Publications by authors named "Giorgos C Karakousis"

153 Publications

Age and Mitogenicity are Important Predictors of Sentinel Lymph Node Metastasis in T1a Melanoma.

Ann Surg Oncol 2021 Apr 8. Epub 2021 Apr 8.

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

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http://dx.doi.org/10.1245/s10434-021-09929-5DOI Listing
April 2021

Ninety-day mortality after total gastrectomy for gastric cancer.

Surgery 2021 Mar 28. Epub 2021 Mar 28.

Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Pennsylvania, PA. Electronic address:

Background: Total gastrectomy for gastric cancer is associated with significant 30-day mortality, but this endpoint may underestimate the short-term mortality of the procedure.

Methods: Retrospective analysis was performed using the National Cancer Database (2004-2015). Patients who underwent total gastrectomy for stage I to III gastric adenocarcinoma were identified and divided into cohorts based on 90-day mortality. Predictors of mortality were analyzed using multivariable logistic regression, and annual trends in mortality rates were calculated by Joinpoint Regression.

Results: Of the 5,484 patients who underwent total gastrectomy, 90-day and 30-day mortality rates were 9.1% and 4.7%, respectively. Factors associated with 90-day mortality included increasing age (odds ratio 1.0, P < .001), income below the median (odds ratio 1.2, P = .039), Charlson-Deyo score ≥2 (odds ratio 1.4, P = .039), treatment at low-volume facilities (odds ratio 1.5, P < .001), N1 (odds ratio 2.0, P < .001), N2 (odds ratio 2.0, P < .001), or N3 (odds ratio 2.7, P < .001) stage disease, having <16 lymph nodes harvested (odds ratio 1.5, P < .001), and lack of treatment with chemotherapy (3.7, P < .001). Lack of health insurance (odds ratio 4.1, P = .080), and positive microscopic margins (odds ratio 1.3, P = .080) were correlated, but not significantly associated, with 90-day mortality. The 90-day mortality rate significantly declined from 14.3% in 2004 to 7.9% in 2015 (P = .006), and the 30-day mortality rate significantly declined from 7.7% in 2004 to 4.8% in 2015 (P = .009).

Conclusion: Nearly half of the deaths within 90 days after total gastrectomy for cancer occur beyond 30 days postoperative. Ninety-day mortality has improved over time, but rates remain high, suggesting the need for improved out-of-hospital postoperative care beyond 30 days.
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http://dx.doi.org/10.1016/j.surg.2021.02.010DOI Listing
March 2021

What is the patient experience of surgical care during the coronavirus disease 2019 (COVID-19) pandemic? A mixed-methods study at a single institution.

Surgery 2020 Dec 29. Epub 2020 Dec 29.

Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.

Background: The coronavirus disease 2019 outbreak has spread worldwide and has resulted in hospital restrictions. The perceived impact of these practices on patients undergoing essential surgeries is less understood.

Methods: Adult (≥18 years) patients who underwent medically necessary surgical procedures spanning multiple surgical specialties from March 23, 2020, to April 24, 2020, during the coronavirus disease 2019 pandemic were identified as eligible for a phone survey. Survey responses were analyzed using a mixed-methods approach involving descriptive statistics and thematic analysis of coded and annotated survey results.

Results: Of the 212 patients who underwent medically necessary surgical procedures during the coronavirus disease 2019 pandemic, the majority of these patients were male (61.3%), White (83.5%), married or with a domestic partner (68.9%), and underwent oncologic procedures (69.3%). Of the 46 patients (21.7%) who completed the survey, the majority of these patients indicated that coronavirus disease 2019 pandemic restrictions had no impact on their inpatient hospital stay and were satisfied with their decision to proceed with surgery. Severity of patient condition (44.4%), the risk/benefit discussion with the surgeon (24.4%), and coronavirus disease 2019 education and testing (19.5%) were the most important factors in proceeding with surgery during the pandemic; 34.4% of patients said their inpatient postoperative course was negatively affected by the lack of visitors.

Conclusion: Medically necessary, time-sensitive surgical procedures, as determined by the surgeon, can be performed during a pandemic with good patient satisfaction provided there is an appropriate discussion between the surgeon and patient about the risks and benefits.
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http://dx.doi.org/10.1016/j.surg.2020.12.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833934PMC
December 2020

ASO Author Reflections: Preoperative Biopsy for Retroperitoneal Sarcoma.

Ann Surg Oncol 2021 Feb 26. Epub 2021 Feb 26.

Department of Surgery, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.

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http://dx.doi.org/10.1245/s10434-021-09735-zDOI Listing
February 2021

Preoperative Biopsy in Patients with Retroperitoneal Sarcoma: Usage and Outcomes in a National Cohort.

Ann Surg Oncol 2021 Feb 16. Epub 2021 Feb 16.

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104, USA.

Introduction: Preoperative biopsy (PBx) is often recommended for retroperitoneal sarcoma (RPS), but its utilization rate and impact on perioperative management and outcomes remains undefined.

Methods: Using the National Cancer Database, patients who underwent resection of non-metastatic RPS were identified (2006-2014). Patients who did and did not undergo PBx of the primary tumor were compared using propensity matching, and factors associated with survival were assessed by multivariable analysis.

Results: Of 2620 patients, 1110 (42.4%) underwent PBx. Factors significantly associated with performance of PBx included male sex [odds ratio (OR) 1.2, P = 0.035], tumor size ≤ 5 cm (OR 1.5, P = 0.012), tumor size > 5 to ≤ 10 cm (OR 1.3, P = 0.009), non-well-differentiated liposarcoma histology (OR 2.0, P ≤ 0.001), and treatment at a high-volume center (OR 1.3, P = 0.021). Receipt of PBx was significantly associated with administration of neoadjuvant radiation (OR 8.8, P < 0.001) or systemic therapy (OR 3.3, P < 0.001), radical surgical resection (OR 1.6, P < 0.001), and complete tumor resection (OR 1.5, P < 0.003). Neoadjuvant radiation [hazard ratio (HR) 0.7, P = 0.003] and complete tumor resection (HR 0.6, P < 0.001) were significantly associated with improved overall survival (OS). Performance of PBx was not associated with OS (HR 1.1, P = 0.070), and following propensity matching, 5-year OS did not differ between the two groups (56.5% PBx vs 58.4% no PBx, P = 0.247).

Conclusions: A minority of patients with non-metastatic RPS undergo PBx. PBx does not negatively impact survival, but may indirectly improve outcomes in select patients by virtue of receipt of neoadjuvant therapy and attainment of complete tumor resection.
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http://dx.doi.org/10.1245/s10434-021-09691-8DOI Listing
February 2021

The impact of the affordable care act on surgeon selection amongst colorectal surgery patients.

Am J Surg 2021 Feb 4. Epub 2021 Feb 4.

University of Pennsylvania, Department of Surgery, Center for Surgery and Health Economics, Philadelphia, PA, USA.

Background: It is unclear how the Affordable Care Act's state-based Medicaid Expansion (ME) has impacted surgeon selection for colorectal resections (CRS).

Methods: We performed a risk-adjusted DID analysis on state discharge data of CRS patients aged 26-64 from NY (Expansion) and FL (non-Expansion) before (2012-2013) and after (2016-2017) ME. Primary outcome was use of a high-volume or colorectal-boarded surgeon. Subset analysis performed on insurance status.

Results: Among 78,866 CRS patients, ME was associated with a 5.9% increase in Medicaid enrollment. ME was associated with a 0.73 (95%CI: 0.67-0.69; p < 0.001) reduced odds of high-volume surgeon usage by commercially insured patients when compared to usage by commercially insured patients in the non-expansion state. No statistically significant difference was noted in the use of a colorectal-boarded surgeon following reform.

Conclusions: ME was associated with an increase in Medicaid enrollment and a decrease in the use of high-volume surgeons by the commercially insured.
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http://dx.doi.org/10.1016/j.amjsurg.2021.01.041DOI Listing
February 2021

Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).

Nat Med 2021 02 8;27(2):301-309. Epub 2021 Feb 8.

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

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.
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http://dx.doi.org/10.1038/s41591-020-01188-3DOI Listing
February 2021

Association of the Affordable Care Act's Medicaid expansion with the diagnosis and treatment of clinically localized melanoma: A National Cancer Database study.

J Am Acad Dermatol 2021 Feb 4. Epub 2021 Feb 4.

Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.

Background: The Affordable Care Act's Medicaid expansion is associated with earlier diagnosis and improved care among lower socioeconomic status populations with cancer, but its impact on melanoma is undefined.

Objective: To determine the association of Medicaid expansion with stage of diagnosis and use of sentinel lymph node biopsy in nonelderly adult patients with newly diagnosed clinically localized melanoma.

Methods: Quasi-experimental, difference-in-differences retrospective cohort analysis using data from the National Cancer Database from 2010 to 2017. Patients from expansion versus nonexpansion states and diagnosed before (2010-2013) versus after (2014-2017) expansion were identified.

Results: Of 83,322 patients, 46.6% were female, and the median age was 55 years (interquartile range, 49-60). After risk adjustment, Medicaid expansion was associated with a decrease in the diagnosis of T1b stage or higher melanoma (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.88-0.98; P = .011) and decrease in uninsured status (OR, 0.61; 95% CI, 0.52-0.72; P < .001) but was not associated with a difference in sentinel lymph node biopsy performance when indicated (OR, 1.06; 95% CI, 0.95-1.20; P = .29).

Limitations: Retrospective study using a national database.

Conclusion: In this study of patients with clinically localized melanoma, Medicaid expansion was associated with a decrease in the diagnosis of later T-stage tumors.
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http://dx.doi.org/10.1016/j.jaad.2021.01.097DOI Listing
February 2021

Impact of COVID-19 Restrictions on Demographics and Outcomes of Patients Undergoing Medically Necessary Non-Emergent Surgeries During the Pandemic.

World J Surg 2021 04 28;45(4):946-954. Epub 2021 Jan 28.

Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Background: The COVID-19 pandemic has resulted in large-scale healthcare restrictions to control viral spread, reducing operating room censuses to include only medically necessary surgeries. The impact of restrictions on which patients undergo surgical procedures and their perioperative outcomes is less understood.

Methods: Adult patients who underwent medically necessary surgical procedures at our institution during a restricted operative period due to the COVID-19 pandemic (March 23-April 24, 2020) were compared to patients undergoing procedures during a similar time period in the pre-COVID-19 era (March 25-April 26, 2019). Cardinal matching and differences in means were utilized to analyze perioperative outcomes.

Results: 857 patients had surgery in 2019 (pre-COVID-19) and 212 patients had surgery in 2020 (COVID-19). The COVID-19 era cohort had a higher proportion of patients who were male (61.3% vs. 44.5%, P < 0.0001), were White (83.5% vs. 68.7%, P < 0.001), had private insurance (62.7% vs. 54.3%, p 0.05), were ASA classification 4 (10.9% vs. 3%, P < 0.0001), and underwent oncologic procedures (69.3% vs. 42.7%, P < 0.0001). Following 1:1 cardinal matching, COVID-19 era patients (N = 157) had a decreased likelihood of discharge to a nursing facility (risk difference-8.3, P < 0.0001) and shorter median length of stay (risk difference-0.6, p 0.04) compared to pre-COVID-19 era patients. There was no difference between the two patient cohorts in overall morbidity and 30-day readmission.

Conclusions: COVID-19 restrictions on surgical operations were associated with a change in the racial and insurance demographics in patients undergoing medically necessary surgical procedures but were not associated with worse postoperative morbidity. Further study is necessary to better identify the causes for patient demographic differences.
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http://dx.doi.org/10.1007/s00268-021-05958-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842172PMC
April 2021

The effects of the Affordable Care Act on access and outcomes of colon surgery.

Am J Surg 2021 Jan 19. Epub 2021 Jan 19.

University of Pennsylvania, Center for Surgery and Health Economics, Department of Surgery, Philadelphia, PA, USA.

Background: Insurance status has been strongly associated with both access to and outcomes of colon resection (CRS). Under the Affordable Care Act (ACA), individual states opted to participate in Medicaid expansion (ME) and adopt essential health benefits (EHB).

Methods: We performed a quasi-experimental difference-in-differences (DID) analysis of 2012-2017 state-level inpatient claims with risk adjustment. We examined frequency of emergent presentation and in-hospital death. Subset analyses were performed by insurance type.

Results: Among the 73,961 CRS patients, 49.6% were in a state with both ME and EHB, 34.7% presented emergently, and 2.0% died. Adoption of ME and EHB was associated with a significant, 24%, reduction in the likelihood of in-hospital mortality, and no significant change in emergent presentation for CRS.

Conclusions: The ACA's ME was strongly associated with a decrease in mortality following colon resection among Medicaid beneficiaries. These findings support the adoption of healthcare policies that improve access to insurance.
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http://dx.doi.org/10.1016/j.amjsurg.2021.01.019DOI Listing
January 2021

Distinct Populations of Immune-Suppressive Macrophages Differentiate from Monocytic Myeloid-Derived Suppressor Cells in Cancer.

Cell Rep 2020 Dec;33(13):108571

Cancer Immunology, AstraZeneca, Gaithersburg, MD 20878, USA. Electronic address:

Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a genomic profile matching that of M-MDSCs. Immune-suppressive activity of M-MDSC-derived macrophages is dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promotes M2 polarization of macrophages. Tissue-resident- and Mon-derived macrophages lack expression of this protein. S100A9-dependent immune-suppressive activity of macrophages involves transcription factor C/EBPβ. The presence of S100A9-positive macrophages in tumor tissues is associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study reveals the pathway of the development of immune-suppressive macrophages and suggests an approach to their selective targeting.
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http://dx.doi.org/10.1016/j.celrep.2020.108571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809772PMC
December 2020

Adjuvant Radiation Therapy for Clinical Stage III Melanoma in the Modern Therapeutic Era.

Ann Surg Oncol 2020 Nov 23. Epub 2020 Nov 23.

Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.

Background: Adjuvant radiation therapy (RT) can decrease lymph node basin (LNB) recurrences in patients with clinically evident melanoma lymph node (LN) metastases following lymphadenectomy, but its role in the era of modern systemic therapies (ST), immune checkpoint or BRAF/MEK inhibitors, is unclear.

Patients And Methods: Patients at four institutions who underwent lymphadenectomy (1/1/2010-12/31/2019) for clinically evident melanoma LN metastases and received neoadjuvant and/or adjuvant ST with RT, or ST alone, but met indications for RT, were identified. Comparisons were made between ST alone and ST/RT groups. The primary outcome was 3-year cumulative incidence (CI) of LNB recurrence. Secondary outcomes included 3-year incidences of in-transit/distant recurrence and survival estimates.

Results: Of 98 patients, 76 received ST alone and 22 received ST/RT. Median follow-up time for patients alive at last follow-up was 44.6 months. The ST/RT group had fewer inguinal node metastases (ST 36.8% versus ST/RT 9.1%; P = 0.04), and more extranodal extension (ST 50% versus ST/RT 77.3%; P = 0.02) and positive lymphadenectomy margins (ST 2.6% versus ST/RT 13.6%; P = 0.04). The 3-year CI of LNB recurrences was lower for the ST/RT group compared with the ST group (13.9% versus 25.2%), but this reduction was not statistically significant (P = 0.36). Groups did not differ significantly in in-transit/distant recurrences (P = 0.24), disease-free survival (P = 0.14), or melanoma-specific survival (P = 0.20).

Conclusions: In the era of modern ST, RT may still have value in reducing LNB recurrences in melanoma with clinical LN metastases. Further research should focus on whether select patient populations derive benefit from combination therapy, and optimizing indications for RT following neoadjuvant ST.
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http://dx.doi.org/10.1245/s10434-020-09384-8DOI Listing
November 2020

Modified Metabolic Syndrome Predicts Worse Outcomes in Obese Patients Undergoing Inguinal Hernia Repair.

J Gastrointest Surg 2020 Nov 18. Epub 2020 Nov 18.

Division of Gastrointestinal Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

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http://dx.doi.org/10.1007/s11605-020-04873-3DOI Listing
November 2020

National trends in the presentation of surgically resected appendiceal adenocarcinoma over a decade.

J Surg Oncol 2021 Feb 10;123(2):606-613. Epub 2020 Nov 10.

Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Rates of nonoperative management of acute appendicitis and appendiceal adenocarcinoma have increased over a decade, but the presentation and outcomes of appendiceal adenocarcinoma over this period is not well-characterized.

Methods: Patients with surgically resected Stage I-III appendiceal adenocarcinoma were identified from the 2006 to 2015 National Cancer Data Base and classified into two cohorts, 2006-2010 and 2011-2015, based on year of diagnosis. Three-year overall survival (OS) was analyzed using Cox proportional hazards regression and Kaplan-Meier survival estimates.

Results: Of 4233 patients, 1369 (32.3%) and 2864 (67.7%) were diagnosed in 2006-2010 and 2011-2015, respectively. Following multivariable analysis, patients in 2011-2015 were more likely to be <40 years of age (6.4% vs. 4.7%, odds ratio [OR] 1.53, p .015), present with pT4 tumors (40.2% vs. 34.4%, OR 1.46, p .004), and undergo hyperthermic intraperitoneal chemotherapy (4.4% vs. 2.4%, OR 1.97, p .001). Comparing patients diagnosed in 2011-2015 to 2006-2010, adjusted 3-year OS was no different among all patients (81.1% vs. 79%, p .778).

Conclusions: There has been an increase in the proportion of patients with pT4 appendix tumors over time, primarily among older (≥60 years) patients. Even so, these shifts in presentation have not resulted in differences in survival outcomes.
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http://dx.doi.org/10.1002/jso.26295DOI Listing
February 2021

sFRP2 Supersedes VEGF as an Age-related Driver of Angiogenesis in Melanoma, Affecting Response to Anti-VEGF Therapy in Older Patients.

Clin Cancer Res 2020 Nov;26(21):5709-5719

Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Purpose: Angiogenesis is thought to be critical for tumor metastasis. However, inhibiting angiogenesis using antibodies such as bevacizumab (Avastin), has had little impact on melanoma patient survival. We have demonstrated that both angiogenesis and metastasis are increased in older individuals, and therefore sought to investigate whether there was an age-related difference in response to bevacizumab, and if so, what the underlying mechanism could be.

Experimental Design: We analyzed data from the AVAST-M trial of 1,343 patients with melanoma treated with bevacizumab to determine whether there is an age-dependent response to bevacizumab. We also examined the age-dependent expression of VEGF and its cognate receptors in patients with melanoma, while using syngeneic melanoma animal models to target VEGF in young versus old mice. We also examined the age-related proangiogenic factor secreted frizzled-related protein 2 (sFRP2) and whether it could modulate response to anti-VEGF therapy.

Results: We show that older patients respond poorly to bevacizumab, whereas younger patients show improvement in both disease-free survival and overall survival. We find that targeting VEGF does not ablate angiogenesis in an aged mouse model, while sFRP2 promotes angiogenesis and in young mice. Targeting sFRP2 in aged mice successfully ablates angiogenesis, while the effects of targeting VEGF in young mice can be overcome by increasing sFRP2.

Conclusions: VEGF is decreased during aging, thereby reducing response to bevacizumab. Despite the decrease in VEGF, angiogenesis is increased because of an increase in sFRP2 in the aged tumor microenvironment. These results stress the importance of considering age as a factor for designing targeted therapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642114PMC
November 2020

Are Volume Pledge Standards Worth the Travel Burden for Major Abdominal Cancer Operations?

Ann Surg 2020 Oct 14. Epub 2020 Oct 14.

Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.

Objective: The study objective is to determine the association between travel distance and surgical volume on outcomes after esophageal, pancreatic, and rectal cancer resections.

Summary Of Background Data: "Take the Volume Pledge" aims to centralize esophagectomies, pancreatectomies, and proctectomies to hospitals meeting minimum volume standards. The impact of travel, and possible care fragmentation, on potential benefits of centralized surgery is not well understood.

Methods: Using the National Cancer Database (2004-2016), patients who underwent esophageal, pancreatic, or rectal resections at far HVH meeting volume standards versus local intermediate (IVH) and low-volume (LVH) hospitals were identified. Perioperative outcomes and 5-year OS were compared.

Results: Of 49,454 patients, 17,544 (34.5%) underwent surgery at far HVH, 11,739 (23.7%) at local IVH, and 20,171 (40.8%) at local LVH. The median (interquartile range) travel distances were 77.1 (51.1-125.4), 13.2 (5.8-27.3), and 7.8 (3.1-15.5) miles to HVH, IVH, and LVH, respectively. By multivariable analysis, LVH was associated with increased 30-day mortality for all resections compared to HVH, but IVH was associated with mortality only for proctectomies [odds ratio 1.90, 95% confidence interval (CI) 1.31-2.75]. Compared to HVH, both IVH (hazard ratio 1.25, 95% CI 1.19-1.31) and LVH (hazard ratio 1.35, 95% CI 1.29-1.42) were associated with decreased 5-year OS.

Conclusions: Compared to far HVH, 30-day mortality was higher for all resections at LVH, but only for proctectomies at IVH. Five-year OS was consistently worse at local LVH and IVH. Improving long-term outcomes at IVH may provide opportunities for greater access to quality cancer care.
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http://dx.doi.org/10.1097/SLA.0000000000004361DOI Listing
October 2020

Do microscopic surgical margins matter for primary gastric gastrointestinal stromal tumor?

Surgery 2021 02 27;169(2):419-425. Epub 2020 Aug 27.

Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.

Background: Although tumor size and mitotic rate are established prognostic factors for worse survival in patients undergoing surgical resection for gastric gastrointestinal stromal tumors, the impact of microscopic margins, or R1 resection, is not completely established.

Methods: Patients who received no neoadjuvant therapy and underwent surgical resection for stage I to III gastric gastrointestinal stromal tumors were identified from the 2010 to 2013 National Cancer Database and divided into 2 cohorts, R0 and R1 resections. Cox proportional hazards ratio and Kaplan Meier survival estimates were utilized to analyze 5-y overall survival.

Results: Of 2,084 patients, those with R1 resection (57, 2.7%) were more likely to have tumors >10 cm (28.1% vs 11.9%, odds ratio 3.51, P = .017) and stage III disease (26.3% vs 11.2%, odds ratio 2.26, P = .047). Although margin status was associated with higher risk tumors, it was not associated with receipt of adjuvant therapy. After multivariate Cox regression, R1 and R0 patients did not have a difference in 5-y overall survival (82.5% vs 88.6%, hazards ratio 1.26, P = .49). When stratified by stage of disease, there remained no difference in survival across all stages when comparing R1 and R0 patients.

Conclusion: Positive microscopic margins are uncommon but do not appear to impact survival outcomes in patients with resected localized gastric gastrointestinal stromal tumors.
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http://dx.doi.org/10.1016/j.surg.2020.07.018DOI Listing
February 2021

ASO Author Reflection: Sentinel Lymph Node Biopsy in Thin Melanoma.

Ann Surg Oncol 2020 Dec 24;27(Suppl 3):901-902. Epub 2020 Aug 24.

Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA.

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http://dx.doi.org/10.1245/s10434-020-09029-wDOI Listing
December 2020

Survival Outcomes Following Lymph Node Biopsy in Thin Melanoma-A Propensity-Matched Analysis.

Ann Surg Oncol 2021 Mar 10;28(3):1634-1641. Epub 2020 Aug 10.

Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA.

Background: The use of sentinel lymph node biopsy in patients with T1 melanoma ≤ 1 mm has not been reported in a prospective clinical trial setting, so these clinical outcomes remain understudied. This study seeks to evaluate overall survival (OS) with and without lymph node biopsy (LNB) in patients with clinical T1N0M0 melanoma (0.5-1.0 mm).

Patients And Methods: Patients were identified using the National Cancer Data Base (2004-2012). After stratification into 0.5-0.7-mm and 0.8-1.0-mm groups, patients undergoing LNB were propensity score-matched 1:1 to patients not undergoing LNB. OS was compared using the Kaplan-Meier method and the stratified log-rank test.

Results: Resection was performed in 28,846 patients, and LNB in 14,028 (49%); 15,194 were included in propensity score-matched analysis. The LNB and no-LNB groups were well balanced on all studied covariates (standardized mean difference < 0.10). Among patients with tumors 0.5-0.7 mm, 5- and 10-year OS were 94.7% and 82.7%, respectively, for the LNB group compared with 94.3% and 84.4% for the no-LNB group (p = 0.35). Among patients with tumors 0.8-1.0 mm in thickness, 5- and 10-year OS were 93.9% and 81.6%, respectively, for the LNB group compared with 90.3% and 74.3% for the no-LNB group (p < 0.0001).

Conclusions: There was no difference in OS by LNB status in patients with lesions 0.5-0.7 mm, consistently with recommendations against its routine use in this group. In lesions 0.8-1.0 mm, receipt of LNB was associated with a clinically small but significant improvement in OS. Further study is warranted to better understand this outcome difference.
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http://dx.doi.org/10.1245/s10434-020-08997-3DOI Listing
March 2021

A case of tumor-to-tumor metastasis of cutaneous malignant melanoma.

J Cutan Pathol 2020 Dec 6;47(12):1196-1199. Epub 2020 Sep 6.

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

We report a case of tumor-to-tumor metastasis of a cutaneous malignant melanoma to a synchronous thyroid Hurthle cell carcinoma. A 42-year-old male underwent a biopsy of right inguinal lymphadenopathy which showed metastatic melanoma. The primary lesion was identified on his right posterior leg, and staging workup discovered a synchronous left thyroid lobe nodule concerning for a follicular neoplasm. He underwent excision of the primary melanoma, right inguinal lymphadenectomy, and total thyroidectomy. The resected thyroid contained a 6.6-cm, well-encapsulated left-sided nodule, red-brown in color and homogenous in consistency, with areas of focal hemorrhage and no grossly identifiable calcification. Microscopically, large tumor cells with distinct cell borders were present, with deeply eosinophilic and granular cytoplasm, large nuclei with prominent nucleoli, and loss of polarity consistent with oncocytes. A microscopic single focus of vascular invasion was identified, and a diagnosis of angioinvasive Hurthle cell carcinoma was made. Within the Hurthle cell carcinoma, multiple deposits of metastatic melanoma were seen. These findings were indicative of tumor-to-tumor metastasis of the cutaneous melanoma to the angioinvasive Hurthle cell carcinoma. Our findings show the ability of melanoma to metastasize to a pre-existing neoplasm.
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http://dx.doi.org/10.1111/cup.13829DOI Listing
December 2020

Does multicenter care impact the outcomes of surgical patients with gastrointestinal malignancies requiring complex multimodality therapy?

J Surg Oncol 2020 Jun 20. Epub 2020 Jun 20.

Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Regionalization of oncologic care has increased, but less is known whether patient outcomes are influenced by receipt of multimodality care through multicenter care (MCC) or single-center care (SCC).

Methods: Patients from 2004 to 2015 National Cancer Data Base diagnosed with stage II-III esophageal (EA), stage II-III pancreatic (PA), and stage II-IV rectal (RA) adenocarcinoma who underwent resection at a high volume center (HVC) and required radiation and/or chemotherapy were included. MCC (care at 2+ facilities) and SCC patients were propensity-score matched 1:2 and Cox proportional hazards regression used to analyze survival.

Results: On multivariable regression analysis, MCC in RA patients (N = 325/2097, 15.5%) was more associated with residing ≥40 miles from the HVC (odds ratio [OR] = 2.37; P = .044) and receipt of neoadjuvant chemotherapy (1.42, P = .040). In PA patients (N = 75/380, 19.7%), residing ≥40 miles from the HVC (OR = 3.22; P = .001), and in EA patients (N = 88/534, 16.5%), younger patients (<50 years: OR = 2.96; P = .011) were associated with MCC. Following propensity score matching, EA (N = 147), PA (N = 133), and RA (N = 661) patients had no difference in 1-year and 3-year overall survival when comparing MCC to SCC.

Conclusions: The use of MCC appears safe without a difference in survival and may offer significant advantages in convenience to patients as they undergo their complex oncologic care.
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http://dx.doi.org/10.1002/jso.26075DOI Listing
June 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

Age and Melanocytic Lesions.

Surg Oncol Clin N Am 2020 Jul;29(3):369-386

Department of Surgery, Hospital of the University of Pennsylvania, 3400 Spruce Street, 4 Silverstein, Philadelphia, PA 19104, USA.

Age plays a dynamic role in incidence, presentation, and extent of disease for cutaneous melanoma. Even within the spectrum of juvenile melanoma, there exists a range of spitzoid and nonspitzoid melanocytic and melanoma lesions. Spitzoid melanomas, a more favorable disease in juvenile patients, are malignant lesions and require treatment as such. Lymph node metastases in melanoma occur at lower rates in older patients compared with younger counterparts, yet the rate of metastases is still high. Age appears to play an important role in the development and progression of melanoma, and understanding the differences across age populations is important when counseling patients.
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http://dx.doi.org/10.1016/j.soc.2020.02.005DOI Listing
July 2020

Preoperative Transfusion for Anemia in Patients Undergoing Abdominal Surgery for Malignancy.

J Gastrointest Surg 2020 May 27. Epub 2020 May 27.

Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Background: Transfusion guidelines have been established for severe anemia, but limited data is available regarding the utility of preoperative transfusion. This study evaluates the predictive factors and relative value of preoperative transfusion in oncologic patients with moderate anemia undergoing abdominal surgery.

Methods: Using the American College of Surgeons National Surgical Quality Improvement Program database, adult patients with moderate anemia (hematocrit 21-27%) who underwent non-emergent abdominal oncologic resection from 2005 to 2017 were identified. Preoperative transfusion and non-transfused patients were propensity score matched based on baseline covariates. Outcomes were compared using univariate and Poisson regression analysis.

Results: Of 6222 patients, preoperative transfused (N = 1000, 16.1%) patients were more likely to have bleeding disorders (12.1% vs 6.7%, p < 0.0001) and baseline thrombocytopenia (12% vs 7.3%, p < 0.0001) and had shorter operative length (< 180 min: 69.4% vs 59.8%, p < 0.0001). After matching (N = 987/group), preoperative transfusion was associated with higher rates of intraoperative/postoperative transfusion (odds ratio 1.24, p 0.017) and surgical site infections (odds ratio 1.67, p 0.004) and longer length of stay (incidence rate ratio 1.06, p < 0.0001).

Conclusions: Preoperative transfusion is associated with increased surgical site infections and longer hospital stay and should be carefully considered in oncologic patients given the absence of improvement in outcomes.
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http://dx.doi.org/10.1007/s11605-020-04656-wDOI Listing
May 2020

National trends in ventral hernia repairs for patients with intra-abdominal metastases.

Surgery 2020 09 18;168(3):509-517. Epub 2020 May 18.

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia PA.

Background: Ventral hernias in patients with intra-abdominal metastases may not be addressed owing to other oncologic priorities, but they can affect quality of life and lead to sequelae necessitating an emergency operation. We compared the national trends and perioperative outcomes for elective and nonelective ventral hernia repairs for patients with intra-abdominal metastases.

Methods: Patients were identified from the National Inpatient Sample (2003-2015). Temporal trends were described using average annual percent change. Perioperative outcomes between elective and nonelective ventral hernia repairs were compared using multivariable regressions.

Results: An estimated 947,112 ventral hernia repairs were performed nationally, including 5,602 (0.6%) in patients with intra-abdominal metastases. Among patients with intra-abdominal metastases, 40.1% had a nonelective ventral hernia repair, mean (standard deviation) age was 64 (12) years, and 65.1% were women. Between 2003 and 2015, the total number of ventral hernia repairs performed nationally did not change (average annual percent change 0.062, P = .84). For patients with intra-abdominal metastases, although there was no change in the number of elective ventral hernia repairs (average annual percent change 0.65, P = .59), the number of nonelective ventral hernia repairs increased significantly (average annual percent change 2.7, P = .025). By multivariable analyses, patients with intra-abdominal metastases who underwent a nonelective repair were more likely to experience complications (odds ratio 1.76, P = .001), nonroutine discharge (odds ratio 1.93, P < .001), and mortality (odds ratio 2.27, P = .035). Nonelective ventral hernia repairs was also associated with a 38.5% (P < .001) longer hospital stay and 24.4% (P < .001) higher charges.

Conclusion: The number of nonelective ventral hernia repairs, which is associated with substantial perioperative morbidity, has increased significantly among patients with intra-abdominal metastases. Surgeons should consider a nonemergency operation for select patients to mitigate the burden of nonelective ventral hernia repairs.
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http://dx.doi.org/10.1016/j.surg.2020.04.005DOI Listing
September 2020

Patterns of Metastasis in Merkel Cell Carcinoma.

Ann Surg Oncol 2021 Jan 13;28(1):519-529. Epub 2020 May 13.

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Background: Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine malignancy with a propensity for regional and distant spread. Because of the relative infrequency of this disease, the patterns of metastasis in MCC are understudied.

Methods: Patients with American Joint Committee on Cancer (8th edition) stage I-IV MCC treated at our institution were identified (1/1/2008-2/28/2018). The first site of metastasis was classified as regional [regional lymph node (LN) basin, in-transit] or distant. Distant metastasis-free (DMFS) and MCC-specific (MSS) survival were estimated.

Results: Of 133 patients, 64 (48%) had stage I, 13 (10%) stage II, 48 (36%) stage III, and 8 (6%) stage IV disease at presentation. The median follow-up time in patients who remained alive was 36 (interquartile range 20-66) months. Regional or distant metastases developed in 78 (59%) patients. The first site was regional in 87%, including 73% with isolated LN involvement, and distant in 13%. Thirty-seven (28%) patients eventually developed distant disease, which most commonly involved the abdominal viscera (51%) and distant LNs (46%) first. The lung (0%) and brain (3%) were rarely the first distant sites. Stage III MCC at presentation was significantly associated with worse DMFS (hazard ratio 4.87, P = 0.001) and stage IV disease with worse MSS (hazard ratio 6.30, P = 0.002).

Conclusions: Regional LN metastasis is the most common first metastatic event in MCC, confirming the importance of nodal evaluation. Distant disease spread appears to have a predilection for certain sites. Understanding these patterns could help to guide surveillance strategies.
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http://dx.doi.org/10.1245/s10434-020-08587-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220648PMC
January 2021

Developmental Relationships of Four Exhausted CD8 T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms.

Immunity 2020 05 11;52(5):825-841.e8. Epub 2020 May 11.

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

CD8 T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despite this, the developmental biology of exhausted CD8 T cells (Tex) remains poorly defined, restraining improvement of strategies aimed at "re-invigorating" Tex cells. Here, we defined a four-cell-stage developmental framework for Tex cells. Two TCF1 progenitor subsets were identified, one tissue restricted and quiescent and one more blood accessible, that gradually lost TCF1 as it divided and converted to a third intermediate Tex subset. This intermediate subset re-engaged some effector biology and increased upon PD-L1 blockade but ultimately converted into a fourth, terminally exhausted subset. By using transcriptional and epigenetic analyses, we identified the control mechanisms underlying subset transitions and defined a key interplay between TCF1, T-bet, and Tox in the process. These data reveal a four-stage developmental hierarchy for Tex cells and define the molecular, transcriptional, and epigenetic mechanisms that could provide opportunities to improve cancer immunotherapy.
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http://dx.doi.org/10.1016/j.immuni.2020.04.014DOI Listing
May 2020

Predictors of lymph node metastases in patients with mucinous appendiceal adenocarcinoma.

J Surg Oncol 2020 Sep 28;122(3):399-406. Epub 2020 Apr 28.

Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Lymph node metastasis (LN+) is a prognostic factor in appendiceal cancers, but predictors and outcomes for LN+  in mucinous appendiceal adenocarcinoma (MAC) remain poorly defined.

Methods: Patients were identified from the 2010 to 2016 NCDB who underwent surgical resection as first-line management for Stage I-III mucinous appendiceal cancer. A LN+ risk-score model was developed using multivariable regression on a training data set and internally validated using a testing data set. Three-year overall survival (OS) was analyzed by Cox proportional hazards regression.

Results: Of 1158 patients, LN+ (N = 244, 21.1%) patients were more likely to have higher pT group and grade of disease, lymphovascular invasion (LVI), and positive margins on univariate analyses. Predictive factors associated with LN+ on multivariable analysis included positive surgical margins (odds ratio [OR] 3.00, P <.0001), higher grade (moderately differentiated: OR, 2.16, P < .0001; poorly or undifferentiated: OR, 3.07, P < .0001), and LVI (OR, 7.28, P < .0001). A validated risk-score model using these factors was developed with good performance (AUC 0.749). LN+ patients had a worse 3-year OS compared with LN- patients (17.4% vs 82.6%, hazard ratio 1.96, P = .001).

Conclusions: LN+ is associated with worse survival in patients with MAC. A risk-score model using margin status, LVI, and grade can accurately risk stratify patients for LN+.
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http://dx.doi.org/10.1002/jso.25963DOI Listing
September 2020

Association of Antibiotic Exposure With Survival and Toxicity in Patients With Melanoma Receiving Immunotherapy.

J Natl Cancer Inst 2021 Feb;113(2):162-170

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA.

Background: Gut microbial diversity is associated with improved response to immune checkpoint inhibitors (ICI). Based on the known detrimental impact that antibiotics have on microbiome diversity, we hypothesized that antibiotic receipt prior to ICI would be associated with decreased survival.

Methods: Patients with stage III and IV melanoma treated with ICI between 2008 and 2019 were selected from an institutional database. A window of antibiotic receipt within 3 months prior to the first infusion of ICI was prespecified. The primary outcome was overall survival (OS), and secondary outcomes were melanoma-specific mortality and immune-mediated colitis requiring intravenous steroids. All statistical tests were two-sided.

Results: There were 568 patients in our database of which 114 received antibiotics prior to ICI. Of the patients, 35.9% had stage III disease. On multivariable Cox proportional hazards analysis of patients with stage IV disease, the antibiotic-exposed group had statistically significantly worse OS (hazard ratio [HR] = 1.81, 95% confidence interval [CI] = 1.27 to 2.57; P <.001). The same effect was observed among antibiotic-exposed patients with stage III disease (HR = 2.78, 95% CI = 1.31 to 5.87; P =.007). When limited to only patients who received adjuvant ICI (n = 89), antibiotic-exposed patients also had statistically significantly worse OS (HR = 4.84, 95% CI = 1.09 to 21.50; P =.04). The antibiotic group had a greater incidence of colitis (HR = 2.14, 95% CI = 1.02 to 4.52; P =.046).

Conclusion: Patients with stage III and IV melanoma exposed to antibiotics prior to ICI had statistically significantly worse OS than unexposed patients. Antibiotic exposure was associated with greater incidence of moderate to severe immune-mediated colitis. Given the large number of antibiotics prescribed annually, physicians should be judicious with their use in cancer populations likely to receive ICI.
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http://dx.doi.org/10.1093/jnci/djaa057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850522PMC
February 2021