Molecular mechanisms of cancer metastasis via the lymphatic versus the blood vessels

Cancer metastasis is the process by which primary cancer cells invade through the lymphatic or blood vessels to distant sites. The molecular mechanisms by which cancer cells spread either through the lymphatic versus blood vessels or both are not well established. Two major developments have helped us to understand the process more clearly. First, the development of the sentinel lymph node (SLN) concept which is well established in melanoma and breast cancer. The SLN is the first lymph node in the draining nodal basin to receive cancer cells. Patients with a negative SLN biopsy show a significantly lower incidence of distant metastasis, suggesting that the SLN may be the major gateway for cancer metastasis in these cancer types. Second, the discovery and characterization of several biomarkers including VEGF-C, LYVE-1, Podoplanin and Prox-1 have opened new vistas in the understanding of the induction of lymphangiogenesis by cancer cells. Cancer cells must complete multiple steps to invade the lymphatic system, some of which may be enabled by the evolution of new traits during cancer progression. Thus, cancer cells may spread initially through the main gateway of the SLN, from which evolving cancer clones can invade the blood vessels to distant sites. Cancer cells may also enter the blood vessels directly, bypassing the SLN to establish distant metastases. Future studies need to pinpoint the molecules that are used by cancer cells at different stages of metastasis via different routes so that specific therapies can be targeted against these molecules, with the goal of stopping or preventing cancer metastasis.

Novel Bathymetry of Lake Afdera Reveals Fault Structures and Volcano-Tectonic Features of an Incipient Transform Zone (Afar, Ethiopia)

Lake Afdera is a hypersaline endorheic lake situated at 112 m below sea-level in the Danakil Depression. The Danakil Depression is located in the northern part of the Ethiopian Afar and features an advanced stage of continental rifting. The remoteness and inhospitable environment explain the limited scientific research and knowledge about this lake. Bathymetric data were acquired during 2 weeks expeditions in January/February 2016 and 2017 using an easily deployable echosounder system mounted on an inflatable motorized boat. This study presents the first complete bathymetric map of the lake Afdera. Bathymetric results show that the lake has an average depth of 20.9 m and a total volume of 2.4 km3. The maximum measured depth is 80 m, making Lake Afdera the deepest known lake in Afar and the lowest elevation of the Danakil Depression. Comparison with historical reports shows that the lake level did not fluctuate significantly during the last 50 years. Two distinct tectonic basins to the north and the south are recognized. Faults of different orientations control the morphology of the northern basin. In contrast, the southern basin is affected by volcano-tectonic processes, unveiling a large submerged caldera. Comparison between the orientation of faults throughout the lake with the regional fault pattern indicates that the lake is part of two transfer zones: the major Alayta–Afdera Transfer Zone and the smaller Erta Ale–Tat’Ali Transfer Zone. The interaction between these Transfer Zones and the rift axis forms the equivalent of a developing nodal basin which explains the lake’s position as the deepest point of the depression. This study provides evidence for the development of an incipient transform fault on the floor of the Afar depression.

The sentinel node invasion level (SNIL) as a prognostic parameter in melanoma

Sentinel lymph node (SN) tumor burden is becoming increasingly important and is likely to be included in future N classifications in melanoma. Our aim was to investigate the prognostic significance of melanoma infiltration of various anatomically defined lymph node substructures. This retrospective cohort study included 1250 consecutive patients with SN biopsy. The pathology protocol required description of metastatic infiltration of each of the following lymph node substructures: intracapsular lymph vessels, subcapsular and transverse sinuses, cortex, paracortex, medulla, and capsule. Within the SN with the highest tumor burden, the SN invasion level (SNIL) was defined as follows: SNIL 1 = melanoma cells confined to intracapsular lymph vessels, subcapsular or transverse sinuses; SNIL 2 = melanoma infiltrating the cortex or paracortex; SNIL 3 = melanoma infiltrating the medulla or capsule. We classified 338 SN-positive patients according to the non-metric SNIL. Using Kaplan–Meier estimates and Cox models, recurrence-free survival (RFS), melanoma-specific survival (MSS) and nodal basin recurrence rates were analyzed. The median follow-up time was 75 months. The SNIL divided the SN-positive population into three groups with significantly different RFS, MSS, and nodal basin recurrence probabilities. The MSS of patients with SNIL 1 was virtually identical to that of SN-negative patients, whereas outgrowth of the metastasis from the parenchyma into the fibrous capsule or the medulla of the lymph node indicated a very poor prognosis. Thus, the SNIL may help to better assess the benefit-risk ratio of adjuvant therapies in patients with different SN metastasis patterns.

The Eastern Romanche ridge-transform intersection (Equatorial Atlantic): slow spreading under extreme low mantle temperatures. Preliminary results of the SMARTIES cruise.

<p>A strong edge effect is predicted at the intersections between long-offset transforms and mid ocean ridge segments. The Equatorial Atlantic hosts several megatransforms, where the connections of potentially low mantle temperatures due to the large lithospheric age contrast with melt production are poorly understood. The SMARTIES cruise focused on the Romanche transform that offsets the Mid Atlantic Ridge (MAR) laterally by 900 km with an age offset of 55 Ma. The eastern Ridge-Transform Intersection (RTI) markedly shows the effects of the lateral cooling of the ridge segment. To better understand the thermal regime at these complex domains, we acquired surface geophysical data and bathymetry of the area, and geological observations and sampling during 25 HOV Nautile dives. The integrated study of rock characteristics and of geophysical surveys allows tackling the connections between magmatism and tectonics. A network of 19 OBS was also deployed to study the seismic activity during the cruise in collaboration with the ILAB project.</p><p>There is a striking change in deformation patterns along the ridge axis moving away from the transform southwards. The bathymetry is extremely complex, with several structural directions, partly resulting from transtension. A low melt supply is focused at the ridge axis resulting in a long oblique axial domain, that forms a relay zone between the roughly north-south ridge axis in the south and the area close to the transform fault, while the transform fault domain is highly complex. Trends oblique to both the main spreading axis direction and the transform fault direction are widespread. A clear Principal Transform Displacement Zone (PTDZ) can be followed as a long, near continuous alignment, on the seafloor of the wide Romanche valley. However, the valley morphology suggests a migration of the PTDZ and intense deformation within the transform domain. The RTI is complex and the position of the spreading axis clearly evolved with time, through at least two and possibly three eastward ridge jumps.</p><p>Six Nautile dives explored the northern wall of the Romanche, the damaged zone of the transform fault, and the exceptionally deep nodal basin. The north wall exposes a very thick basalt unit covered with a thick layer of sediments. Eight dives explored the southern flank of the Romanche identifying fragments of old Oceanic Core Complexes (OCCs) formed by highly deformed peridotites, and a large OCC located at the RTI that exposes mylonitized peridotites and is dissected by several normal faults. The magmatic zones of the axial domain (nine dives) are formed by volcanic ridges affected by important tectonic activity. The dives show pillow and tube volcanic flows with intersecting faults. An oblique elongated faulted and sedimented ridge (2 dives) parallel to the oblique relay zone was shown to be of peridotitic nature Recent faults have been observed, as well as traces of high-T hydrothermal activity consistent with black-smoker type venting, recently overprinted by low temperature diffuse venting related to active faulting.</p>

Retrospective analysis of patients with sentinel lymph node (SLN) positive melanoma (MEL) who received adjuvant nivolumab (NIVO) without completion lymph node dissection (CLND).

9590 Background: Until recently, most patients (pts) with SLN+ MEL underwent CLND, a procedure mandated in published trials of adjuvant anti-PD-1 therapy to date. Following MSLT-II, this practice has dramatically changed with most pts now undergoing surveillance or adjuvant therapy without CLND. In addition, pts with in-transit/satellite MEL were excluded or not reported in these prior adjuvant studies. Our aim was to explore real-world outcomes of adjuvant NIVO in these pts. Methods: We carried out a single center retrospective analysis of stage 3 MEL pts who received adjuvant NIVO. Results: 32 pts with SLN+ MEL who did not undergo a CLND and started adjuvant NIVO within 3 months of surgery were included. Median age was 60 (26-77); per AJCC v7, 12 pts had Stage 3A, 11 stage 3B, and 9 pts had Stage 3C MEL. One was acral MEL; 18 had an ulcerated primary. 6 pts had BRAF-mutant MEL, 20 had BRAF-WT, and 6 unknown. NIVO treatment was 240 mg Q2wks or 480 mg Q4wks, up to one year. 21 pts developed grade 1/2 immune-related adverse events (irAEs), and 1 pt stopped NIVO due to toxicity (fatigue). With median follow-up of 7 months, only 1 pt had a recurrence, which was in the in SLN+ nodal basin; pt was rendered disease-free with surgery. The relapse-free rate (RFS) rate at 1 year was 95% (95% CI, 71-100). Of 21 pts with in-transit/satellite recurrent MEL (median age 68 [29-84]) who started adjuvant NIVO (no prior drug treatment), 5 had BRAF-mutant MEL, 14 BRAF-WT, 2 unknown; two were acral-lentiginous. 3 pts had recurrences: 2 regional and 1 distant mets, treated with surgery, TVEC, or BRAF-targeted therapy. Median follow-up was 8 months from NIVO start; 1-year RFS was 72% (95% CI 32-91). 15 pts developed irAEs; in 12, these were grade 1-2 and in 3, were grade 3 that led to discontinuation. Conclusions: While preliminary, these findings suggest that adjuvant anti-PD-1 therapy may be effective in SLN+ pts who forego CLND prior to adjuvant treatment, as 1-year RFS rate appears similar to rates in the published adjuvant anti-PD-1 trials that mandated CLND. This therapy may be similarly effective in pts with resected in-transit/satellite stage 3 melanoma. Further follow-up will be presented.

[99mTc]Tilmanocept Lymphscintigraphy after inconclusive [99mTc]Nanocolloid Scan in Breast Cancer

IntroductionLymphatic mapping for identification and subsequent removal of the sentinel lymph node (SLN) is an established procedure in breast cancer and cutaneous melanoma to minimize the extent of surgery (and thus, associated morbidity), simplify histopathological processing and subsequently provide prognostic information and help choose the optimal patient management. Established methods for SLN mapping include visual identification of nodal staining after peritumoral injection of a (blue) dye or the use of lymphoscintigraphy with technetium-labelled nanocolloid. In experienced hands, success rates for both methods exceed 95 %, nonetheless in some patients they fail despite correct application and imaging techniques. Potential reasons for false-negative SLN detection rates –beyond poor tracer injection technique or imaging of the wrong nodal basin- include inadequate pathologic examination of the SLN or complete replacement of the SLN with neoplastic disease, causing the injected tracer to completely bypass the infiltrated node 1.Beyond colloid particles, the more specific receptor-targeting small molecule [99mTc]Tilmanocept has recently been approved for scintigraphic SLN detection. Tilmanocept, or mannosyl diethylene-triamine-pentaacetate (DTPA) dextran, has a small molecular size of approximately 7 nm and works via specific binding to the mannose receptor (CD206) 2. The mannose receptor is particularly overexpressed on macrophages and dendritic precursor cells within lymph nodes, thus uptake in lymph nodes is not dependent on particle size 2, 3. In pilot studies scintigraphic SLN detection with [99mTc]Tilmanocept was superior to dye staining 4. Given its beneficial properties, [99mTc]Tilmanocept might offer advantages over the alternatively used radiocolloids. We present four cases of [99mTc]Tilmanocept application after inconclusive or unsuccessful attempts of SLN detection using [99mTc]nanocolloid lymphoscintigraphy.

Lymphadenopathy

Lymphadenopathy is a pathological or abnormal state of one or more lymph nodes in a nodal basin that occurs in response to pathogens, immunogens, or malignant cells that are detected within the lymph. Malignant lymphadenopathy may be detected by physical exam and/or imaging findings, but it is ultimately confirmed or excluded by histological evaluation. This chapter, appearing in the section on nipple, skin, and lymph nodes, reviews key imaging and clinical features, imaging protocols and pitfalls, differential diagnoses, and management recommendations of lymphadenopathy detected by mammography, tomosynthesis, and ultrasound (US). Topics include the anatomy and physiology of breast lymphatic function, the anatomy and imaging features of lymph nodes, differential diagnosis of lymphadenopathy, and the imaging assessment of the axillary nodal basin in the context of known breast cancer.

The fine line between regional and metastatic pelvic lymph nodes in rectal cancer: Patterns of care among U.S. radiation oncologists.

758 Background: Management of rectal cancer with involved lateral pelvic lymph nodes (LPLNs) at the time of diagnosis – the stage we refer institutionally to as Stage 3.5 – is controversial. Asian investigators consider internal, external and common iliac lymph nodes (LNs) as regional disease and treat these patients (pts) with curative intent, which often includes LPLN dissection. Conversely, AJCC 7thedition classifies internal iliac LNs as regional, whereas both external and common iliac LNs as metastatic. NCCN guidelines recommend definitive trimodality therapy for Stage III rectal cancer, and palliative chemotherapy for Stage IV disease. Radiation oncologists (ROs) in the U.S. irradiate iliac LNs in the setting of other pelvic malignancies, but it is unknown how they approach newly diagnosed rectal cancer pts with LPLN involvement. Methods: We conducted an anonymous IRB-approved online survey of practicing U.S. ROs, probing their approach to management of rectal cancer pts with clinically involved LPLNs. Results: We received 220 responses. Among the responders, 85 are academically affiliated and the majority self-declared a specialization in treating GI malignancies, with 98 seeing more than 10 rectal cancer pts annually. Among respondents, 10.5% and 34.2% recommend biopsy of clinically involved internal and common iliac LNs, respectively. The vast majority of responders – 98.6% and 94.5% – treat involved internal and common iliac LNs with curative intent, respectively. Respondents recommend treatment intensification to involved internal iliac LNs by dissection of the nodal basin (88.2%) and radiation therapy (RT) boost (59.1%), and treatment intensification to involved common iliac LNs by LN dissection (76.4%) and RT boost (63.6%). Conclusions: Our analysis reveals that the vast majority of surveyed U.S. ROs approach pts with involved LPLNs, both regional (internal iliac) and metastatic (i.e. common iliac) with curative intent. They recommend treatment intensification with surgical resection and/or RT boost to involved nodes. Prospective clinical trials need to determine the appropriate management of pts with Stage 3.5 rectal cancer.

Impact of Surgically and Radiologically Detected Incidental Internal Mammary Lymph Node Enlargement in Breast Cancer Patients Undergoing Free-Flap Breast Reconstruction

Background The internal mammary lymph node (IMLN) basin is considered the second most important regional nodal basin in breast cancer. IMLNs are often not detected radiologically and left untreated, with symptomatic recurrence being 0.1%. Challenges in accessibility have been an obstacle in achieving a comprehensive treatment plan, especially with undetermined and radiologically enlarged IMLN. Free autologous tissue breast reconstruction is considered the gold standard, and the familiarity of microvascular surgeons in using the internal mammary vessels (IMVs) puts them in a unique position to shed more light on the natural pathological process of IMLN metastases. Materials and Methods A retrospective data analysis study was conducted evaluating 270 patients who underwent 307 free flaps for breast reconstruction using the IMV in the period between 2009 and 2017. Patient's demographics and clinicopathological data including IMLN harvest, radiological, operative details, adjuvant therapy, postoperative morbidity, and follow-up outcome data were analyzed. Results Eighty-nine enlarged IMLNs were surgically retrieved from 30.7% (83/270) of the patients (73 delayed, 10 immediate breast reconstructions) with an age range of 29 to 77 years (mean: 45). Eighty six were incidentally encountered during surgery, whereas in three, the enlarged IMLN was preoperatively, radiologically determined and biopsied during computed tomography (CT) scan staging and was retrieved subsequently during surgery. IMLN metastases were confirmed in 8.4% (7/83) of the patients in whom IMLNs were retrieved with subsequent modification of the proposed adjuvant therapy. The follow-up period ranged from 3 to 84 months (mean: 42) for the involved IMLN patients. Two patients (28% [2/7]) showed signs of disease progression with mortality. Conclusion Microvascular surgeons in a multidisciplinary setting would provide a valuable role in improving outcomes of patients with IMLN metastases through better diagnosis and staging of incidentally enlarged metastatic IMLN and provision of an effective approach for locoregional disease control.