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TARGIT-A was a pragmatic randomized noninferiority trial including women with early-stage breast cancer treated postlumpectomy with either external beam radiation therapy (EBRT) or 50 kV x-rays delivered intraoperatively with or without EBRT, as indicated. The long-term update of the pre-pathology cohort did not include a 10-year estimate of the primary endpoint of local failure (although tabular 5-year data was provided). Here, we used the data from the pre-pathology manuscript to estimate the cumulative incidence of local failure.Using digitizer software and the published survival curves, we extracted the Kaplan-Meier rate of local recurrence-free survival and overall survival. The extracted data were calibrated to the published point-estimates to within ±0.5%. The data were then fit to parametric survival models, and overall survival and local recurrence-free survival curves were subtracted to give the estimate of local failure in the presence of the competing risk of death. Bootstrap resampling was used to assess for parameter uncertainty in the modeling process.Our analysis estimated that the risk of local failure at 10 years in the TARGIT-A pre-pathology cohort is approximately 1.7% with EBRT (95% confidence interval [CI], 0%-4.3%) and 5.5% in the pragmatic risk-adapted TARGIT strategy (95% CI, 2.9%-8.0%). A weighted average estimate suggests that the risk of local failure in low-risk women treated with TARGIT alone is approximately 6.6% at 10 years (95% CI, 3.3%-10.0%), with an estimated difference of 4.9% (95% CI, 0.6%-9.2%) compared with EBRT.These data allow for contextualization and informed decisions when considering megavoltage EBRT, kilovoltage intraoperatively, or omission of radiation therapy entirely.

Recombinant human high-dose IL2 (HD-IL2; aldesleukin) was one of the first approved immune-oncology agents based upon clinical activity in renal cell carcinoma (RCC) and metastatic melanoma but use was limited due to severe toxicity. Next-generation IL2 agents designed to improve tolerability are in development, increasing the need for future identification of genomic markers of clinical benefit and/or clinical response. In this retrospective study, we report clinical and tumor molecular profiling from patients with metastatic RCC (mRCC) treated with HD-IL2 and compare findings with patients with RCC treated with anti-PD-1 therapy. Genomic characteristics common and unique to IL2 and/or anti-PD-1 therapy response are presented, with insight into rational combination strategies for these agents. Residual pretreatment formalin-fixed paraffin embedded tumor samples from n = 36 patients with HD-IL2 mRCC underwent RNA-sequencing and corresponding clinical data were collected. A de novo 40-gene nearest centroid IL2 treatment response classifier and individual gene and/or immune marker signature differences were correlated to clinical response and placed into context with a separate dataset of n = 35 patients with anti-PD-1 mRCC. Immune signatures and genes, comprising suppressor and effector cells, were increased in patients with HD-IL2 clinical benefit. The 40-gene response classifier was also highly enriched for immune genes. While several effector immune signatures and genes were common between IL2 and anti-PD-1 treated patients, multiple inflammatory and/or immunosuppressive genes, previously reported to predict poor response to anti-PD-L1 immunotherapy, were only increased in IL2–responsive tumors. These findings suggest that common and distinct immune-related response markers for IL2 and anti-PD-1 therapy may help guide their use, either alone or in combination. Significance: Next-generation IL2 agents, designed for improved tolerability over traditional HD-IL2 (aldesleukin), are in clinical development. Retrospective molecular tumor profiling of patients treated with HD-IL2 or anti-PD-1 therapy provides insights into genomic characteristics of therapy response. This study revealed common and distinct immune-related predictive response markers for IL2 and anti-PD-1 therapy which may play a role in therapy guidance, and rational combination strategies for these agents.

Recombinant human high-dose IL2 (HD-IL2; aldesleukin) was one of the first approved immune-oncology agents based upon clinical activity in renal cell carcinoma (RCC) and metastatic melanoma but use was limited due to severe toxicity. Next-generation IL2 agents designed to improve tolerability are in development, increasing the need for future identification of genomic markers of clinical benefit and/or clinical response. In this retrospective study, we report clinical and tumor molecular profiling from patients with metastatic RCC (mRCC) treated with HD-IL2 and compare findings with patients with RCC treated with anti-PD-1 therapy. Genomic characteristics common and unique to IL2 and/or anti-PD-1 therapy response are presented, with insight into rational combination strategies for these agents.Residual pretreatment formalin-fixed paraffin embedded tumor samples from n = 36 patients with HD-IL2 mRCC underwent RNA-sequencing and corresponding clinical data were collected. A de novo 40-gene nearest centroid IL2 treatment response classifier and individual gene and/or immune marker signature differences were correlated to clinical response and placed into context with a separate dataset of n = 35 patients with anti-PD-1 mRCC.Immune signatures and genes, comprising suppressor and effector cells, were increased in patients with HD-IL2 clinical benefit. The 40-gene response classifier was also highly enriched for immune genes. While several effector immune signatures and genes were common between IL2 and anti-PD-1 treated patients, multiple inflammatory and/or immunosuppressive genes, previously reported to predict poor response to anti-PD-L1 immunotherapy, were only increased in IL2–responsive tumors.These findings suggest that common and distinct immune-related response markers for IL2 and anti-PD-1 therapy may help guide their use, either alone or in combination.Significance:Next-generation IL2 agents, designed for improved tolerability over traditional HD-IL2 (aldesleukin), are in clinical development. Retrospective molecular tumor profiling of patients treated with HD-IL2 or anti-PD-1 therapy provides insights into genomic characteristics of therapy response. This study revealed common and distinct immune-related predictive response markers for IL2 and anti-PD-1 therapy which may play a role in therapy guidance, and rational combination strategies for these agents.

this is a test

40 gene IL-2 response classifier and related immune cell types

Co-surgeon approach for bilateral mastectomy may lead to shorter operative times and improved outcomes compared with single-surgeon approach, but cost differences remain unclear. Economic models were applied to determine whether either approach offered a lower cost opportunity.A retrospective review of 409 patients undergoing single-surgeon or co-surgeon bilateral mastectomy between January 1, 2010 through April 30, 2016 was conducted. Outcomes included narcotic and antinausea doses, length of stay (LOS), and operative time. Analyses stratified by reconstruction and no reconstruction included Wilcoxon tests, Poisson regression, generalized linear models, and a cost calculator.Of 409 patients, 310 had reconstruction and 99 had no reconstruction. Compared with single-surgeon approach, co-surgeon approach was associated with less operative time and shorter LOS (233 vs. 250 min and 1.0 vs. 1.8 days no reconstruction; and 429 vs. 493 min and 2.2 vs. 2.8 days reconstruction). Economic analysis demonstrated less operative time, shorter LOS, and lower average cost for co-surgeon approach ($32,400 vs. $34,400 no reconstruction; and $76,700 vs. $79,400 reconstruction).Compared with the single-surgeon, the co-surgeon approach with reconstruction was associated with a statistically significant decrease in operative time and LOS. Economic analysis estimated the co-surgeon approach could lead to lower costs.

Supplementary Tables S1 through S3 Supplementary Figures S1 through S3

Purpose: E4697 was a multicenter intergroup randomized placebo-controlled phase III trial of adjuvant GM-CSF and/or a multiepitope melanoma peptide vaccine for patients with completely resected, high-risk stage III/IV melanoma.Experimental Design: A total of 815 patients were enrolled from December 1999 to October 2006 into this six-arm study. GM-CSF was chosen to promote the numbers and functions of dendritic cells (DC). The melanoma antigen peptide vaccine (Tyrosinase368-376 (370D), gp100209-217 (210M), MART-127-35) in montanide was designed to promote melanoma-specific CD8+ T-cell responses.Results: Although the overall RFS and OS were not significantly improved with the vaccine or GM-CSF when compared with placebo, immunomodulatory effects were observed in peripheral blood and served as important correlates to this therapeutic study. Peripheral blood was examined to evaluate the impact of GM-CSF and/or the peptide vaccine on peripheral blood immunity and to investigate potential predictive or prognostic biomarkers. A total of 11.3% of unvaccinated patients and 27.1% of vaccinated patients developed peptide-specific CD8+ T-cell responses. HLA-A2+ patients who had any peptide-specific CD8+ T-cell response at day +43 tended to have poorer OS in univariate analysis. Patients receiving GM-CSF had significant reduction in percentages of circulating myeloid dendritic cells (mDC) and plasmacytoid DC (pDC) at day +43. In a subset of patients who received GM-CSF, circulating myeloid-derived suppressor cells (MDSC), and anti-GM-CSF–neutralizing antibodies (Nabs) were also modulated. The majority of patients developed anti-GM-CSF Nabs, which correlated with improved RFS and OS.Conclusions: The assessment of cellular and humoral responses identified counterintuitive immune system changes correlating with clinical outcome. Clin Cancer Res; 23(17); 5034–43. ©2017 AACR.

A primary new capability of JWST is the ability to penetrate the dust in star-forming galaxies to identify and study the properties of young star clusters that remain embedded in dust and gas. In this Letter we combine new infrared images taken with JWST with our optical Hubble Space Telescope (HST) images of the starbursting barred (Seyfert2) spiral galaxy NGC 1365. We find that this galaxy has the richest population of massive young clusters of any known galaxy within 30 Mpc, with ∼30 star clusters that are more massive than 106Me and younger than 10 Myr. Sixteen of these clusters are newly discovered from our JWST observations. An examination of the optical images reveals that 4 of 30 (∼13%) are so deeply embedded that they cannot be seen in the Hubble I band (AV  10 mag), and that 11 of 30 (∼37%) are missing in the HST B band, so age and mass estimates from optical measurements alone are challenging. These numbers suggest that massive clusters in NGC 1365 remain completely obscured in the visible for ∼1.3 ± 0.7 Myr and are either completely or partially obscured for ∼3.7 ± 1.1 Myr. We also use the JWST observations to gain new insights into the triggering of star cluster formation by the collision of gas and dust streamers with gas and dust in the bar. The JWST images reveal previously unknown structures (e.g., bridges and overshoot regions from stars that form in the bar) that help us better understand the orbital dynamics of barred galaxies and associated star-forming rings. Finally, we note that the excellent spatial resolution of the NIRCAM F200W filter provides a better way to separate barely resolved compact clusters from individual stars based on their sizes., La lista completa de autores que integran el documento puede consultarse en el archivo., Instituto de Astrofísica de La Plata

Neoadjuvant systemic therapy (NST) for triple-negative breast cancer and HER2-positive breast cancer yields a pathological complete response in approximately 60% of patients. A pathological complete response to NST predicts an excellent prognosis and can be accurately determined by percutaneous image-guided vacuum-assisted core biopsy (VACB). We evaluated radiotherapy alone, without breast surgery, in patients with early-stage triple-negative breast cancer or HER2-positive breast cancer treated with NST who had an image-guided VACB-determined pathological complete response.This multicentre, single-arm, phase 2 trial was done in seven centres in the USA. Women aged 40 years or older who were not pregnant with unicentric cT1-2N0-1M0 triple-negative breast cancer or HER2-positive breast cancer and a residual breast lesion less than 2 cm on imaging after clinically standard NST were eligible for inclusion. Patients had one biopsy (minimum of 12 cores) obtained by 9G image-guided VACB of the tumour bed. If no invasive or in-situ disease was identified, breast surgery was omitted, and patients underwent standard whole-breast radiotherapy (40 Gy in 15 fractions or 50 Gy in 25 fractions) plus a boost (14 Gy in seven fractions). The primary outcome was the biopsy-confirmed ipsilateral breast tumour recurrence rate determined using the Kaplan-Meier method assessed in the per-protocol population. Safety was assessed in all patients who received VACB. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02945579.Between March 6, 2017, and Nov 9, 2021, 58 patients consented to participate; however, four (7%) did not meet final inclusion criteria and four (7%) withdrew consent. 50 patients were enrolled and underwent VACB following NST. The median age of the enrolled patients was 62 years (IQR 55-77); 21 (42%) patients had triple-negative breast cancer and 29 (58%) had HER2-positive breast cancer. VACB identified a pathological complete response in 31 patients (62% [95% CI 47·2-75·4). At a median follow-up of 26·4 months (IQR 15·2-39·6), no ipsilateral breast tumour recurrences occurred in these 31 patients. No serious biopsy-related adverse events or treatment-related deaths occurred.Eliminating breast surgery in highly selected patients with an image-guided VACB-determined pathological complete response following NST is feasible with promising early results; however, additional prospective clinical trials evaluating this approach are needed.US National Cancer Institute (National Institutes of Health).

Background It is unknown whether all thick melanomas share the same prognostic features. We present a large, multi-institutional study on thick melanoma, evaluating for factors prognostic of survival. Methods We queried the database of the Sentinel Lymph Node Working Group for patients with thick melanoma (>4 mm) who had a sentinel lymph node biopsy from 1993 to 2018. Clinicopathologic characteristics were correlated with overall survival. Results There were 1,235 patients with a median follow-up of 28 months. Median thickness was 5.9 mm, with 713, 356, and 166 cases having a thickness of >4 to 6, >6 to 10, and >10 mm, respectively. Ulceration was seen in 51.2% of cases, while sentinel lymph node metastases were seen in 439 of 1,235 (35.5%) cases. For melanomas >4 to 6 mm, age, thickness, ulceration, lymphovascular invasion, and sentinel lymph node metastasis were correlated with overall survival (all P 6 to 10 mm, only sex and sentinel lymph node metastasis were prognostic of overall survival (both P 10 mm, only sentinel lymph node metastasis predicted overall survival on multivariable analyses (P Conclusion Prognostic markers of overall survival for thick melanoma include thickness, ulceration, and sentinel lymph node metastasis, but also include other unique factors such as lymphovascular invasion. Moreover, certain prognostic markers for survival are associated with different subgroups of thick melanoma, which vary based on thickness group.

Sentinel lymph node biopsy (SLNB) is recommended for intermediate thickness melanoma, but for thick melanoma, guidelines are less definitive about the use of SLNB in this population. We present a study on thick melanoma evaluating for prognostic factors.The Sentinel Lymph Node Working Group database was queried for thick ( 4 mm) melanoma cases that had a SLNB from 1993 to 2018. Clinicopathologic characteristics were correlated with SLN status and melanoma-specific survival (MSS).There were 1235 patients. Median follow-up was 28 months. Median thickness was 5.9 mm, with 956, 175, and 104 cases presenting thickness 4-8, 8-12, and 12 mm, respectively. SLN metastases were seen in 439 of 1235 (35.5%) cases and in 33.9%, 40.6%, and 42.3% of melanomas 4-8, 8-12, and 12 mm, respectively. In each thickness group, MSS was significantly worse for SLN-positive compared with SLN-negative cases (all P 0.005). Multivariable analysis showed that SLN metastasis, male gender, increasing thickness, lymphovascular invasion, and microsatellitosis significantly predicted worse MSS for melanomas 4-8 mm, with SLN metastasis showing the greatest risk (HR 2.17, 95% CI 1.64-2.87, P 0.0001). For melanomas 8 mm, only SLN metastasis significantly predicted MSS ( 8-12 mm: HR 3.93, 95% CI 2.00-7.73, P 0.0001; 12 mm: HR 3.58, 95% CI 1.56-8.22, p 0.0027).Thick melanoma patients with SLN metastasis have significantly worse MSS compared with SLN-negative patients, even in the thickest cases, and SLN status is the most powerful and/or only predictor of MSS. Given these results, SLNB shows important prognostic value in this population and is indicated for clinically localized thick melanoma.

The National Comprehensive Cancer Network (NCCN) developed clinical practice guidelines for germline pathogenic variants in highly penetrant genes, such as TP53 and PTEN, and in moderately penetrant genes, such as CHEK2, ATM and PALB2. Whether the practice of radiographic surveillance of patients with pathogenic variants in genes other than BRCA1/2 complies with current NCCN guidelines remains unclear. Retrospective review of patients identified with pathogenic variants in genes other than BRCA1/2 from 2007 through 2017 to determine if radiographic surveillance was in accordance with NCCN guidelines for mammography and consideration of magnetic resonance imaging (MRI). Exclusions included variants of unknown significance, pathogenic variants not associated with an increased risk of breast cancer, and previous breast cancer diagnosis. After exclusions, 35 patients with pathogenic variants in ATM, CDH1, CHEK2, NBN, PALB2, PTEN, and STK11 genes were reviewed to assess whether radiographic surveillance was in accordance with NCCN guidelines. Guidelines for those with variants in ATM, CHEK2 and NBN includes annual mammography with tomosynthesis and consideration of breast MRI at age 40, variants in CDH1 and PALB2 at age 30, variants in PTEN at age 30–35 or 5–10 years before the earliest family breast cancer, and variants in STK11 at age 25. Of these 35 patients, 11 (31%) received mammography only; 11 (31%) received mammography and MRI, and 13 (37%) received no radiographic surveillance. Two of the 35 (6%) patients who received radiographic surveillance were diagnosed with ductal carcinoma in situ or invasive breast cancer. Thirty-one percent of patients with pathogenic variants in genes other than BRCA1/2 received both mammography and MRI. Thirty-seven percent of patients with these highly penetrant and moderately penetrant genes received no radiographic follow-up, clearly demonstrating an opportunity for improvement.

Using PHANGS-HST NUV-U-B-V-I imaging of 17 nearby spiral galaxies, we study samples of star clusters and stellar associations, visually selected to be bright and relatively isolated, for three purposes: to compute aperture corrections for star cluster photometry, to explore the utility of quantitative morphologies in the analysis of clusters and associations, and to compare to synthetic stellar population models. We provide a technical summary of our procedures to determine aperture corrections, a standard step in the production of star cluster candidate catalogs, and compare to prior work. We also use this specialized sample to launch an analysis into the measurement of star cluster light profiles. We focus on one measure, $M_{20}$ (normalized second order moment of the brightest 20% of pixels), applied previously to study the morphologies of galaxies. We find that $M_{20}$ in combination with UB-VI colors, yields a parameter space where distinct loci are formed by single-peaked symmetric clusters, single-peaked asymmetric clusters, and multi-peaked associations. We discuss the potential applications for using $M_{20}$ to gain insight into the formation and evolution of clusters and associations. Finally, we compare the color distributions of this sample with various synthetic stellar population models. One finding is that the standard procedure of using a single-metallicity SSP track to fit the entire population of clusters in a given galaxy should be revisited, as the oldest globular clusters will be more metal-poor compared to clusters formed recently., 20 figures, 4 tables, 23 pages. Accepted for publication in MNRAS

The residual cancer burden class informs survival outcomes after neoadjuvant chemotherapy. We evaluated the prognostic ability of the RCB for survival outcomes in women with different phenotypic subtypes of breast cancer treated with neoadjuvant chemotherapy. Additional variables were assessed for inclusion with the RCB to further improve the model's discriminative ability.We conducted a retrospective review of patients completing at least 75% of the recommended cycles of neoadjuvant chemotherapy between 1 January 2010 and 31 December 2016. Phenotypic subtypes were defined by hormone receptor and human epidermal growth factor receptor 2 (HER2) status at diagnosis, classified as HR+/HER2-, HER2+, or triple-negative breast cancer (TNBC). The RCB class was calculated and survival endpoints of overall survival, recurrence-free survival, and distant recurrence-free survival were analyzed using Kaplan-Meier and Cox proportional hazards methods. The discriminative ability of the models was quantified by Harrell's C-index.Overall, 532 women met the inclusion criteria. Median follow-up was 65 months. In univariate models, RCB was significantly associated with OS, RFS, and DRFS. The RCB class had good discriminative ability for OS, RFS, and DRFS survival, with Harrell's C-indices of 0.68, 0.67, and 0.68, respectively. The RCB class discriminated well for each survival endpoint within HER2+ and TNBC, but did not discriminate well for HR+/HER2- (OS Harrell's C-indices of 0.77, 0.75, and 0.52, respectively).The RCB class was prognostic for OS, RFS, and DRFS after neoadjuvant chemotherapy, but prognostic discrimination between patients with subtype HR+/HER2- was not observed during the follow-up period for which the overall event rate was low.

BACKGROUND AND OBJECTIVES The prognostic significance of regression in predicting melanoma recurrences is unknown. We present a large multicenter study correlating regression with recurrence. METHODS The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with regression data. Clinicopathologic factors were correlated with overall and first-site of recurrence and with recurrence-free survival (RFS). RESULTS There were 4790 patients and the median follow-up was 39.6 months. Regression and recurrences were seen in 1081 (22.6%) and 773 (16.1%) cases, respectively. First-site locoregional and distant recurrences were seen in 412 (8.6%) and 352 (7.3%) patients, respectively. Regression was seen in 15.8% and 24.7% of all cases with and without recurrences (p

Some authors report that patients receiving neoadjuvant chemotherapy have fewer lymph nodes harvested during axillary dissection and more dissections with < 10 nodes compared with patients who undergo surgery initially. We sought to determine whether there was a difference between these patient groups in terms of number of nodes harvested and number of dissections with < 10 nodes. Retrospective review of 258 patients diagnosed with breast cancer who underwent an axillary lymph node dissection between July 1,2015, and December 31, 2017 was performed. Chi-squared test was used to assess differences between patient groups. Of 258 patients undergoing dissection, 48 per cent received neoadjuvant chemotherapy; 52 per cent underwent surgery as first therapeutic intervention. Mean number of nodes resected; 14.3 + 6.3 for patients with no prior chemotherapy versus 14.9 + 6.6 for patients with neoadjuvant chemotherapy ( P = 0.48). For patients undergoing surgery as first intervention, 21 per cent had < 10 nodes harvested. For patients receiving neo-adjuvant chemotherapy, 20 per cent had < 10 nodes harvested. Patients who received neoadjuvant chemotherapy showed no statistically significant difference in the number of lymph nodes harvested during axillary dissection compared with patients undergoing surgery as first intervention. Neoadjuvant chemotherapy does not reduce the node harvest at the time of axillary dissection.

Factors that predict melanoma recurrence after a negative sentinel lymph node biopsy (SLNB) are not well-defined. We evaluated melanoma recurrence patterns, factors prognostic for recurrence, and the impact of recurrence on outcomes after a negative SLNB. The Sentinel Lymph Node Working Group database was evaluated from 1996 to 2016 for negative SLNB melanoma patients. Clinicopathologic characteristics were correlated with recurrence, overall survival (OS), and melanoma-specific survival (MSS). Median follow-up was 32.1 months. Recurrences developed in 558 of 5351 negative SLN patients (10.4%). First-site of recurrence included a local or in-transit recurrence (LITR) in 221 cases (4.1%), nodal recurrence (NR) in 109 cases (2%), and distant recurrence (DR) in 220 cases (4.1%). On multivariable analysis, age, thickness, head/neck or lower extremity primary, and microsatellitosis significantly predicted for an LITR as first-site. Having an LITR as first-site significantly predicted for a subsequent NR and DR, and significantly predicted for worse OS and MSS. Furthermore, thickness and head/neck or lower extremity primary significantly predicted for an NR as first-site, while a prior LITR significantly predicted for a subsequent NR. Factors significantly predictive for a DR included thickness, head/neck or trunk primary, ulceration, and lymphovascular invasion. Patients with any type of locoregional recurrence were at higher risk for a DR. Recurrences occur in 10.4% of negative SLN patients, with LITR and DR being the most common types. Importantly, having an LITR significantly predicts for a subsequent NR and DR, and is prognostic for worse survival after a negative SLNB.

In a previous paper, we applied the Gaia DR2 catalog to improve the astrometric accuracy of about 1.7 billion objects in Pan-STARRS1 Data Release 2 (PS1 DR2). We report here on further improvements made by utilizing Gaia EDR3 and correcting for the effects of differential chromatic refraction (DCR) in declination. We extend the correction algorithm in Paper 1 by iteratively subtracting color- and declination-dependent PS1/Gaia EDR3 declination residuals. We determine the astrometric improvement for ~440 million reference objects that are point-like and cross-match to Gaia EDR3. For this set of objects, Gaia EDR3 provides a ~3% improvement in PS1 astrometry over Gaia DR2, and DCR corrections provide an additional ~5% improvement. DCR corrections increase substantially for objects observed away from the zenith. DCR corrections lead to an astrometric improvement of ~30% for blue objects (0, Comment: 14 pages, 11 figures, to be published in the Astronomical Journal

We present an innovative and widely applicable approach for the detection and classification of stellar clusters, developed for the PHANGS-HST Treasury Program, an $NUV$-to-$I$ band imaging campaign of 38 spiral galaxies. Our pipeline first generates a unified master source list for stars and candidate clusters, to enable a self-consistent inventory of all star formation products. To distinguish cluster candidates from stars, we introduce the Multiple Concentration Index (MCI) parameter, and measure inner and outer MCIs to probe morphology in more detail than with a single, standard concentration index (CI). We improve upon cluster candidate selection, jointly basing our criteria on expectations for MCI derived from synthetic cluster populations and existing cluster catalogues, yielding model and semi-empirical selection regions (respectively). Selection purity (confirmed clusters versus candidates, assessed via human-based classification) is high (up to 70$\%$) for moderately luminous sources in the semi-empirical selection region, and somewhat lower overall (outside the region or fainter). The number of candidates rises steeply with decreasing luminosity, but pipeline-integrated Machine Learning (ML) classification prevents this from being problematic. We quantify the performance of our PHANGS-HST methods in comparison to LEGUS for a sample of four galaxies in common to both surveys, finding overall agreement with $50-75\%$ of human verified star clusters appearing in both catalogues, but also subtle differences attributable to specific choices adopted by each project. The PHANGS-HST ML-classified Class 1 or 2 catalogues reach $\sim1$ magnitude fainter, $\sim2\times$ lower stellar mass, and are $2{-}5\times$ larger in number, than attained in the human classified samples., 36 pages, 18 figures, updated to v2, accepted to MNRAS

High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.

The prognostic significance of regression in melanoma is debated. We present a large multicenter study correlating regression with sentinel lymph node metastasis and melanoma-specific survival.The Sentinel Lymph Node Working Group database was reviewed from 1993 to 2018. Patients with known regression and sentinel lymph node status were included. Clinicopathologic factors were correlated with regression, sentinel lymph node status, and melanoma-specific survival.There were 4,790 patients; median follow-up was 39.6 months. Regression was present in 1,081 (22.6%) cases, and 798 (16.7%) patients had sentinel lymph node metastases. On multivariable analysis, male sex, truncal tumors, and decreasing thickness were significantly associated with regression (P.05), whereas head/neck or leg tumors had lower rates of regression (P.05). Regression was significantly correlated with a decreased risk of sentinel lymph node disease on multivariable analysis (odds ratio 0.68, 95% confidence interval 0.54-0.85; P = .0008). Multivariable analysis also showed that increasing age, male sex, increasing thickness, ulceration, lymphovascular invasion, microsatellitosis, and sentinel lymph node metastasis were significantly (P.05) associated with worse melanoma-specific survival, while regression was significantly associated with better melanoma-specific survival (hazard ratio 0.75, 95% confidence interval 0.57-0.99; P = .043).This large study shows that regression is significantly associated with better outcomes in patients with melanoma and is correlated with a lower risk of sentinel lymph node metastasis and a better melanoma-specific survival.

e16501 Background: High-dose interleukin-2 (HD IL-2) was the first approved immune-oncology (IO) agent based on proven clinical efficacy in renal cell carcinoma (RCC) and metastatic melanoma, but its use was limited due to significant toxicities. Multiple next-generation IL-2 agents designed to retain efficacy while improving tolerability are in development. Yet, understanding of genomic markers that define optimized target pharmacology is incomplete. Newer evaluation techniques not available at the time of previous HD IL-2 experience may allow for identification of pertinent genomic markers. In this retrospective study, we report for the first time, RNA sequencing (RNAseq) of peripheral blood mononuclear cell (PBMC) samples from metastatic (mRCC) patients before, during and after HD IL-2 treatment. Detailed immunogenomic responses to HD IL-2 treatment with insight into traditional flow cytometry (FC) are presented. Methods: PBMC samples were collected for n = 23 HD IL-2 treated mRCC patients between 2009 and 2015 on Day 1, 3 and 5. Patient samples underwent prior FC analysis described elsewhere (Foureau et al, 2014; Cancer Immunol. Immunother. 63(12)). RNAseq was performed using NovaSeq6000 (Illumina) paired end sequencing on bulk PBMC samples from immediately before (Day 1), during (Day 3) and post-treatment (Day 5) Cycle 1 and/or Cycle 2 of the first course of HD IL-2. Individual genes and signatures for immune and proliferation differences were analyzed. Results: RNAseq analysis of PBMC samples demonstrated that CD8+ T cells transiently decreased in the blood during treatment but recovered to baseline on Day 5, and CD4 Treg cells increased on Day 3 and Day 5, which confirmed prior FC findings. TCR clonality was unchanged which indicates that T cell recovery and expansion is widespread and not driven by a specific subset of T cells. Additional notable insights included increased monocytes at Day 3, with the opposite for NK and B cells (Day 3 decrease and Day 5 expansion). Using a novel GeneCentric proliferation signature, increased expression was noted on Day 3 and Day 5 vs. Day 1, reflecting pronounced IL-2 induced proliferation. Conclusions: Immunogenomics provided further detail regarding IL-2 activity in addition to recapitulating several parameters from FC. Expression analysis of minimally invasive PBMC samples demonstrates the importance of this novel genomic approach to understand the pharmacology of IL-2 and related derivatives.

We present a new catalogue of radio sources in the face-on spiral galaxy M83. Radio observations taken in 2011, 2015, and 2017 with the Australia Telescope Compact Array (ATCA) at 5.5 and 9 GHz have detected 270 radio sources. Although a small number of these sources are background extragalactic sources, most are either H II regions or supernova remnants (SNRs) within M83 itself. Three of the six historical supernovae are detected, as is the very young remnant that had been identified in a recent study, which is likely the result of a supernova that exploded in the last ~100 years but was missed. All of these objects are generally fading with time. Confusion limits our ability to measure the radio emission from a number of the SNRs in M83, but 64 were detected in unconfused regions, and these have the approximate power-law luminosity function which has been observed in other galaxies. The SNRs in M83 are systematically smaller in diameter and brighter than those that have been detected at radio wavelengths in M33. A number of the radio sources are coincident with X-ray sources in M83; most of these coincident sources turn out to be supernova remnants. Our dual frequency observations are among the most sensitive to date for a spiral galaxy outside the Local Group; despite this we were not able to place realistic constraints on the spectral indices, and as a result, it was not possible to search for supernova remnants based on their radio properties alone., Comment: 23 pages, 17 figures, 8 tables. Accepted for publication in MNRAS. The full machine-readable catalogues are provided in the source (MRT) folder

We use the Gaia DR2 catalog to improve the astrometric accuracy of about 1.7 billion objects in Pan-STARRS1 Data Release 2 (PS1 DR2). We also obtain proper motions for these PS1 objects. The cross match between Gaia and PS1 reveals residuals that are correlated on a scale of about 1 arcmin. We apply a spatially adaptive correction algorithm for all PS1 objects having more than two detections to reduce these residuals and align the object positions to Gaia. For point-like PS1 objects that cross match to Gaia, the algorithm reduces PS1/Gaia residuals by 33% in position (median value of 13.5 mas reduced to 9.0 mas) and by 24% in proper motion (median value of 6.3 mas/yr reduced to 4.8 mas/yr). The residuals for the corrected positions are smallest for objects with the most point-like morphologies and with intermediate magnitudes of about 17 mag. The residual errors in declination are systematically larger than those in right ascension; the declination errors increase with zenith angle in proportion to the air mass of the observations. Declination positional residuals at a given declination generally vary with color and are consistent with the effects of differential atmospheric refraction. In principle, these residuals could be reduced further by taking into account object color., Comment: 22 pages, 31 figures

The PHANGS program is building the first dataset to enable the multi-phase, multi-scale study of star formation across the nearby spiral galaxy population. This effort is enabled by large survey programs with ALMA, VLT/MUSE, and HST, with which we have obtained CO(2-1) imaging, optical spectroscopic mapping, and high resolution UV-optical imaging, respectively. Here, we present PHANGS-HST, which has obtained five band NUV-U-B-V-I imaging of the disks of 38 spiral galaxies at distances of 4-23 Mpc, and parallel V and I band imaging of their halos, to provide a census of tens of thousands of compact star clusters, and multi-scale stellar associations. The combination of HST, ALMA, and VLT/MUSE observations will yield an unprecedented joint catalog of the observed and physical properties of ~100,000 star clusters, associations, HII regions, and molecular clouds. With these basic units of star formation, PHANGS will systematically chart the evolutionary cycling between gas and stars, across a diversity of galactic environments found in nearby galaxies. We discuss the design of the PHANGS-HST survey, and provide an overview of the HST data processing pipeline and first results, highlighting new methods for selecting star cluster candidates, morphological classification of candidates with convolutional neural networks, and identification of stellar associations over a range of physical scales with a watershed algorithm. We describe the cross-observatory imaging, catalogs, and software products to be released. These high-level science products will seed a broad range of investigations, in particular, the study of embedded stellar populations and dust with JWST, for which a PHANGS Cycle 1 Treasury program to obtain eight band 2-21 $\mu$m imaging has been approved., Comment: ApJS in press. Accepted draft includes moderate revision and updates to the originally posted submitted version. 27 pages, 11 figures, 1 table. Data products released at https://archive.stsci.edu/hlsp/phangs-hst/

Microsatellitosis (mS) in melanoma has been considered a marker of unfavorable tumor biology, leading to the current American Joint Committee on Cancer staging of IIIB/C/D disease, despite few investigative studies of this entity limited by the small sample sizes and incomplete nodal microstaging. We sought to better characterize outcomes and prognostic factors in a multi-institutional cohort of patients with mS and nodal microstaging. The Sentinel Lymph Node Working Group cohort included 414 mS patients who underwent sentinel lymph node (SLN) biopsy. Cox regression analysis was used to evaluate the prognostic significance of established clinicopathologic characteristics. Melanoma-specific survival (MSS) of patients with mS was compared with 3002 similarly staged patients from the Surveillance, Epidemiology, and End Results (SEER) Program registry. The median age of the mS cohort was 64.9 years; 39.6% were female. Median thickness was 3 mm, 40.6% of cases were ulcerated, and the SLN positivity rate was 46.7%. Increasing thickness, male sex, and SLN positivity were significantly associated with poorer MSS. Stage IIIB/C/D 5-year MSS rates were 86.3% (95% confidence interval [CI] 79.4–93.3%), 54.1% (95% CI 45.4–59.7%), and 44.2% (95% CI 25.4–63.0%), respectively. MSS survival for the stage IIIB mS cohort was significantly better than a similarly staged SEER cohort (5-year MSS of 70.1%, 95% CI 66.0–74.2%), while no significant difference was observed for the stage IIIC or D cohorts. SLN metastases are common and are a significant prognostic factor in patients with mS. Survival in stage IIIB patients with mS was considerably more favorable than their stage would otherwise suggest, which has important implications for decisions regarding adjuvant therapy for patients with mS.

Background The ACOSOG (American College of Surgeons Oncology Group) Z1071 assessed the feasibility of performing sentinel lymph node biopsy (SLNB) in node-positive patients who completed neoadjuvant chemotherapy (NACT). Historically, adoption of clinical research into practice takes years. The goal of this study was to determine the effect of Z1071 on our practice. Materials and Methods This is a retrospective review of Z1071’s influence on a single institution’s practice. Patients with biopsy-proven positive axillary lymph nodes before NACT were eligible for the study. After NACT, patients with nodal response according to imaging and exam were candidates for SLNB. Two cohorts were stratified according to diagnosis date before and after Z1071 results were presented on December 5, 2012 at the San Antonio Breast Cancer Symposium. Fisher exact tests and nonparametric rank tests were used to compare cohorts. Results The pre-Z1071 cohort included 74 patients and the post-Z1071 cohort 56 for a total of 130 patients. Post-Z1071, 73% (41/56) underwent a SLNB with an average of 4 nodes removed. Moreover, 27% (15/56) of patients had an axillary lymph node dissection as first intervention post-Z1071, compared with 99% (73/74) pre-Z1071. Axillary pathologic complete response pre-Z1071 was 35% (26/74) and post-Z1071 was 27% (15/56) (P = .35). Conclusion This report shows that meaningful practice changes can be implemented rapidly. Changes in practice generated by clinical trial results should be monitored and outcomes followed.

Background Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. Methods To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. Results The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. Conclusion These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy. Electronic supplementary material The online version of this article (10.1186/s40425-018-0362-6) contains supplementary material, which is available to authorized users.

Guidelines for melanoma recommend sentinel lymph node biopsy (SLNB) in patients with melanomas ≥1 mm thickness. Recent single institution studies have found tumors1.5 mm a low-risk group for positive SLNB.A retrospective review of the Sentinel Lymph Node Working Group multicenter database identified patients with intermediate thickness melanoma (1.01-4.00 mm) who had SLNB, and assessed predictors for positive SLNB.3460 patients were analyzed, 584 (17%) had a positive SLNB. Univariate factors associated with a positive SLNB included age60 (p .001), tumor on the trunk/lower extremity (p .001), Breslow depth ≥2 mm (p .001), ulceration (p .001), mitotic rate ≥1/mmIntermediate thickness melanoma has significant heterogeneity of SLNB positivity. Low-risk subgroups can be found among older patients in the absence of high-risk features.

Genetic testing is important for comprehensive cancer care. Commercial analysis of the BRCA1/2 genes has been available since 1996, and testing for hereditary breast and ovarian cancer syndrome is well established. The National Comprehensive Cancer Network (NCCN) guidelines identify individuals for whom BRCA1/2 analysis is appropriate and define management recommendations for mutation carriers. Despite recommendations, not all who meet NCCN criteria undergo genetic testing. We assess the frequency that individuals meeting NCCN criteria decline BRCA1/2 analysis, as well as factors that affect the decision-making process. A retrospective chart review was performed from September 2013 through August 2014 of individuals who received genetic counseling at the Levine Cancer Institute. A total of 1082 individuals identified through the retrospective chart review met NCCN criteria for BRCA1/2 analysis. Of these, 267 (24.7%) did not pursue genetic testing. Of the Nontested cohort, 59 (22.1%) were disinterested in testing and 108 (40.4%) were advised to gather additional genetic or medical information about their relatives before testing. The remaining 100 (37.5%) individuals were insured and desired to undergo genetic testing but were prohibited by the expense. Eighty five of these 100 patients were responsible for the total cost of the test, whereas the remaining 15 faced a prohibitive copay expense. Financial concerns are a major deterrent to the pursuit of BRCA1/2 analysis among those who meet NCNN criteria, especially in patients diagnosed with breast or ovarian cancer. These findings highlight the need to address financial concerns for genetic testing in this high-risk population.

INTRODUCTION Prior to the "no ink on tumor" SSO/ASTRO consensus guideline, approximately 20% of women with stage I/II breast cancers undergoing breast conservation surgery at our institution underwent margin re-excision. On May 20, 2013, our institution changed the definition of negative margins from 2 mm to "no ink on tumor." METHODS A retrospective review was conducted of patients who had surgery at our institution with clinical stage I/II breast cancers between June 1, 2011 and May 1, 2015. In the pre-guideline cohort (pre) and post-guideline cohort (post), negative margins were 2 mm and "no ink on tumor," respectively. RESULTS Implementation of the guideline resulted in a significant decrease in the positive/close margin rate (29.6% pre vs 10.1% post; P

Objective There is currently no consensus regarding how to address pelvic sentinel lymph nodes (PSLNs) in melanoma. Thus, our objectives were to identify the incidence and clinical impact of PSLNs. Methods Retrospective review of a prospectively collected multi-institutional melanoma database. Results Of 2476 cases of lower extremity and trunk melanomas, 227 (9%) drained to PSLNs (181 to both PSLNs and superficial (inguinal or femoral) sentinel lymph nodes (SSLN) and 46 to PSLNs alone). Seventeen (7.5%) of 227 PSLN cases were positive for nodal metastasis, 8 of which drained to PSLNs only while 9 drained to both PSLNs and SSLNs. Complication rates between PSLN and SSLN biopsy were similar (15% vs. 14% respectively). In 181 cases with drainage to both SSLNs and PSLNs, PSLN biopsy upstaged one patient (0.6%), and completion dissection based on a positive PSLN did not upstage any. Conclusions PSLN biopsy is safe, however in the setting of negative SSLNs there is minimal clinical impact. We therefore recommend PSLN biopsy when the SSLNs are positive or when the tumor drains to PSLNs alone.

Background The seventh edition of the American Joint Commission on Cancer staging manual (AJCC7, published 2009), updated thin cutaneous melanoma staging protocols with the incorporation of mitotic rate (MR). In these patients, higher MR is associated with decreased survival. This study utilizes the National Cancer Data Base (NCDB) to evaluate MR reporting since AJCC7. Methods The NCDB was queried for patients with primary cutaneous melanoma from 1998 to 2013. Because MR reporting was infrequent prior to implementing AJCC7, records from 2010 to 2013 were analyzed. Categorical variables were compared with chi-square tests; univariate and multivariate logistic regression models were constructed to determine the effects of covariates on MR reporting. Results A total of 107,134 patients met inclusion criteria. From 2010 to 2013, MR reporting increased dramatically (64.3-80.9%). On multivariate analysis, factors significantly related to increased MR reporting include later diagnosis year, T-classification (T1a and b vs. T1), facility type (academic vs. other specified types of cancer programs), facility volume, patient income, level of education, and county population (metropolitan vs. urban and rural). Conclusions MR reporting increased dramatically after the introduction of AJCC7; however, disparities in reporting remain across facility types. Further investigation of procedures performed in academic settings that may influence reporting of MR is warranted. J. Surg. Oncol. 2017;115:281-286. © 2017 Wiley Periodicals, Inc.