BackgroundProgrammed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab.MethodsIn this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety.ResultsObjective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported.ConclusionsCosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile.Trial registration numberNCT03212404.

Background: The axillo-inguinal (or inguino-axillary) is a compensatory lymphatic drainage pathway regularly utilized by lymphedema therapists when applying manual lymphatic drainage (MLD) for upper and lower extremity lymphedema. However, there is limited evidence of the frequency of this pathway and the characteristics of patients with lymphedema in which this pathway is present. Indocyanine green (ICG) lymphography is an imaging technique that has the capability to identify lymphatic drainage pathways in lymphedema when combined with MLD. In this study, we used ICG lymphography in patients with upper and lower extremity lymphedema to investigate the presence of this pathway and its clinical characteristics. Methods and Results: A retrospective cohort audit of 563 patients with lymphedema (285 with upper extremity and 278 with lower extremity) who underwent ICG lymphography was conducted in combination with MLD. Compensatory lymphatic drainage was investigated. Patients demonstrating the axillo-inguinal pathway were identified, and their clinical characteristics were recorded. The axillo-inguinal pathway was not demonstrated in any patient with upper extremity and only five patients with lower extremity lymphedema. Of these five patients, all were female with a history of secondary cancer-related lymphedema following gynecological cancer. The majority (four) had bilateral lymphedema extending to the lower abdomen and presented with a greater severity of lymphedema. Conclusions: These findings suggest that the axillo-inguinal pathway is an infrequent compensatory drainage pathway in lower extremity lymphedema and rare in upper extremity lymphedema. Our findings have clinical implications for lymphedema management, in particular, the sequence in which MLD is applied.

The objective of the study was to characterize the baseline intra-individual and inter-individual variability of immune cell subsets within abdominoplasty skin specimens. Abdominoplasty biopsies were taken from 5 patients and analysed using the Vectra 3 automated quantitative pathology imaging system with inForm software. Adjacent skin regions demonstrated intra-patient variability in immune subset counts ranging from 1- to 5-fold. Inter-variability between patients was approximately 2- to 7-fold for most subsets, except for HLA-DR+ antigen presenting cells, which varied 19-fold. Our data highlight the importance of including multiple patients and multiple patient samples when designing dermatological studies that utilise abdominoplasty skin.

Background and Objectives: The contralateral inguinal pathway (CIP) to the inguinal nodal region of the contralateral limb has been described in lower-limb lymphedema (LLLE). This audit aimed to use indocyanine green (ICG) lymphography to determine characteristics of patients with CIP to inform conservative therapy. Methods: Patients with confirmed LLLE (n = 278) were categorized into secondary cancer-related (n = 82), secondary non–cancer-related (n = 86), or primary (n = 110). Patient characteristics, limb volume and bioimpedance spectroscopy (BIS) extracellular fluid ratio, and ICG lymphography of lymphatic pathways and dermal backflow areas were recorded. Results: Forty-seven patients (16.9%) had movement of ICG dye via CIP. Of these, 30 (63.8%) had secondary cancer-related, 8 (17.0%) had secondary non–cancer-related, and 9 (19.1%) had primary LLLE. Cancer-related LLE (P < .001) and unilateral LLLE (P = .017) were significant indicators of CIP, with 36.6% of patients with cancer-related LLLE demonstrating this pathway. CIP was significantly associated with dermal backflow in shin (P = .016), calf (P = .006), thigh (P < .001), inguinal (P < .001), pubic (P < .001), and abdominal regions (P = .001). Patients with CIP had significantly higher volume differences between limbs (P < .001), severity of lymphedema (P < .001), and BIS measurements (P < .001) than patients without CIP. Conclusion: A compensatory lymphatic drainage pathway from the affected limb to the contralateral inguinal lymph node region was evident in 16.9% of patients with LLLE. This pathway was most observed in unilateral cancer-related lymphedema, particularly where edema was present in proximal thigh, inguinal, pubic, and lower abdominal regions. Directing manual lymphatic drainage to the contralateral inguinal drainage region should be considered especially for patients with cancer-related LLLE.

The lower limbs are a common body site affected by chronic edema. Imaging examination of the lymphatic system is useful to diagnose lymphoedema, identify structural changes in individuals, and guide interventional strategies. In this study, we used a protocol combining indocyanine green (ICG) lymphography and ICG-guided manual lymphatic drainage (MLD) for the diagnostic assessment of lower limb lymphoedema. Patients with lower limb lymphoedema were divided into three groups by their medical history: primary, secondary cancer-related, or secondary non-cancer-related. ICG lymphography was conducted in three phases: initial observation, MLD to accelerate ICG dye transit and reduce imaging time, and imaging data collection. Lymphatic drainage regions were recorded, and the MD Anderson Cancer Center ICG staging was applied. We collected routine lymphoedema assessment data, including limb volume and bioimpedance spectroscopy measurements. Three hundred and twenty-six lower limbs that underwent ICG lymphography were analyzed. Eight drainage regions were identified. The ipsilateral inguinal and popliteal were recognized as the original regions, and the remaining six regions were considered compensatory regions that occur only in lymphoedema. More than half of the secondary cancer-related lower limb lymphoedema (57.6%) continued to drain to the ipsilateral inguinal region. The incidence of drainage to the ipsilateral inguinal region was even higher for the primary (82.8%) and secondary non-cancer-related (87.1%) groups. Significant associations were observed between cancer-related lymphoedema and the presence of compensatory drainage regions. We proposed a prospective ICG lymphography protocol for the diagnostic assessment of lower limb lymphoedema in combination with MLD. Eight drainage regions were identified, including two original and six compensatory regions.

ObjectiveRetrograde movement of lymph owing to damaged and/or incompetent valves in the lymphatic vessels has been considered a pathological feature of lymphedema. This study aimed to determine the prevalence of retrograde lymph flow and the characteristics of patients with this condition using indocyanine green (ICG) lymphography. MethodsAn audit of 679 patients with upper or lower limb swelling who underwent ICG lymphography was undertaken over a 4-year period. Harvey’s technique was applied to identify retrograde flow in the lymph collecting vessel during ICG lymphography. The characteristics of patients with retrograde lymph flow were recorded. ResultsTwenty-one patients (3.7%; lower limb, n = 19; upper limb, n = 2) were identified as having retrograde flow in lymph collecting vessels out of 566 confirmed lymphedema patients (lower limb, n = 275; upper limb, n = 291). Of the two patients with upper limb lymphedema (ULLE), one had a short segment of retrograde lymph flow in the forearm. The other patient with ULLE and one patient with lower limb lymphedema (LLLE) were previously diagnosed with lymphedema-distichiasis syndrome. Of the remaining 18 patients with LLLE and retrograde lymph flow, nine had initiating insect bites with lymphangitis and three had palpable benign enlarged inguinal lymph nodes evident before lower limb swelling onset. None had cancer-related LLLE. ConclusionsRetrograde lymph flow with valve incompetence in the lymph-collecting vessels was a rare finding in ULLE and a relatively uncommon finding in LLLE, contradicting the conventional understanding of pathological changes in lymphedema. ICG lymphography identified anticipated retrograde lymph flow in two patients with lymphedema distichiasis. In the remaining patients, retrograde lymph flow may have resulted from toxic or asymptomatic lymphangitis but there was no association with secondary cancer-related lymphedema. These findings have implication for conservative management as well as lymphovenous anastomosis surgery where both ends of a transected lymph collecting vessel would be potential targets for anastomoses.

9537 Background: Programmed death receptor-1 (PD-1)–blocking antibodies are approved as monotherapy treatment for patients (pts) with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or radiation. Cosibelimab is a high-affinity, fully human programmed death ligand-1 (PD-L1)–blocking antibody with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against tumor cells. Study CK-301-101 (NCT03212404) is a global, multicenter, multicohort, pivotal trial that enrolled pts with select advanced cancers for treatment with cosibelimab. Here we present the primary analysis of the registration-enabling expansion cohort in pts with metastatic CSCC. Methods: Adult pts with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had metastatic (nodal and/or distant) CSCC not amenable to local therapy were eligible to participate. Cosibelimab was administered as a fixed dose of 800 mg every 2 weeks (Q2W) intravenously. The primary endpoint was confirmed objective response rate (ORR; complete response [CR] + partial response [PR]) assessed by independent central review according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and the key secondary endpoint was duration of response. Results: Seventy-eight pts with metastatic CSCC were treated with cosibelimab and comprise the efficacy and safety populations (59M/19F; median age: 71 years). The confirmed ORR was 47.4% (95% CI: 36.0, 59.1; 6 CRs and 31 PRs) and the median duration of response was not reached at the time of data cutoff (median duration of follow-up: 15.2 months), with 76% of responses ongoing (range: 1.4-31.8+ months). The Kaplan–Meier estimated probability of maintaining a response at 6 and 24 months was 88.1% and 72.5%, respectively. Treatment-related adverse events (TRAEs) were reported in 54 pts (69.2%); 7 pts (9.0%) experienced at least 1 grade 3 TRAE (no grade 4 or grade 5 TRAEs were reported) with the most common being increased serum lipase in 2 pts. Conclusions: Treatment with cosibelimab monotherapy resulted in a robust ORR with durable responses and demonstrated a predictable and manageable safety profile in pts with metastatic CSCC, supporting its use in the treatment of this cancer. Clinical trial information: NCT03212404.

ObjectiveTo perform a preliminary usability evaluation of a novel, compact pneumatic compression device in patients with lymphoedema.MethodsThis open-label, single-arm trial had two phases: the first focused on the fitting of the pneumatic compression device (Aria FreeTM, Aria Health, San Diego CA, USA) and the second focused on evaluating the comfort of the entire system during a 45-min usage period. Both phases were conducted in a monitored clinical environment. Patients aged ≥18 years with a diagnosis of lower limb lymphoedema who had used a pneumatic compression device for ≥3 months were eligible. Patients rated subjective fit, comfort and usability on an 11-point Likert scale (where higher scores indicate better fit/comfort/usability). The truncated cone method was used to infer limb volume before and after therapy in phase 2.ResultsTwenty-four patients were screened, and 15 were enrolled (80% female; mean age 62 years); all completed both study phases. Patients rated the garment as easy to set up and fit (median score 6.5), and all reported that the therapy was comfortable (median score 10; p < 0.001 vs. reference score of 6). There was a 1.85% reduction in limb volume after device use for 45 min (p = 0.018 vs. before therapy). No safety issues were identified.ConclusionsThe new pneumatic compression device fitted well, was easy to use and reduced leg oedema.

Background and objectiveAn epidemic of silicosis has emerged due to a failure to control risks associated with exposure to high‐silica content respirable dust generated while working with artificial stone products. Methods for quantification of alveolar crystal burden are needed to advance our understanding of the pathobiology of silica‐related lung injury as well as assisting in the diagnosis, clinical management and prognostication of affected workers. The objective of this study was to develop and validate novel methods to quantify alveolar crystal burden in bronchoalveolar lavage (BAL) fluid from patients with artificial stone silicosis.MethodsNew methods to quantify and analyse alveolar crystal in BAL from patients with artificial stone silicosis were developed. Crystals were isolated and counted by microscopy and alveolar crystal burden was calculated using a standard curve generated by titration of respirable α‐Quartz. The utility of the assay was then assessed in 23 patients with artificial stone silicosis.ResultsAlveolar crystal burden was greater in patients with silicosis (0.44 picograms [pg]/cell [0.08–3.49]) compared to patients with other respiratory diagnoses (0.057 pg/cell [0.01–0.34]; p < 0.001). Alveolar crystal burden was positively correlated with years of silica exposure (ρ = 0.49, p = 0.02) and with decline in diffusing capacity of the lungs for carbon monoxide (ρ = −0.50, p = 0.02).ConclusionAlveolar crystal burden quantification differentiates patients with silicosis from patients with other respiratory disorders. Furthermore, crystal burden is correlated with the rate of decline in lung function in patients with artificial stone silicosis.

Both ultrasound and the Seldinger technique have been shown to improve outcomes during vascular access.[1 2][1] International guidelines recommend ultrasound-guidance when difficulties are encountered or expected.[1 3–5][1] However, difficulties still occur, and a broader array of adjuncts is