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Associations between TERT promoter mutations and survival in superficial spreading and nodular melanomas in a large prospective patient cohort

Chang, Gregory A; Robinson, Eric; Wiggins, Jennifer M; Zhang, Yilong; Tadepalli, Jyothirmayee S; Schafer, Christine N; Darvishian, Farbod; Berman, Russell S; Shapiro, Richard; Shao, Yongzhao; Osman, Iman; Polsky, David
Survival outcomes in melanoma, and their association with mutations in the telomerase reverse transcriptase (TERT) promoter, remain uncertain. In addition, few studies have examined whether these associations are affected by a nearby common germline polymorphism, or vary based on melanoma histopathological subtype. We analyzed 408 primary tumors from a prospective melanoma cohort for somatic TERT-124[C>T] and TERT-146[C>T] mutations, the germline polymorphism rs2853669, and BRAFV600 and NRASQ61 mutations. We tested the associations between these variants and clinicopathologic factors and survival outcomes. TERT-124[C>T] was associated with thicker tumors, ulceration, mitoses (>0/mm2), nodular histotype and CNS involvement. In a multivariable model controlling for AJCC stage, TERT-124[C>T] was an independent predictor of shorter recurrence-free survival (RFS) (HR=2.58, p=0.001), and overall survival (HR=2.47, p=0.029). Patients with the germline variant and TERT-124[C>T] mutant melanomas had significantly shorter RFS than those patients lacking either or both sequence variants (p<0.04). The impact of the germline variant appeared to be more pronounced in superficial spreading compared to nodular melanoma. No associations were found between survival and TERT-146[C>T], BRAF or NRAS mutations. These findings strongly suggest that TERT-124[C>T] mutation is a biomarker of aggressive primary melanomas, an effect that may be modulated by rs2853669.
PMID: 35469904
ISSN: 1523-1747
CID: 5205542

Adherence to guidelines at the patient- and hospital-levels is associated with improved overall survival in patients with gastric cancer

Kaslow, Sarah R; Ma, Zhongyang; Hani, Leena; Prendergast, Katherine; Vitiello, Gerardo; Lee, Ann Y; Berman, Russell S; Goldberg, Judith D; Correa-Gallego, Camilo
BACKGROUND AND OBJECTIVES/OBJECTIVE:Adherence to evidence-based guidelines in gastric cancer is low. We aimed to evaluate adherence to National Comprehensive Cancer Network (NCCN) Guidelines for gastric cancer at both patient- and hospital-levels and examine associations between guideline adherence and treatment outcomes, including overall survival (OS). METHODS:We applied stage-specific, annual NCCN Guidelines (2004-2015) to patients with gastric cancer treated with curative-intent within the National Cancer Database and compared characteristics of patients who did and did not receive guideline-adherent care. Hospitals were evaluated by guideline adherence rate. We identified associations with OS through multivariable Cox regression. RESULTS:Of 37 659 patients included, 32% received NCCN Guideline-adherent treatment. OS was significantly associated with both guideline adherence (51 months for patients receiving guideline-adherent treatment vs. 22 for patients receiving nonadherent treatment, p < 0.001). Treatment at a hospital with higher adherence was associated with longer OS (21 months for patients treated at lowest adherence quartile hospitals vs. 37 months at highest adherence quartile hospitals, p < 0.001), regardless of type of treatment received. CONCLUSIONS:Guideline-adherent treatment was strongly associated with longer median OS. Guideline adherence should be used as a benchmark for focused quality improvement for physicians taking care of patients with gastric cancer and institutions at large.
PMID: 35471731
ISSN: 1096-9098
CID: 5217392

Diagnostic laparoscopy is underutilized in the staging of gastric adenocarcinoma regardless of hospital type: An US safety net collaborative analysis

Leder Macek, Aleeza J; Wang, Annie; Turgeon, Michael K; Lee, Rachel M; Russell, Maria C; Porembka, Matthew R; Alterio, Rodrigo; Ju, Michelle; Kronenfeld, Joshua; Goel, Neha; Datta, Jashodeep; Maker, Ajay V; Fernandez, Manuel; Richter, Harry; Berman, Russell S; Correa-Gallego, Camilo; Lee, Ann Y
BACKGROUND:Diagnostic laparoscopy (DL) is a key component of staging for locally advanced gastric adenocarcinoma (GA). We hypothesized that utilization of DL varied between safety net (SNH) and affiliated tertiary referral centers (TRCs). METHODS:Patients diagnosed with primary GA eligible for DL were identified from the US Safety Net Collaborative database (2012-2014). Clinicopathologic factors were analyzed for association with use of DL and findings on DL. Overall survival (OS) was analyzed by Kaplan-Meier method. RESULTS:Among 233 eligible patients, 69 (30%) received DL, of which 24 (35%) were positive for metastatic disease. Forty percent of eligible SNH patients underwent DL compared to 21.5% at TRCs. Lack of insurance was significantly associated with decreased use of DL (OR 0.48, p < 0.01), while African American (OR 6.87, p = 0.02) and Asian race (OR 3.12, p ≤ 0.01), signet ring cells on biopsy (OR 3.14, p < 0.01), and distal tumors (OR 1.62, p < 0.01) were associated with increased use. Median OS of patients with a negative DL was better than those without DL or a positive DL (not reached vs. 32 vs. 12 months, p < 0.005, Figure 1). CONCLUSIONS:Results from DL are a strong predictor of OS in GA; however, the procedure is underutilized. Patients from racial minority groups were more likely to undergo DL, which likely accounts for higher DL rates among SNH patients.
PMID: 35699351
ISSN: 1096-9098
CID: 5282572

Dermatofibrosarcoma Protuberans: What Is This?

Vitiello, Gerardo A; Lee, Ann Y; Berman, Russell S
Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive dermal-based sarcoma. Metastatic potential is extremely low, primarily in the setting of fibrosarcomatous transformation. DFSP is characterized by a t(17;22) (q22;q13) translocation that results in active PDGFB signaling. Surgical resection with negative margins (typically including the underlying fascia) is the potentially curative treatment. Delayed wound closure should be considered for cases requiring extensive resection or tissue rearrangement. Tyrosine kinase inhibitors, such as imatinib, have shown response rates of 50% to 60% in patients with locally advanced or metastatic disease. Radiation can be useful for residual or recurrent diseases.
PMID: 35952694
ISSN: 1558-3171
CID: 5287152

Outcomes After Surgical Palliation of Patients With Gastric Cancer

Nohria, Ambika; Kaslow, Sarah R; Hani, Leena; He, Yanjie; Sacks, Greg D; Berman, Russell S; Lee, Ann Y; Correa-Gallego, Camilo
INTRODUCTION/BACKGROUND:Surgery is an option for symptom palliation in patients with metastatic gastric cancer. Operative outcomes after palliative interventions are largely unknown. Herein, we assess the trends of surgical palliation use for patients with gastric cancer and describe outcomes of patients undergoing surgical palliation compared to nonsurgical palliation. METHODS:Patients with clinical Stage IV gastric cancer in the National Cancer Database (2004-2015) who received surgical or nonsurgical palliation were selected. We identified factors associated with palliative surgery. Survival differences were assessed by Kaplan-Meier estimate, Cox proportional hazard regression, and log rank test. RESULTS:Six thousand eight hundred twenty nine patients received palliative care for gastric cancer. Most patients (87%, n = 5944) received nonsurgical palliation: 29% radiation therapy, 57% systemic treatment, and 14% pain management. The number of patients receiving palliative care increased between 2004 and 2015; however, use of surgical palliation declined significantly (22% in 2004, 8% in 2015; P < 0.001). Median overall survival (OS) for the cohort was 5.65 mo (95% confidence interval 5.45-5.85); 1-year and 2-year OS were 24% and 9%, respectively. Older age at diagnosis and diagnosis between 2004 and 2006 were significantly associated with undergoing surgical palliation. Patients who underwent surgical palliation had significantly shorter median OS and a 20% higher hazard of mortality than those who received nonsurgical palliation. CONCLUSIONS:Patients with metastatic gastric cancer experience very short survival. While palliative surgery is used infrequently, the observed association with shorter median OS underscores the importance of careful patient selection. Palliative surgery should be offered judiciously and expectations about outcomes clearly established.
PMID: 35809355
ISSN: 1095-8673
CID: 5280742

Systemic therapy for duodenal adenocarcinoma: An analysis of the National Cancer Database (NCDB)

Kaslow, Sarah R; Prendergast, Katherine; Vitiello, Gerardo A; Hani, Leena; Berman, Russell S; Lee, Ann Y; Correa-Gallego, Camilo
BACKGROUND:National Comprehensive Cancer Network guidelines recommend resection and adjuvant chemotherapy for patients with locally advanced duodenal adenocarcinoma. Outcomes after systemic treatment in this rare malignancy have not been well studied. We examined utilization patterns of systemic treatment and compared overall survival of patients receiving neoadjuvant therapy, surgery alone, and adjuvant therapy. METHODS:Patients with stage 0 to III duodenal adenocarcinoma undergoing curative-intent surgery were identified within the National Cancer Database from 2006 to 2015. Outcomes, including median overall survival and 30- and 90-day mortality, were compared based on treatment sequence (neoadjuvant, adjuvant, or surgery alone). Propensity score matching on likelihood of receiving systemic treatment and landmark analysis were performed to mitigate bias. RESULTS:Of the 2,956 patients meeting inclusion criteria, most patients with known clinical stage had locally advanced disease (72%), of which 53% received systemic therapy (8% neoadjuvant, 45% adjuvant). After landmark analysis on the propensity matched cohort, patients with locally advanced disease who received systemic treatment had longer median overall survival compared to patients who underwent surgery alone (49 vs 40 months, P = .018) and a 20% lower hazard of mortality (hazard ratio 0.80, 95% confidence interval 0.69-0.93, P = .003). Patients who received neoadjuvant and adjuvant therapy had similar survival outcomes. CONCLUSION/CONCLUSIONS:Adjuvant therapy was underutilized in patients with National Comprehensive Cancer Network guideline indications, despite an association with longer median overall survival and decreased hazard of mortality. Neoadjuvant therapy, although rarely used, had similar survival to adjuvant therapy. Given its other potential benefits, systemic treatment in the neoadjuvant setting may be a reasonable option in adequately selected patients with clinically advanced duodenal adenocarcinoma.
PMID: 35437164
ISSN: 1532-7361
CID: 5218192

The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases - A multicenter cohort study

Holmberg, Carl-Jacob; Ny, Lars; Hieken, Tina J; Block, Matthew S; Carr, Michael J; Sondak, Vernon K; Örtenwall, Christoffer; Katsarelias, Dimitrios; Dimitriou, Florentia; Menzies, Alexander M; Saw, Robyn Pm; Rogiers, Aljosja; Straker, Richard J; Karakousis, Giorgos; Applewaite, Rona; Pallan, Lalit; Han, Dale; Vetto, John T; Gyorki, David E; Tie, Emilia Nan; Vitale, Maria Grazia; Ascierto, Paulo A; Dummer, Reinhard; Cohen, Jade; Hui, Jane Yc; Schachter, Jacob; Asher, Nethanel; Helgadottir, H; Chai, Harvey; Kroon, Hidde; Coventry, Brendon; Rothermel, Luke D; Sun, James; Carlino, Matteo S; Duncan, Zoey; Broman, Kristy; Weber, Jeffrey; Lee, Ann Y; Berman, Russell S; Teras, Jüri; Ollila, David W; Long, Georgina V; Zager, Jonathan S; van Akkooi, Alexander; Olofsson Bagge, Roger
PURPOSE/OBJECTIVE:Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. METHODS:A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. RESULTS:A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. CONCLUSION/CONCLUSIONS:Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.
PMID: 35644725
ISSN: 1879-0852
CID: 5236022

Deep learning and pathomics analyses reveal cell nuclei as important features for mutation prediction of BRAF-mutated melanomas

Kim, Randie H; Nomikou, Sofia; Coudray, Nicolas; Jour, George; Dawood, Zarmeena; Hong, Runyu; Esteva, Eduardo; Sakellaropoulos, Theodore; Donnelly, Douglas; Moran, Una; Hatzimemos, Aristides; Weber, Jeffrey S; Razavian, Narges; Aifantis, Iannis; Fenyo, David; Snuderl, Matija; Shapiro, Richard; Berman, Russell S; Osman, Iman; Tsirigos, Aristotelis
Image-based analysis as a method for mutation detection can be advantageous in settings when tumor tissue is limited or unavailable for direct testing. Here, we utilize two distinct and complementary machine learning methods of analyzing whole slide images (WSI) for predicting mutated BRAF. In the first method, WSI of melanomas from 256 patients were used to train a deep convolutional neural network (CNN) in order to develop a fully automated model that first selects for tumor-rich areas (Area Under the Curve AUC=0.96) then predicts for mutated BRAF (AUC=0.71). Saliency mapping was performed and revealed that pixels corresponding to nuclei were the most relevant to network learning. In the second method, WSI were analyzed using a pathomics pipeline that first annotates nuclei and then quantifies nuclear features, demonstrating that mutated BRAF nuclei were significantly larger and rounder nuclei compared to BRAF WT nuclei. Lastly, we developed a model that combines clinical information, deep learning, and pathomics that improves the predictive performance for mutated BRAF to AUC=0.89. Not only does this provide additional insights on how BRAF mutations affect tumor structural characteristics, machine learning-based analysis of WSI has the potential to be integrated into higher order models for understanding tumor biology.
PMID: 34757067
ISSN: 1523-1747
CID: 5050512

Surgical Treatment of Patients with Poorly Differentiated Pancreatic Neuroendocrine Carcinoma: An NCDB Analysis

Kaslow, Sarah R; Vitiello, Gerardo A; Prendergast, Katherine; Hani, Leena; Cohen, Steven M; Wolfgang, Christopher; Berman, Russell S; Lee, Ann Y; Correa-Gallego, Camilo
BACKGROUND:Consensus guidelines discourage resection of poorly differentiated pancreatic neuroendocrine carcinoma (panNEC) given its association with poor long-term survival. This study assessed treatment patterns and outcomes for this rare malignancy using the National Cancer Database (NCDB). METHODS:Patients with non-functional pancreatic neuroendocrine tumors in the NCDB (2004-2016) were categorized based on pathologic differentiation. Logistic and Cox proportional hazard regressions identified associations with resection and overall survival (OS). Survival was compared using Kaplan-Meier and log-rank tests. RESULTS:Most patients (83%) in the cohort of 8560 patients had well-differentiated tumors (panNET). The median OS was 47 months (panNET, 63 months vs panNEC, 17 months; p < 0.001). Surgery was less likely for older patients (odds ratio [OR], 0.97), patients with panNEC (OR, 0.27), and patients with metastasis at diagnosis (OR, 0.08) (all p < 0.001). After propensity score-matching of these factors, surgical resection was associated with longer OS (82 vs 29 months; p < 0.001) and a decreased hazard of mortality (hazard ratio [HR], 0.37; p < 0.001). Surgery remained associated with longer OS when stratified by differentiation (98 vs 41 months for patients with panNET and 36 vs 8 months for patients with panNEC). Overall survival did not differ between patients with panNEC who underwent surgery and patients with panNET who did not (both 39 months; p = 0.294). CONCLUSIONS:Poorly differentiated panNEC exhibits poorer survival than well-differentiated panNET. In the current cohort, surgical resection was strongly and independently associated with improved OS, suggesting that patients with panNEC who are suitable operative candidates should be considered for multimodality therapy, including surgery.
PMID: 35246811
ISSN: 1534-4681
CID: 5173682

ASO Visual Abstract: Surgical Treatment of Patients with Poorly Differentiated Pancreatic Neuroendocrine Carcinoma-An NCDB Analysis

Kaslow, Sarah R; Vitiello, Gerardo A; Prendergast, Katherine; Hani, Leena; Cohen, Steven M; Wolfgang, Christopher; Berman, Russell S; Lee, Ann Y; Correa-Gallego, Camilo
PMID: 35249164
ISSN: 1534-4681
CID: 5173692