, midline hernia or other quality of life impairment. The purpose of this study was to describe the authors' experience using HELP modification of abdominoplasty (Hydrodissection and Epidural anesthesia for Lateral Plication) to restore abdominal wall firmness. 46 consecutive post-pregnancy RD patients were enrolled. The mean intraoperative inter rectus distance was 4.6 cm. RD is not always the only structure that has been elongated. Firmness of the abdominal wall depends also on lateral fascia structures. Our study reports the total plicated distance addressing the lateral laxity in the abdominal wall. In this series total plication was 7.8 cm. In this series 16 patients had a midline hernia. We did not see hernia recurrences, and the rectus bellies were <5mm apart from each other in all participants verified with ultrasound after two years of follow up. Patient perspective of care and surgical outcome were recorded: HRQoL domains were significantly higher postoperatively implicating better health. Lumbar back pain visual analogy scale score was 4.5±2.3 preoperatively and 0.5 ±0.9 postoperatively. The ability to perform sit-ups increased from 0 to 11 suggesting better motor control. Total complication rate was 10.9%. HELP modification seems to offer a reliable and effective treatment method for RD repair with and without a small midline hernia with low complication rate.

The Cost of Breast Cancer Surgery - Is the Money Spent Reflected on Health-related Quality of Life?

BACKGROUND/AIM: Different treatment options of breast cancer (BC) are dependent on certain cancer- and patient-related features. The cost of treatment varies among patients. This study describes the cost distribution in the treatment of Finnish patients with BC for two years and relates the costs to important outcomes of modern BC treatment. PATIENTS AND METHODS: Health-related quality of life (HRQoL) of 1,065 patients was measured prospectively at baseline, and 3, 6, 12, and 24 months thereafter with a generic (15D) and a disease-specific (EORTC QLQ C-30 BR23) HRQoL-instrument. Clinical data and costs of care were collected from hospital records. Patients were divided into four groups according to the surgical approach: breast-conserving surgery (BCS n=661), mastectomy (n=319), immediate reconstruction (IBR n=51), and delayed reconstruction (DR n=34), and the costs according to the clinic responsible for treatment: oncological-, breast surgery-, and plastic surgery unit. Total costs of care during follow-up are presented groupwise alongside HRQoL results. RESULTS: The mean total cost for BC surgery was 6,015 Euros for BCS, 8,114 euros for mastectomy, 18,217 Euros for IBR, and 19,041 Euros for DR. BCS, IBR, and DR produced good HRQoL. Mastectomy patients had the lowest overall HRQoL and highest cost accumulation at the oncology unit. HRQoL of IBR and DR patients was similar. CONCLUSION: DR produces good HRQoL but generates the highest costs of care. If patients that require reconstruction could be identified earlier and offered IBR instead of mastectomy followed by later DR, the costs of care might be reduced.

Delay in the initiation of adjuvant chemotherapy in patients with breast cancer with mastectomy with or without immediate breast reconstruction.

BACKGROUND: Patients with breast cancer undergoing mastectomy should be offered the option of immediate breast reconstruction (IBR). The aim of this retrospective study was to assess whether there is a delay in the initiation of adjuvant chemotherapy in patients undergoing mastectomy with or without IBR. METHOD: The study included patients aged 70 years or younger with clinically node-negative breast cancer who underwent unilateral mastectomy with IBR (IBR group) or mastectomy alone (no-IBR group) followed by adjuvant chemotherapy at the Helsinki University Hospital between January 2012 to July 2018. RESULTS: A total of 645 patients were included; 186 in the IBR group and 459 in the no-IBR group. Sixty-six (35.5 per cent) patients in the IBR group and 102 (22.2 per cent) patients in the no-IBR group received their first chemotherapy cycle later than 6 weeks after surgery (P < 0.001). The respective numbers for later than 8 weeks were 17 (9.1 per cent) and 14 (3.1 per cent) (P = 0.001). Among all 645 patients, postoperative complications were a significant risk factor for a delay in the initiation of chemotherapy. Sixty-seven (39.9 per cent) patients with and 101 (21.2 per cent) patients without complications had a delay in chemotherapy (P < 0.001). The delay in chemotherapy was due to complications in 39 (59.1 per cent) in the IBR group and in 28 (27.5 per cent) in the no-IBR group (P < 0.001). CONCLUSION: Patients undergoing mastectomy alone were more likely to receive adjuvant chemotherapy within 6 weeks after surgery compared with the IBR patients. IBR significantly increased the risk of postoperative complications in comparison with mastectomy alone. The complications, in turn, were a significant risk factor for delay in adjuvant chemotherapy.

Surgery, Limb Edema and Health-related Quality of Life: A Prospective Follow-up Study on Patients With Cutaneous Malignant Melanoma.

BACKGROUND/AIM: The latest developments in oncological therapies for malignant melanoma, and the discovery that complete lymph node dissection offers no survival benefit, are changing the landscape of melanoma surgery. There is a need for more information on health-related quality of life (HRQoL) consequences of melanoma surgery. PATIENTS AND METHODS: This longitudinal cohort study was carried out from 2004 to 2009 in the Helsinki and Uusimaa Hospital District and patients were followed-up at 6, 12 and 24 months. The patients were asked to fill in the generic 15D questionnaire and the cancer-specific European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30). In addition, they were asked selected questions from the EORTC Item Library regarding upper and lower limb edema. RESULTS: A total of 169 (64.5%) patients with local or locally advanced melanoma referred for surgical treatment responded, of whom 161 were included in the final analysis. For the whole patient group, distress, depression and emotional function improved over time. Worse HRQoL in some of the dimensions were associated with female sex, skin transplant versus direct wound closure and complications 30 days or more after surgery, but none was associated with worse overall HRQoL. Postoperative complications, type of wound closure or lymph node surgery had no effect on overall HRQoL. Patient-reported limb edema was associated with worse overall HRQoL at baseline and during follow-up by both instruments. Patients reporting limb edema reported worse mobility and more pain throughout the study. CONCLUSION: Patient-reported limb edema, regardless of the cause, seems to be an important predictor of worse HRQoL among patients with melanoma.

Therapeutic Value of Sentinel Lymph Node Biopsy in Patients With Melanoma: A Randomized Clinical Trial.

Importance: Sentinel lymph node (SLN) biopsy is a standard staging procedure for cutaneous melanoma. Regional disease control is a clinically important therapeutic goal of surgical intervention, including nodal surgery. Objective: To determine how frequently SLN biopsy without completion lymph node dissection (CLND) results in long-term regional nodal disease control in patients with SLN metastases. Design, Setting, and Participants: The second Multicenter Selective Lymphadenectomy Trial (MSLT-II), a prospective multicenter randomized clinical trial, randomized participants with SLN metastases to either CLND or nodal observation. The current analysis examines observation patients with regard to regional nodal recurrence. Trial patients were aged 18 to 75 years with melanoma metastatic to SLN(s). Data were collected from December 2004 to April 2019, and data were analyzed from July 2020 to January 2022. Interventions: Nodal observation with ultrasonography rather than CLND. Main Outcomes and Measures: In-basin nodal recurrence. Results: Of 823 included patients, 479 (58.2%) were male, and the mean (SD) age was 52.8 (13.8) years. Among 855 observed basins, at 10 years, 80.2% (actuarial; 95% CI, 77-83) of basins were free of nodal recurrence. By univariable analysis, freedom from regional nodal recurrence was associated with age younger than 50 years (hazard ratio [HR], 0.49; 95% CI, 0.34-0.70; P < .001), nonulcerated melanoma (HR, 0.36; 95% CI, 0.36-0.49; P < .001), thinner primary melanoma (less than 1.5 mm; HR, 0.46; 95% CI, 0.27-0.78; P = .004), axillary basin (HR, 0.61; 95% CI, 0.44-0.86; P = .005), fewer positive SLNs (1 vs 3 or more; HR, 0.32; 95% CI, 0.14-0.75; P = .008), and SLN tumor burden (measured by diameter less than 1 mm [HR, 0.39; 95% CI, 0.26-0.60; P = .001] or less than 5% area [HR, 0.36; 95% CI, 0.24-0.54; P < .001]). By multivariable analysis, younger age (HR, 0.57; 95% CI, 0.39-0.84; P = .004), thinner primary melanoma (HR, 0.40; 95% CI, 0.22-0.70; P = .002), axillary basin (HR, 0.55; 95% CI, 0.31-0.96; P = .03), SLN metastasis diameter less than 1 mm (HR, 0.52; 95% CI, 0.33-0.81; P = .007), and area less than 5% (HR, 0.58; 95% CI, 0.38-0.88; P = .01) were associated with basin control. When looking at the identified risk factors of age (50 years or older), ulceration, Breslow thickness greater than 3.5 mm, nonaxillary basin, and tumor burden of maximum diameter of 1 mm or greater and/or metastasis area of 5% or greater and excluding missing value cases, basin disease-free rates at 5 years were 96% (95% CI, 88-100) for patients with 0 risk factors, 89% (95% CI, 82-96) for 1 risk factor, 86% (95% CI, 80-93) for 2 risk factors, 80% (95% CI, 71-89) for 3 risk factors, 61% (95% CI, 48-74) for 4 risk factors, and 54% (95% CI, 36-72) for 5 or 6 risk factors. Conclusions and Relevance: This randomized clinical trial was the largest prospective evaluation of long-term regional basin control in patients with melanoma who had nodal observation after removal of a positive SLN. SLN biopsy without CLND cleared disease in the affected nodal basin in most patients, even those with multiple risk factors for in-basin recurrence. In addition to its well-validated value in staging, SLN biopsy may also be regarded as therapeutic in some patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00297895.

Metastatic outgrowth encompasses COL-I, FN1, and POSTN up-regulation and assembly to fibrillar networks regulating cell adhesion, migration, and growth.

Although the outgrowth of micrometastases into macrometastases is the rate-limiting step in metastatic progression and the main determinant of cancer fatality, the molecular mechanisms involved have been little studied. Here, we compared the gene expression profiles of melanoma lymph node micro- and macrometastases and unexpectedly found no common up-regulation of any single growth factor/cytokine, except for the cytokine-like SPP1. Importantly, metastatic outgrowth was found to be consistently associated with activation of the transforming growth factor-beta signaling pathway (confirmed by phospho-SMAD2 staining) and concerted up-regulation of POSTN, FN1, COL-I, and VCAN genes-all inducible by transforming growth factor-beta. The encoded extracellular matrix proteins were found to together form intricate fibrillar networks around tumor cell nests in melanoma and breast cancer metastases from various organs. Functional analyses suggested that these newly synthesized protein networks regulate adhesion, migration, and growth of tumor cells, fibroblasts, and endothelial cells. POSTN acted as an anti-adhesive molecule counteracting the adhesive functions of FN1 and COL-I. Further, cellular FN and POSTN were specifically overexpressed in the newly forming/formed tumor blood vessels. Transforming growth factor-beta receptors and the metastasis-related matrix proteins, POSTN and FN1, in particular, may thus provide attractive targets for development of new therapies against disseminated melanoma, breast cancer, and possibly other tumors, by affecting key processes of metastasis: tumor/stromal cell migration, growth, and angiogenesis.