Publications by authors named "Mark Faries"

154 Publications

ASO Author Reflections: Minimally Invasive Inguinal Lymphadenectomy, an Incremental Step in the Evolution of the Management of Advanced Melanoma.

Ann Surg Oncol 2022 Apr 30. Epub 2022 Apr 30.

Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

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http://dx.doi.org/10.1245/s10434-022-11847-zDOI Listing
April 2022

Oncologic Outcomes of Multi-Institutional Minimally Invasive Inguinal Lymph Node Dissection for Melanoma Compared with Open Inguinal Dissection in the Second Multicenter Selective Lymphadenectomy Trial (MSLT-II).

Ann Surg Oncol 2022 May 2. Epub 2022 May 2.

Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Minimally invasive inguinal lymphadenectomy (MILND) is safe and feasible, but limited data exist regarding oncologic outcomes.

Methods: This study performed a multi-institutional retrospective cohort analysis of consecutive MILND performed for melanoma between January 2009 and June 2016. The open ILND (OILND) comparative cohort comprised patients enrolled in the second Multicenter Selective Lymphadenectomy Trial (MSLT-II) between December 2004 and March 2014.The pre-defined primary end point was the same-basin regional nodal recurrence, calculated using properties of binomial distribution. Time to events was calculated using the Kaplan-Meier method. The secondary end points were overall survival, progression-free survival, melanoma-specific survival (MSS), and distant metastasis-free survival (DMFS).

Results: For all the patients undergoing MILND, the same-basin regional recurrence rate was 4.4 % (10/228; 95 % confidence interval [CI], 2.1-7.9 %): 8.2 % (4/49) for clinical nodal disease and 3.4 % (6/179) for patients with a positive sentinel lymph node (SLN) as the indication. For the 288 patients enrolled in MSLT-II who underwent OILND for a positive SLN, 17 (5.9 %) had regional node recurrence as their first event. After controlling for ulceration, positive LN count and positive non-SLNs at the time of lymphadenectomy, no difference in OS, PFS, MSS or DMFS was observed for patients with a positive SLN who underwent MILND versus OILND.

Conclusion: This large multi-institutional experience supports the oncologic safety of MILND for melanoma. The outcomes in this large multi-institutional experience of MILND compared favorably with those for an OILND population during similar periods, supporting the oncologic safety of MILND for melanoma.
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http://dx.doi.org/10.1245/s10434-022-11758-zDOI Listing
May 2022

Quantitative Nodal Burden and Mortality across Solid Cancers.

J Natl Cancer Inst 2022 Mar 21. Epub 2022 Mar 21.

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Nodal staging systems vary substantially across solid tumors, implying significant heterogeneity in the behavior of nodal variables in various contexts. We hypothesized, in contradiction to this, that metastatic lymph node (LN) number is a universal and dominant predictor of outcome across solid tumors.

Methods: Retrospective cohort analysis of 1,304,498 patients in the National Cancer Database undergoing surgery between 2004-2015 across 16 solid cancer sites. Multivariable Cox regression analyses were constructed using restricted cubic splines to model the association between nodal number and mortality. Recursive partitioning analysis (RPA) was used to derive nodal classification systems for each solid cancer based on metastatic LN count. The reproducibility of these findings was assessed in 1,969,727 patients from the Surveillance, Epidemiology, and End Results registry. Two-sided tests were used for all statistical analyses.

Results: Consistently across disease sites, mortality risk increased continuously with increasing number of metastatic LNs (P < 0.001 for all spline segments). Each RPA-derived nodal classification system produced multiple prognostic groups spanning a wide spectrum of mortality risk (P < 0.001). Multivariable models using these RPA-derived nodal classifications demonstrated improved concordance with mortality compared to models using American Joint Committee on Cancer staging in sites where nodal classification is not based on metastatic LN count. Each RPA-derived nodal classification system was reproducible in a large validation cohort for all-cause and cause-specific mortality (P < 0.001). High quantitative nodal burden was the single strongest tumor-intrinsic variable associated with mortality in 12 of 16 disease sites.

Conclusions: Quantitative metastatic LN burden is a fundamental driver of mortality across solid cancers and should serve as a foundation for pathologic nodal staging across solid tumors.
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http://dx.doi.org/10.1093/jnci/djac059DOI Listing
March 2022

Sentinel lymph node melanoma metastases: Assessment of tumor burden for clinical prediction of outcome in the first Multicenter Selective Lymphadenectomy Trial (MSLT-I).

Eur J Surg Oncol 2022 Feb 12. Epub 2022 Feb 12.

John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA, USA; The Angeles Clinic and Research Institute, Los Angeles, USA; Cedars Sinai Medical Center, Los Angeles, CA, USA.

Purpose: As clinical management decisions in patients with Stage III melanoma have become more complex, precise pathologic characterization of sentinel lymph node (SLN) metastases has become critical to guide management. The extent of SLN involvement correlates with risk of adverse outcomes, but reported methods of disease quantification vary. We examined SLN metastases from patients participating in an international clinical trial and compared several methods of tumor burden quantification.

Methods: SLNs from 146 node-positive patients in the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) were centrally-reviewed and characterized by number of tumor-positive nodes, percent nodal area tumor replacement, maximum dimension of largest metastasis, tumor penetrative depth, number of tumor foci, metastasis microanatomic location, and extracapsular extension. These data were analyzed for correlation with non-SLN metastasis and melanoma-specific survival (MSS).

Results: The median number of tumor-involved SLNs was 1. The median maximum metastasis dimension was 1.11 mm. Median SLN area involvement was 1.5%. Tumor burden measures were highly correlated with each other. Factors associated with non-SLN metastasis by univariable analysis were primary tumor ulceration and extent of metastases. Tumor thickness, ulceration, non-SLN metastasis and multiple measures of SLN tumor burden were significantly related to MSS on univariable analysis. After multivariable adjustment, number of involved SLNs (p = 0.05) and percent nodal area tumor replacement (p = 0.02) were independent predictors of MSS.

Conclusion: Central review of MSLT-I pathology indicates that primary tumor and SLN tumor characteristics predict non-SLN metastasis and MSS. Percent nodal involvement was more powerfully prognostic than the more commonly used maximum dimension of largest metastasis.
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http://dx.doi.org/10.1016/j.ejso.2022.01.021DOI Listing
February 2022

Immunohistochemistry for Preferentially Expressed Antigen in Melanoma in the Differential Diagnosis of Melanocytic Lesions of the Nail Apparatus.

Am J Dermatopathol 2022 Feb 2. Epub 2022 Feb 2.

Department of Pathology and Laboratory Medicine; Department of Dermatology; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA; The Angeles Clinic & Research Institute, Los Angeles, CA; and Department of Pathology, Rush Foundation Hospital, Meridian, MS.

Abstract: Nail unit melanocytic lesions present a unique set of diagnostic challenges because of the unfamiliarity with clinical assessment and the lack of experience with histologic examination. Because the first surgical specimen received in the pathology laboratory is typically small, sometimes suboptimal biopsy, the distinction between melanoma and its histologic mimics can be difficult. For this reason, there has been a continued interest in the development of ancillary markers that may assist in the differential diagnosis of nail unit melanocytic lesions. Upregulation of preferentially expressed antigen in melanoma (PRAME) has been reported to be a common event in melanomas, and PRAME immunohistochemistry has been shown to be helpful in evaluating various melanocytic neoplasms. In this study, we evaluated PRAME protein expression in a series of nail unit melanocytic lesions. Twenty-five nail unit melanomas (including small biopsy and amputation specimens) and 32 control benign melanocytic lesions were retrospectively retrieved. Nuclear PRAME staining was scored as percentage and intensity labeling. All melanoma cases showed the nuclear expression of PRAME, which was usually diffuse and strong. In specimens where the neoplastic cells are limited in number, the staining was restricted to the tumor cells, corresponding to the initial H&E impression. All control cases were negative for PRAME expression. PRAME expression is helpful in distinguishing between melanomas and other nail unit melanocytic lesions. This antibody also proved to be diagnostically valuable in detecting melanoma cells in small specimens with minimal disease.
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http://dx.doi.org/10.1097/DAD.0000000000002143DOI Listing
February 2022

Neoadjuvant Systemic Therapy (NAST) in Patients with Melanoma: Surgical Considerations by the International Neoadjuvant Melanoma Consortium (INMC).

Ann Surg Oncol 2022 Jun 28;29(6):3694-3708. Epub 2022 Jan 28.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Exciting advances in melanoma systemic therapies have presented the opportunity for surgical oncologists and their multidisciplinary colleagues to test the neoadjuvant systemic treatment approach in high-risk, resectable metastatic melanomas. Here we describe the state of the science of neoadjuvant systemic therapy (NAST) for melanoma, focusing on the surgical aspects and the key role of the surgical oncologist in this treatment paradigm. This paper summarizes the past decade of developments in melanoma treatment and the current evidence for NAST in stage III melanoma specifically. Issues of surgical relevance are discussed, including the risk of progression on NAST prior to surgery. Technical aspects, such as the definition of resectability for melanoma and the extent and scope of routine surgery are presented. Other important issues, such as the utility of radiographic response evaluation and method of pathologic response evaluation, are addressed. Surgical complications and perioperative management of NAST related adverse events are considered. The International Neoadjuvant Melanoma Consortium has the goal of harmonizing NAST trials in melanoma to facilitate rapid advances with new approaches, and facilitating the comparison of results across trials evaluating different treatment regimens. Our ultimate goals are to provide definitive proof of the safety and efficacy of NAST in melanoma, sufficient for NAST to become an acceptable standard of care, and to leverage this platform to allow more personalized, biomarker-driven, tailored approaches to subsequent treatment and surveillance.
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http://dx.doi.org/10.1245/s10434-021-11236-yDOI Listing
June 2022

Dose-Response of Paraxanthine on Cognitive Function: A Double Blind, Placebo Controlled, Crossover Trial.

Nutrients 2021 Dec 15;13(12). Epub 2021 Dec 15.

Exercise & Sport Nutrition Lab, Human Clinical Research Facility, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843, USA.

Paraxanthine (PXN) is a metabolite of caffeine that has recently been reported to enhance cognition at a dose of 200 mg.

Objective: To determine the acute and short-term (7-day) effects of varying doses of PXN on cognitive function and side effects.

Methods: In a double blind, placebo-controlled, crossover, and counterbalanced manner, 12 healthy male and female volunteers (22.7 ± 4 years, 165 ± 7 cm, 66.5 ± 11 kg, 24.4 ± 3 kg/m) ingested 200 mg of a placebo (PLA), 50 mg of PXN (ENFINITY™, Ingenious Ingredients, L.P.) + 150 mg PLA, 100 mg PXN + 100 mg PLA, or 200 mg of PXN. With each treatment experiment, participants completed side effect questionnaires and donated a fasting blood sample. Participants then performed a series of tests assessing cognition, executive function, memory, and reaction time. Participants then ingested one capsule of PLA or PXN treatments. Participants then completed side effects and cognitive function tests after 1, 2, 3, 4, 5, and 6 h of treatment ingestion. Participants continued ingesting one dose of the assigned treatment daily for 6-days and returned to the lab on day 7 to donate a fasting blood sample, assess side effects, and perform cognitive function tests. Participants repeated the experiment while ingesting remaining treatments in a counterbalanced manner after at least a 7-day washout period until all treatments were assessed.

Results: The Sternberg Task Test (STT) 4-Letter Length Present Reaction Time tended to differ among groups ( = 0.06). Assessment of mean changes from baseline with 95% CI's revealed several significant differences among treatments in Berg-Wisconsin Card Sorting Correct Responses, Preservative Errors (PEBL), and Preservative Errors (PAR Rules). There was also evidence of significant differences among treatments in the Go/No-Go Task tests in Mean Accuracy as well as several time points of increasing complexity among STT variables. Finally, there was evidence from Psychomotor Vigilance Task Test assessment that response time improved over the series of 20 trials assessed as well as during the 6-h experiment in the PXN treatment. Acute and short-term benefits compared to PLA were seen with each dose studied but more consistent effects appeared to be at 100 mg and 200 mg doses. No significant differences were observed among treatments in clinical chemistry panels or the frequency or severity of reported side effects. Results provide evidence that acute ingestion of 100 mg and 200 mg of PXN may affect some measures of cognition, memory, reasoning, and response time as well as help sustain attention. Additionally, that acute and daily ingestion of PXN for 7 days is not associated with any clinically significant side effects.

Conclusions: PXN may serve as an effective nootropic agent at doses as low as 50 mg.
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http://dx.doi.org/10.3390/nu13124478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708375PMC
December 2021

Melanoma trials that defined surgical management.

Authors:
Mark B Faries

J Surg Oncol 2022 Jan;125(1):34-37

The Angeles Clinic and Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Treatment of regional lymph nodes in melanoma has been controversial for more than a century. A series of clinical trials evaluating elective lymph node dissection and then sentinel lymph node biopsy have helped define the current standard of care. These trials resulted in increasingly selective application of surgical intervention for regional lymph nodes in melanoma. First by focusing on optimal candidates for elective lymph node dissection and then by identifying patients through sentinel lymph node biopsy. The current standard of sentinel lymph node biopsy for appropriately selected patients and nodal observation for many patients, even with involved sentinel nodes is both more accurate in staging and much less morbid than what came before.
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http://dx.doi.org/10.1002/jso.26744DOI Listing
January 2022

Acute Paraxanthine Ingestion Improves Cognition and Short-Term Memory and Helps Sustain Attention in a Double-Blind, Placebo-Controlled, Crossover Trial.

Nutrients 2021 Nov 9;13(11). Epub 2021 Nov 9.

Human Clinical Research Facility, Exercise & Sport Nutrition Lab, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843, USA.

This study examined the effects of acute paraxanthine (PXN) ingestion on markers of cognition, executive function, and psychomotor vigilance. In a randomized, double blind, placebo-controlled, crossover, and counterbalanced manner, 13 healthy male and female participants were randomly assigned to consume a placebo (PLA) or 200 mg of PXN (ENFINITY™, Ingenious Ingredients, L.P.). Participants completed stimulant sensitivity and side effect questionnaires and then performed the Berg Wisconsin Card Sorting Test (BCST), the Go/No-Go test (GNG), the Sternberg task test (STT), and the psychomotor vigilance task test (PVTT). Participants then ingested one capsule of PLA or PXN treatment. Participants completed side effect and cognitive function tests after 1, 2, 3, 4, 5, and 6 h after ingestion of the supplement. After 7 days, participants repeated the experiment while consuming the alternative treatment. Data were analyzed by general linear model (GLM) univariate analyses with repeated measures using body mass as a covariate, and by assessing mean and percent changes from baseline with 95% confidence intervals (CIs) expressed as means (LL, UL). PXN decreased BCST errors (PXN -4.7 [-0.2, -9.20], = 0.04; PXN -17.5% [-36.1, 1.0], = 0.06) and perseverative errors (PXN -2.2 [-4.2, -0.2], = 0.03; PXN -32.8% [-64.4, 1.2], = 0.04) at hour 6. GNG analysis revealed some evidence that PXN ingestion better maintained mean accuracy over time and Condition R Round 2 response time (e.g., PXN -25.1 [-52.2, 1.9] ms, = 0.07 faster than PLA at 1 h), suggesting better sustained attention. PXN ingestion improved STT two-letter length absent and present reaction times over time as well as improving six-letter length absent reaction time after 2 h (PXN -86.5 ms [-165, -7.2], = 0.03; PXN -9.0% [-18.1, 0.2], = 0.05), suggesting that PXN enhanced the ability to store and retrieve random information of increasing complexity from short-term memory. A moderate treatment x time effect size (η = 0.08) was observed in PVTT, where PXN sustained vigilance during Trial 2 after 2 h (PXN 840 ms [103, 1576], = 0.03) and 4 h (PXN 1466 ms [579, 2353], = 0.002) compared to PL. As testing progressed, the response time improved during the 20 trials and over the course of the 6 h experiment in the PXN treatment, whereas it significantly increased in the PL group. The results suggest that acute PXN ingestion (200 mg) may affect some measures of short-term memory, reasoning, and response time to cognitive challenges and help sustain attention.
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http://dx.doi.org/10.3390/nu13113980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622427PMC
November 2021

Effects of Inositol-Enhanced Bonded Arginine Silicate Ingestion on Cognitive and Executive Function in Gamers.

Nutrients 2021 Oct 24;13(11). Epub 2021 Oct 24.

Exercise & Sport Nutrition Laboratory, Human Clinical Research Facility, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843, USA.

Inositol stabilized arginine silicate (ASI) ingestion has been reported to increase nitric oxide levels while inositol (I) has been reported to enhance neurotransmission. The current study examined whether acute ASI + I (Inositol-enhanced bonded arginine silicate) ingestion affects cognitive function in e-sport gamers. In a double blind, randomized, placebo controlled, and crossover trial, 26 healthy male (n = 18) and female (n = 8) experienced gamers (23 ± 5 years, 171 ± 11 cm, 71.1 ± 14 kg, 20.7 ± 3.5 kg/m) were randomly assigned to consume 1600 mg of ASI + I (nooLVL, Nutrition 21) or 1600 mg of a maltodextrin placebo (PLA). Prior to testing, participants recorded their diet, refrained from consuming atypical amounts of stimulants and foods high in arginine and nitrates, and fasted for 8 h. During testing sessions, participants completed stimulant sensitivity questionnaires and performed cognitive function tests (i.e., Berg-Wisconsin Card Sorting task test, Go/No-Go test, Sternberg Task Test, Psychomotor Vigilance Task Test, Cambridge Brain Sciences Reasoning and Concentration test) and a light reaction test. Participants then ingested treatments in a randomized manner. Fifteen minutes following ingestion, participants repeated tests (Pre-Game). Participants then played their favorite video game for 1-h and repeated the battery of tests (Post-Game). Participants observed a 7-14-day washout period and then replicated the study with the alternative treatment. Data were analyzed by General Linear Model (GLM) univariate analyses with repeated measures using weight as a covariate, paired -tests (not adjusted to weight), and mean changes from baseline with 95% Confidence Intervals (CI). Pairwise comparison revealed that there was a significant improvement in Sternberg Mean Present Reaction Time (ASI + I vs. PLA; < 0.05). In Post-Game assessments, 4-letter Absent Reaction Time ( < 0.05), 6-letter Present Reaction Time ( < 0.01), 6-letter Absent Reaction Time ( < 0.01), Mean Present Reaction Time ( < 0.02), and Mean Absent Reaction Time ( < 0.03) were improved with ASI + I vs. PLA. There was a non-significant trend in Pre-Game Sternberg 4-letter Present Reaction time in ASI + I vs. PLA ( < 0.07). ASI + I ingestion better maintained changes in Go/No-Go Mean Accuracy and Reaction Time, Psychomotor Vigilance Task Reaction Time, and Cambridge Post-Game Visio-spatial Processing and Planning. Results provide evidence that ASI + I ingestion prior to playing video games may enhance some measures of short-term and working memory, reaction time, reasoning, and concentration in experienced gamers.
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http://dx.doi.org/10.3390/nu13113758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618773PMC
October 2021

The lymphatic system and sentinel lymph nodes: conduit for cancer metastasis.

Clin Exp Metastasis 2022 Feb 15;39(1):139-157. Epub 2021 Oct 15.

Ronald O. Perelman Department of Dermatology, Department of Pathology, and NYU Langone Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, 10016, USA.

The lymphatic system is a complicated system consisting of the lymphatic vessels and lymph nodes draining the extracellular fluid containing cellular debris, excess water and toxins to the circulatory system. The lymph nodes serve as a filter, thus, when the lymph fluid returns to the heart, it is completely sterile. In addition, the lymphatic system includes the mucosa-associated lymphoid tissue, such as tonsils, adenoids, Peyers patches in the small bowel and even the appendix. Taking advantage of the drainage system of the lymphatics, cancer cells enter the lymphatic vessels and then the lymph nodes. In general, the lymph nodes may serve as a gateway in the majority of cases in early cancer. Occasionally, the cancer cells may enter the blood vessels. This review article emphasizes the structural integrity of the lymphatic system through which cancer cells may spread. Using melanoma and breast cancer sentinel lymph node model systems, the spread of early cancer through the lymphatic system is progressive in a majority of cases. The lymphatic systems of the internal organs are much more complicated and difficult to study. Knowledge from melanoma and breast cancer spread to the sentinel lymph node may establish the basic principles of cancer metastasis. The goal of this review article is to emphasize the complexity of the lymphatic system. To date, the molecular mechanisms of cancer spread from the cancer microenvironment to the sentinel lymph node and distant sites are still poorly understood and their elucidation should take major priority in cancer metastasis research.
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http://dx.doi.org/10.1007/s10585-021-10123-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967769PMC
February 2022

Development and Validation of a Modified Pathologic Nodal Classification System for Cutaneous Melanoma.

JAMA Surg 2021 11 10;156(11):e214298. Epub 2021 Nov 10.

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California.

Importance: Given the evolving patterns of lymph node evaluation for cutaneous melanoma, it is unclear whether the current nodal classification system will continue to accurately reflect prognosis in the modern era. Existing nodal staging for cutaneous melanoma was developed primarily for patients undergoing completion lymph node dissection (CLND) for node-positive disease and does not produce groups with continuously increasing mortality.

Objective: To develop and validate a modified nodal classification system for cutaneous melanoma.

Design, Setting, And Participants: This retrospective cohort analysis included 105 785 patients with cutaneous melanoma undergoing surgery and nodal evaluation from January 1, 2004, to December 31, 2015, in the National Cancer Database. Extent of lymph node dissection was available for patients diagnosed in 2012 and onward. Multivariable models were generated with number of positive lymph nodes modeled using restricted cubic splines. A modified nodal classification system was derived using recursive partitioning analysis (RPA). The proposed lymph node classification system was validated in 85 499 patients from the Surveillance, Epidemiology, and End Results (SEER-18) database. Data were analyzed from April 9, 2020, to May 28, 2021.

Main Outcomes And Measures: Overall survival.

Results: Among the 105 785 patients included in the analysis (62 496 men [59.1%]; mean [SD] age, 59.9 [15.5] years), number of positive lymph nodes (hazard ratio [HR] per lymph node for 0 to 2 positive lymph nodes, 2.48 [95% CI, 2.37-2-61; P < .001]; HR per lymph node for ≥3 positive lymph nodes, 1.10 [95% CI 1.07-1.13; P < .001]), clinically detected metastases (HR, 1.35; 95% CI, 1.27-1.42; P < .001), and in-transit metastases (HR, 1.48; 95% CI, 1.34-1.65; P < .001) were independently associated with mortality. An RPA-derived system using these variables demonstrated continuously increasing mortality for each proposed lymph node classification group, with HRs of 1.83 (95% CI, 1.76-1.91) for N1a, 2.72 (95% CI, 2.58-2.86) for N1b, 3.79 (95% CI, 3.51-4.08) for N2a, 4.56 (95% CI, 4.22-4.92) for N2b, 6.15 (95% CI, 5.59-6.76) for N3a, and 8.25 (95% CI, 7.64-8.91) for N3b in the proposed system (P < .001). By contrast, the current American Joint Committee on Cancer (AJCC) nodal classification system produced a more haphazard mortality profile, with HRs of 1.83 (95% CI, 1.76-1.91) for N1a, 3.81 (95% CI, 3.53-4.12) for N1b, 2.59 (95% CI, 2.30-2.93) for N1c, 2.71 (95% CI, 2.56-2.87) for N2a, 4.51 (95% CI, 4.17-4.87) for N2b, 3.44 (95% CI, 2.60-4.55) for N2c, 6.06 (95% CI, 5.51-6.67) for N3a, 8.15 (95% CI, 7.54-8.81) for N3b, and 6.90 (95% CI, 5.60-8.49) for N3c. As a sensitivity analysis, the proposed system continued to accurately stratify patients when excluding those undergoing CLND for microscopic lymph node metastases. This system was validated for overall survival and cause-specific mortality in SEER-18. Last, a new overall staging system for node-positive patients was developed by RPA and demonstrated improved concordance vs the AJCC, 8th edition system (C statistic, 0.690 [95% CI, 0.689-0.691] vs 0.666 [95% CI, 0.666-0.668]).

Conclusions And Relevance: The findings of this cohort study suggest that a modified nodal classification system can accurately stratify mortality risk in cutaneous melanoma in an era of increasing use of sentinel lymph node biopsy without CLND and should be considered for future staging systems.
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http://dx.doi.org/10.1001/jamasurg.2021.4298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411360PMC
November 2021

Donald L. Morton Memorial Lecture: the legacy of Donald Morton: past, present and future.

Authors:
Mark B Faries

Clin Exp Metastasis 2022 Feb 18;39(1):101-107. Epub 2021 Jul 18.

The Angeles Clinic and Research Institute and Cedars Sinai Medical Center, Los Angeles, CA, USA.

Donald L. Morton, MD persevered against great odds throughout his life and career. Beginning in the humblest of circumstances, he worked his way to the highest echelon of academic surgery, revolutionized surgical treatment of melanoma with innovations that rippled through the rest of oncology. His research led to dramatically improved disease staging while also decreasing morbidity. He stood as a champion of immunotherapy for many years when few others believed it would ever work. His greatest professional legacy, and the achievement of which he was most proud, is in the accomplishments of those he trained over his many years in the field.
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http://dx.doi.org/10.1007/s10585-021-10110-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286435PMC
February 2022

Safety and efficacy of autologous tumor lysate particle-loaded dendritic cell vaccination in combination with systemic therapies in patients with recurrent and metastatic melanoma.

Melanoma Res 2021 08;31(4):378-388

Cancer Vaccine Development Program, San Antonio, Texas, USA.

Immunotherapy has revolutionized the treatment of melanoma, yet survival remains poor for patients with metastatic disease. The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine has been shown to be safe adjuvant therapy for patients with resected stage III/IV melanoma who complete the primary vaccine series. Here, we describe an open-label trial of patients with metastatic melanoma treated with TLPLDC vaccine in addition to standard of care (SoC) therapies. The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles, which are phagocytosed by autologous dendritic cells ex vivo. Patients who recurred while enrolled in a phase IIb trial of adjuvant TLPLDC vaccine (crossover cohort) and patients with measurable metastatic melanoma cohort were offered TLPLDC vaccine along with SoC therapies. Tumor response was measured by RECIST 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by intention-to-treat analysis. Fifty-four patients were enrolled (28 in crossover cohort; 26 in metastatic melanoma cohort). The vaccine was well-tolerated with no grade ≥3 adverse events when given with SoC therapies to include checkpoint inhibitors, BRAF/MEK inhibitors, tyrosine kinase inhibitors, intralesional therapy and/or radiation. In the crossover arm, OS was 76.5% and PFS was 57.1% (median follow-up of 13.9 months). In the metastatic melanoma arm, OS was 85.7% and PFS was 52.2% (median follow-up 8.5 months). The TLPLDC vaccine is well-tolerated and safe in combination with SoC therapies. Future trials will determine the efficacy of TLPLDC in combination with SoC therapies in metastatic melanoma.
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http://dx.doi.org/10.1097/CMR.0000000000000758DOI Listing
August 2021

Recent Advances in the Treatment of Melanoma.

N Engl J Med 2021 06;384(23):2229-2240

From the Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.D.C.); and Cedars-Sinai Medical Center and the Angeles Clinic and Research Institute, Los Angeles (M.B.F.).

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http://dx.doi.org/10.1056/NEJMra2034861DOI Listing
June 2021

Multi-institutional, prospective, randomized, double-blind, placebo-controlled phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine to prevent recurrence in high-risk melanoma patients: A subgroup analysis.

Cancer Med 2021 07 12;10(13):4302-4311. Epub 2021 May 12.

Cancer Vaccine Development Program, San Antonio, TX, USA.

Background: Checkpoint inhibitors (CPI) in combination with cell-based vaccines may produce synergistic antitumor immunity. The primary analysis of the randomized and blinded phase IIb trial in resected stage III/IV melanoma demonstrated TLPLDC is safe and improved 24-month disease-free survival (DFS) in the per treatment (PT) analysis. Here, we examine efficacy within pre-specified and exploratory subgroups.

Methods: Stage III/IV patients rendered disease-free by surgery were randomized 2:1 to TLPLDC vaccine versus placebo. The pre-specified PT analysis included only patients completing the primary vaccine/placebo series at 6 months. Kaplan-Meier analysis was used to compare 24-month DFS among subgroups.

Results: There were no clinicopathologic differences between subgroups except stage IV patients were more likely to receive CPI. In stage IV patients, 24-month DFS was 43% for vaccine versus 0% for placebo (p = 0.098) in the ITT analysis and 73% versus 0% (p = 0.002) in the PT analysis. There was no significant difference in 24-month DFS when stratified by use of immunotherapy or CPI. For patients with resected recurrent disease, 24-month DFS was 88.9% versus 33.3% (p = 0.013) in the PT analysis. All benefit from vaccination was in the PT analysis; no benefit was found in patients receiving up to three doses.

Conclusion: The TLPLDC vaccine improved DFS in patients completing the primary vaccine series, particularly in the resected stage IV patients. The efficacy of the TLPLDC vaccine will be confirmed in a phase III study evaluating adjuvant TLPLDC + CPI versus Placebo + CPI in resected stage IV melanoma patients.
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http://dx.doi.org/10.1002/cam4.3969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267143PMC
July 2021

Physician Assistant Students' Perceptions and Competencies Concerning Lifestyle Medicine.

J Physician Assist Educ 2021 Jun;32(2):97-101

Alyssa Abreu, MS, is a medical student in the School of Osteopathic Medicine at the University of the Incarnate Word, San Antonio, Texas.

Purpose: With nearly two-thirds of chronic disease attributed to lifestyle, there is a need for physician assistants (PA) to develop competencies in Lifestyle Medicine (LM). The purpose of this study was to assess PA students' skill competencies in exercise and dietary prescription to guide curriculum implementation efforts.

Methods: An online survey was administered to PA students at a single institution.

Results: Overall, 74 (63%) students completed the survey, self-reporting moderate competence (range: 1-6) in conducting a physical exam to approve an exercise program (4.17 ± 1.22), designing a nutritional plan (3.76 ± 1.32), and designing an exercise prescription (3.50 ± 1.32). Only about half of the clinical students felt competent in conducting a physical examination to approve an exercise program (56%), determine maximal heart rate (54%), and design a nutritional plan (58%), and only 25% reported competence in designing an exercise prescription. Additionally, 84% of clinical students reported time spent on LM in their program as "poor" or inadequate, and 100% wanted to learn more.

Conclusions: PA students reported inadequate competence and knowledge in LM but expressed an unanimous interest in learning more about LM during their educational training.
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http://dx.doi.org/10.1097/JPA.0000000000000355DOI Listing
June 2021

Predictors of False Negative Sentinel Lymph Node Biopsy in Clinically Localized Merkel Cell Carcinoma.

Ann Surg Oncol 2021 Nov 22;28(12):6995-7003. Epub 2021 Apr 22.

Division of Endocrine and Oncologic Surgery, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.

Background: Sentinel lymph node biopsy (SLNB) is routinely recommended for clinically localized Merkel cell carcinoma (MCC); however, predictors of false negative (FN) SLNB are undefined.

Methods: Patients from six centers undergoing wide excision and SLNB for stage I/II MCC (2005-2020) were identified and were classified as having either a true positive (TP), true negative (TN) or FN SLNB. Predictors of FN SLNB were identified and survival outcomes were estimated.

Results: Of 525 patients, 28 (5.4%), 329 (62.7%), and 168 (32%) were classified as FN, TN, and TP, respectively, giving an FN rate of 14.3% and negative predictive value of 92.2% for SLNB. Median follow-up for SLNB-negative patients was 27 months, and median time to nodal recurrence for FN patients was 7 months. Male sex (hazard ratio [HR] 3.15, p = 0.034) and lymphovascular invasion (LVI) (HR 2.22, p = 0.048) significantly correlated with FN, and increasing age trended toward significance (HR 1.04, p = 0.067). The 3-year regional nodal recurrence-free survival for males >75 years with LVI was 78.5% versus 97.4% for females ≤75 years without LVI (p = 0.009). Five-year disease-specific survival (90.9% TN vs. 51.3% FN, p < 0.001) and overall survival (69.9% TN vs. 48.1% FN, p = 0.035) were significantly worse for FN patients.

Conclusion: Failure to detect regional nodal microscopic disease by SLNB is associated with worse survival in clinically localized MCC. Males, patients >75 years, and those with LVI may be at increased risk for FN SLNB. Consideration of increased nodal surveillance following negative SLNB in these high-risk patients may aid in early identification of regional nodal recurrences.
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http://dx.doi.org/10.1245/s10434-021-10031-zDOI Listing
November 2021

A Phase IIb Randomized Controlled Trial of the TLPLDC Vaccine as Adjuvant Therapy After Surgical Resection of Stage III/IV Melanoma: A Primary Analysis.

Ann Surg Oncol 2021 Oct 27;28(11):6126-6137. Epub 2021 Feb 27.

The Angeles Clinic, Santa Monica, CA, USA.

Background: Melanoma therapy has changed dramatically over the last decade with improvements in immunotherapy, yet many patients do not respond to current therapies. This novel vaccine strategy may prime a patient's immune system against their tumor and work synergistically with immunotherapy against advanced-stage melanoma.

Methods: This was a prospective, randomized, double-blind, placebo-controlled, phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine administered to prevent recurrence in patients with resected stage III/IV melanoma. Patients were enrolled and randomized 2:1 to the TLPLDC vaccine or placebo (empty yeast cell wall particles and autologous dendritic cells). Both intention-to-treat (ITT) and per treatment (PT) analyses were predefined, with PT analysis including patients who remained disease-free through the primary vaccine/placebo series (6 months).

Results: A total of 144 patients were randomized (103 vaccine, 41 control). Therapy was well-tolerated with similar toxicity between treatment arms; one patient in each group experienced related serious adverse events. While disease-free survival (DFS) was not different between groups in ITT analysis, in PT analysis the vaccine group showed improved 24-month DFS (62.9% vs. 34.8%, p = 0.041).

Conclusions: This phase IIb trial of TLPLDC vaccine administered to patients with resected stage III/IV melanoma shows TLPLDC is well-tolerated and improves DFS in patients who complete the primary vaccine series. This suggests patients who do not recur early benefit from TLPLDC in preventing future recurrence from melanoma. A phase III trial of TLPLDC + checkpoint inhibitor versus checkpoint inhibitor alone in patients with advanced, surgically resected melanoma is under development.

Trial Registration: NCT02301611.
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http://dx.doi.org/10.1245/s10434-021-09709-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914039PMC
October 2021

Comment on "Factors Affecting Sentinel Node Metastasis in Thin (T1) Cutaneous Melanomas: Development and External Validation of a Predictive Nomogram".

J Clin Oncol 2020 09 23;38(27):3233-3234. Epub 2020 Jul 23.

R. Olofsson Bagge, MD, PhD, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital; and Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Michal Kicinski, MSc, PhD, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Mark B. Faries, MD, The Angeles Clinic and Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA; David E. Gyorki, MD, FRACS, Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Karolin Isaksson, MD, PhD, Department of Clinical Sciences Lund, Surgery, Lund University, Lund; and Department of Surgery, Central Hospital Kristianstad, Kristianstad, Sweden; Dimitrios Katsarelias, MD, PhD, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital; and Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Serigne Lo, PhD, Melanoma Institute Australia, The University of Sydney, North Sydney, New South Wales, Australia; Marc Moncrieff, MD, FRCS(Plast), Department of Plastic and Reconstructive Surgery, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, United Kingdom; Andrew Spillane, MD, FRACS, Melanoma Institute Australia, The University of Sydney, North Sydney, New South Wales, Australia; Stefan Suciu, MSc, PhD, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; and Alexander van Akkooi, MD, PhD, Department of Surgical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1200/JCO.20.01680DOI Listing
September 2020

Sentinel Lymph Node Biopsy for Melanoma: Buggy Whip or Roller Bearing?

Ann Surg Oncol 2020 Aug 9;27(8):2586-2588. Epub 2020 Jun 9.

The Angeles Clinic and Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

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http://dx.doi.org/10.1245/s10434-020-08567-7DOI Listing
August 2020

Sentinel Lymph Node Biopsy: Indications and Technique.

Surg Oncol Clin N Am 2020 07;29(3):401-414

The Angeles Clinic and Research Institute, Cedars-Sinai Medical Center, 11800 Wilshire Boulevard, Suite 300, Los Angeles, CA 90025, USA. Electronic address:

Sentinel lymph node biopsy is a key tool in the care of many patients with melanoma. The indications for the procedure have gradually become clearer over the 3 decades since the technique was developed. For appropriately selected patients, it carries enormous significance. Although it is a minimally invasive procedure, it does carry some risk. It is also a multidisciplinary procedure, requiring knowledge and experience from several specialties including nuclear medicine, surgery, and pathology.
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http://dx.doi.org/10.1016/j.soc.2020.02.006DOI Listing
July 2020

Improved Tool for Predicting Sentinel Lymph Node Metastases in Melanoma.

Authors:
Mark B Faries

J Clin Oncol 2020 08 28;38(24):2706-2708. Epub 2020 May 28.

The Angeles Clinic and Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

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http://dx.doi.org/10.1200/JCO.20.01121DOI Listing
August 2020

Systemic Therapy for Melanoma: ASCO Guideline.

J Clin Oncol 2020 11 31;38(33):3947-3970. Epub 2020 Mar 31.

Cleveland Clinic, Cleveland, OH.

Purpose: To provide guidance to clinicians regarding the use of systemic therapy for melanoma.

Methods: ASCO convened an Expert Panel and conducted a systematic review of the literature.

Results: A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma.

Recommendations: In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in -mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in -mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. Additional information is available at www.asco.org/melanoma-guidelines.
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http://dx.doi.org/10.1200/JCO.20.00198DOI Listing
November 2020

Quantitative metastatic lymph node burden and survival in Merkel cell carcinoma.

J Am Acad Dermatol 2021 Feb 16;84(2):312-320. Epub 2020 Jan 16.

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: Current lymph node (LN) staging for Merkel cell carcinoma (MCC) does not account for the number of metastatic LNs, which is a primary driver of survival in multiple cancers.

Objective: To determine the impact of the number of metastatic LNs on survival in MCC.

Methods: Patients with MCC undergoing surgery were identified from the National Cancer Database (NCDB). The association between metastatic LN number and survival was modeled with restricted cubic splines. A novel nodal classification system was derived by using recursive partitioning analysis. MCC patients undergoing surgery in the Surveillance, Epidemiology, and End Results (SEER) Program were used as validation cohort.

Results: Among 3670 patients in the NCDB, increasing metastatic LN number was associated with decreased survival (P < .001). Mortality risk increased continuously with each additional positive LN when using multivariable, nonlinear modeling. According to a novel staging system derived via recursive partitioning analysis, the hazard ratio for death in multivariable regression compared with patients without LN involvement was 1.24 (P = .049), 2.08 (P < .001), 3.24 (P < .001), and 6.13 (P < .001) for the proposed N1a (1-3 metastatic LNs with microscopic detection), N1b (1-3 metastatic LNs with macroscopic detection), N2 (4-8 metastatic LNs), and N3 (≥9 metastatic LNs), respectively. This system was validated in the SEER cohort and showed improved concordance compared with the American Joint Committee on Cancer, Eighth Edition.

Limitations: Retrospective design.

Conclusions: Number of metastatic LNs is the dominant nodal factor driving survival in patients with MCC.
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http://dx.doi.org/10.1016/j.jaad.2019.12.072DOI Listing
February 2021
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