Lineage and ecology define liver tumor evolution in response to treatment.

A tumor ecosystem constantly evolves over time in the face of immune predation or therapeutic intervention, resulting in treatment failure and tumor progression. Here, we present a single-cell transcriptome-based strategy to determine the evolution of longitudinal tumor biopsies from liver cancer patients by measuring cellular lineage and ecology. We construct a lineage and ecological score as joint dynamics of tumor cells and their microenvironments. Tumors may be classified into four main states in the lineage-ecological space, which are associated with clinical outcomes. Analysis of longitudinal samples reveals the evolutionary trajectory of tumors in response to treatment. We validate the lineage-ecology-based scoring system in predicting clinical outcomes using bulk transcriptomic data of additional cohorts of 716 liver cancer patients. Our study provides a framework for monitoring tumor evolution in response to therapeutic intervention.

Metastasectomy for metastatic melanoma in the era of effective systemic therapy.

INTRODUCTION: Effective systemic therapy (EST) in patients with metachronous metastatic melanoma (MMM) improves survival and alters surgical decision-making. Surgical metastasectomy is another treatment option, however, it is unclear if metastasectomy confers survival benefit. This study seeks to identify any survival benefit associated with surgical management of MMM. METHODS: Patients with MMM from 2009 to 2021 were grouped by receipt of metastasectomy and treatment era (pre-versus post-EST). Overall survival (OS) was calculated from date of metastasis and evaluated with Kaplan-Meier analysis. RESULTS: Our dataset identified 226 patients with MMM; 32% were diagnosed pre-EST. On Kaplan-Meier analysis, OS was improved for patients undergoing treatment post-versus pre-EST (p < 0.001). In the post-EST era, metastasectomy was associated with an increase in OS compared to no resection (p = 0.022). CONCLUSIONS: In the post-EST group, EST paired with metastasectomy was associated with improved OS compared to the pre-EST group, suggesting persistent evidence of a survival benefit from metastasectomy.

Referral and treatment patterns in pancreatic acinar cell carcinoma: A regional population-level analysis.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare exocrine tumor of the pancreas. We evaluated the effect disease stage, surgical intervention, and institutional volume status plays in survival. METHODS: We queried the Oregon State Cancer Registry for patients with PACC from 1997 to 2018. Treatment and referral patterns were analyzed, and overall survival (OS) was evaluated with Kaplan-Meier and Cox-proportional hazard analysis. RESULTS: 43 patients were identified. Median OS was 33.1 and 7.1 months in those with locoregional and metastatic disease respectively (p â€‹= â€‹0.008). Surgical intervention was associated with improved OS (hazard ratio 0.28, p â€‹< â€‹0.0001). High volume center (HVC) care trended towards improving OS. While the majority of cases were diagnosed at low volume centers (74%), referral to HVCs was rare (n â€‹= â€‹4) and limited to advanced (stage III/IV) disease. CONCLUSION: Stage and surgical resection influence survival outcomes in PACC, more data is needed to delineate the impact of institutional volume status.

Perceptions of Readiness for Practice After Complex General Surgical Oncology Fellowship: A Survey Study.

BACKGROUND: Surgical subspecialty training aims to meet the needs of practicing surgeons and their communities. This study investigates career preparedness of Complex General Surgical Oncology (CGSO) fellowship graduates, identifies factors associated with practice readiness, and explores potential opportunities to improve the current training model. METHODS: The Society of Surgical Oncology partnered with the National Cancer Institute to conduct a 36-question survey of CGSO fellowship graduates from 2012 to 2022. RESULTS: The overall survey response rate was 38% (221/582) with a slight male predominance (63%). Forty-six percent of respondents completed their fellowship after 2019. Factors influencing fellowship program selection include breadth of cancer case exposure (82%), mentor influence (66%), and research opportunities (38%). Overall, graduates reported preparedness for practice; however, some reported unpreparedness in research (18%) and in specific clinical areas: thoracic (43%), hyperthermic intraperitoneal chemotherapy (HIPEC) (15%), and hepato-pancreato-biliary (15%) surgery. Regarding technical preparedness, 70% reported being "very prepared". Respondents indicated lack of preparedness in robotic (63%) and laparoscopic (33%) surgery approaches. Suggestions for training improvement included increased autonomy and case volumes, program development, and research infrastructure. Current practice patterns by graduates demonstrated discrepancies between ideal contracts and actual practice breakdowns, particularly related to the practice of general surgery. CONCLUSIONS: This study of CGSO fellowship graduates demonstrates potential gaps between trainee expectations and the realities of surgical oncology practice. Although CGSO fellowship appears to prepare surgeons for careers in surgical oncology, there may be opportunities to refine the training model to better align with the needs of practicing surgical oncologists.

Genome-wide profiling of transcription factor activity in primary liver cancer using single-cell ATAC sequencing.

Primary liver cancer (PLC) consists of two main histological subtypes; hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). The role of transcription factors (TFs) in malignant hepatobiliary lineage commitment between HCC and iCCA remains underexplored. Here, we present genome-wide profiling of transcription regulatory elements of 16 PLC patients using single-cell assay for transposase accessible chromatin sequencing. Single-cell open chromatin profiles reflect the compositional diversity of liver cancer, identifying both malignant and microenvironment component cells. TF motif enrichment levels of 31 TFs strongly discriminate HCC from iCCA tumors. These TFs are members of the nuclear/retinoid receptor, POU, or ETS motif families. POU factors are associated with prognostic features in iCCA. Overall, nuclear receptors, ETS and POU TF motif families delineate transcription regulation between HCC and iCCA tumors, which may be relevant to development and selection of PLC subtype-specific therapeutics.

Neoadjuvant therapy does not impact the biliary microbiome in patients with pancreatic cancer.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) often impinges on the biliary tree and obstruction necessitates stent placement increasing the risk of surgical site infections (SSIs). We sought to explore the impact of neoadjuvant therapy on the biliary microbiome and SSI risk in patients undergoing resection. METHODS: A retrospective analysis was performed on 346 patients with PDAC who underwent resection at our institution from 2008 to 2021. Univariate and multivariate methods were utilized for analysis. RESULTS: Biliary stenting rates were similar between groups but resulted in increased bile culture positivity (97% vs. 15%, p < 0.001). Culture positivity did not differ between upfront resection or neoadjuvant chemotherapy (NAC) (77% vs. 80%, p = 0.60). NAC-alone versus neoadjuvant chemoradiotherapy did not impact biliary positivity (80% vs. 79%, p = 0.91), nor did 5-fluorouracil versus gemcitabine-based regimens (73% vs. 85%, p = 0.19). While biliary stenting increased incisional SSI risk (odds ratios [OR]: 3.87, p = 0.001), NAC did not (OR: 0.83, p = 0.54). Upfront resection, NAC, and chemoradiotherapy were not associated with biliary organism-specific changes or antibiotic resistance patterns. CONCLUSIONS: Biliary stenting is the greatest predictor for positive biliary cultures and SSIs in resected PDAC patients. Neither NAC nor radiotherapy impact bile culture positivity, speciation, rates, or antibiotic resistance patterns, and perioperative antibiotic prophylaxis should not differ.

High-volume centers are associated with higher receipt of combined therapy in stage III pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at a locally advanced stage with vascular involvement which was previously viewed as a contraindication to resection. However, high-volume centers are increasingly capable of resecting complex tumors. We aimed to explore patterns of treatment that are uncharacterized on a population level. METHODS: A statewide registry was queried from 2003 to 2018 for stage III PDAC. Stepwise logistic regression and Kaplan-Meier were used for statistical analysis. RESULTS: We identified 424 eligible patients. 348 (82%) received chemotherapy, 17 (4.0%) received resection, and 59 (13.9%) received both; median survival was 10.7, 8.7, and 22.7 months, respectively (P < 0.001). High-volume centers (≥20 cases per year; OR 5.40 [95% CI: 2.76, 10.58], P < 0.001) and later year of diagnosis (OR 1.12/year [95% CI: 1.04, 1.20], P = 0.004) were associated with higher odds of receiving combined therapy. CONCLUSION: PDAC patients with vascular involvement who receive both systemic chemotherapy and surgical resection have improved overall survival. High-volume centers are independently associated with higher odds of receiving combined systemic therapy and surgical resection.

Delayed adjuvant endocrine therapy is associated with decreased recurrence-free survival following neoadjuvant chemotherapy for breast cancer.

BACKGROUND: In hormone receptor-positive breast cancer (HRPBC), endocrine therapy is often initiated after adjuvant radiotherapy given concerns of radiation fibrosis. No studies have investigated how this may impact outcomes in high-risk patients undergoing neoadjuvant chemotherapy (NAC). METHODS: Females with nonmetastatic HRPBC receiving NAC from 2011 to 2017 were identified from our multi-institutional database. Interval from surgery to endocrine therapy (ISET) was calculated in weeks. Recurrence-free survival (RFS) and overall survival (OS) were evaluated with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: Of 280 patients, 179 (64%) received adjuvant radiotherapy; all deaths (n = 25) and 90% (n = 27) of recurrences occurred in this group, which was the focus of subsequent analysis. Median follow-up was 49 months. Recurrences were predominantly distant metastases (n = 21, 81%). Median ISET was 12 weeks (range 0-55 weeks). On multivariable analysis, ISET >14 weeks was independently associated with worse RFS (HR 3.20, 95% C.I. 1.22-8.40, P = 0.02) but not OS (HR 2.15, 95% C.I. 0.75-6.15, P = 0.15). CONCLUSION: In patients with HRPBC treated with NAC and adjuvant radiation, increasing ISET is associated with adverse oncologic outcomes.

Care at high-volume centers is associated with improved outcomes for patients with pancreatic neuroendocrine tumors: A population-level analysis.

BACKGROUND AND OBJECTIVES: Primary resection and debulking of liver metastases have been associated with improved survival in pancreatic neuroendocrine tumors (PNETs). The treatment patterns and outcomes differences between low-volume (LV) institutions and high-volume (HV) institutions remains unstudied. METHODS: A statewide cancer registry was queried for patients with nonfunctional PNET from 1997 to 2018. LV institutions were defined as treating <5 newly diagnosed patients with PNET per year, while HV institutions treated ≥5. RESULTS: We identified 647 patients: 393 with locoregional (n = 236 HV care, n = 157 LV care) and 254 with metastatic disease (n = 116 HV care, n = 138 LV care). Patients with HV care had improved disease-specific survival (DSS) compared to patients with LV care for both locoregional (median 63 vs. 32 months, p < 0.001) and metastatic disease (median 25 vs. 12 months, p < 0.001). In patients with metastatic disease, primary resection (hazard ratio [HR]: 0.55, p = 0.003) and HV institution (HR: 0.63, p = 0.002) were independently associated with improved DSS. Furthermore, diagnosis at a HV center was independently associated with higher odds of receiving primary site surgery (odds ratio [OR]: 2.59, p = 0.01) and metastasectomy (OR: 2.51, p = 0.03). CONCLUSIONS: Care at HV centers is associated with improved DSS in PNET. We recommend referral of all patients with PNETs to HV centers.

Dissecting intratumor heterogeneity in HCC: new research strategies and clinical implications.

Hepatocellular carcinoma (HCC) accounts for the majority of liver cancers and is driven by a multitude of viral, metabolic, and lifestyle factors initiating liver injury that subsequently progresses to cancer. Despite significant medical advancements, current treatment options are limited in their efficacy and overall survival remains poor. Recent studies have suggested that intratumor heterogeneity may play a significant role in treatment response, resistance, and overall prognosis. In this review, we will outline new techniques that utilize both human samples and non-human models to evaluate intratumor heterogeneity. Additionally, we will provide an overview of the clinical implications of intratumor heterogeneity on patients with HCC.

Hospital Volume Threshold for the Treatment of Retroperitoneal Sarcoma.

BACKGROUND: Retroperitoneal sarcomas (RPS) are rare, histologically heterogeneous, and anatomically complex tumors. National Comprehensive Cancer Network guidelines recommend evaluation and management by multidisciplinary teams with experience in sarcoma. Our aim was to determine an appropriate hospital volume threshold for the treatment of RPS. PATIENTS AND METHODS: Patients undergoing resection of RPS were identified from the National Cancer Data Base (1998-2012). Multivariable modeling with restricted cubic splines was employed to examine the association between hospital volume and survival and identify possible hospital volume threshold. RESULTS: The study included 5,340 patients who underwent surgery at 909 different hospitals. Median annual volume was two cases per year. After adjustment, hospital volume was associated with improved survival (p=0.01), without cutoff. The cohort was then grouped into: Low-volume (≤5 cases/year), intermediate-volume (6-10 cases/year), and high-volume (>10 cases/year). The majority of patients were treated in low-volume hospitals (86%), compared to 9% in intermediate- and 5% in high-volume centers; 44% of patients were treated in hospitals that performed one case per year. Compared to low-volume, high-volume hospitals more often had patients with high-grade and larger tumors. Adjusted 90-day mortality was significantly lower in high- vs. low-volume hospitals (odds ratio(OR)=0.25, p=0.02). With adjustment, treatment in high- vs. low-volume hospitals was associated with lower odds of margin positivity (OR=0.58, p=0.001), and improved overall survival (hazard ratio(HR)=0.61, p=0.002). CONCLUSION: Treatment of RPS in high-volume centers is associated with significant reduction in short-term mortality and improved long-term survival. Hospital volume may be a surrogate for the infrastructure and support necessary for the optimal management of these complex malignancies.

Multidisciplinary Approach to Clostridium difficile Infection in Adult Surgical Patients.

BACKGROUND: In 2017, our hospital was identified as a high outlier for postoperative Clostridium difficile infections (CDIs) in the American College of Surgeons NSQIP semi-annual report. The Department of Surgery initiated a CDI task force with representation from Surgery, Infectious Disease, Pharmacy, and Performance Services to analyze available data, identify opportunities for improvement, and implement strategies to reduce CDIs. STUDY DESIGN: Strategies to reduce CDIs were reviewed from the literature and the following multidisciplinary strategies were initiated: antimicrobial stewardship optimization of perioperative order sets to avoid cefoxitin and fluoroquinolone use was completed; penicillin allergy assessment and skin testing were implemented concomitantly; increased use of ultraviolet disinfectant strategies for terminal cleaning of CDI patient rooms; increased hand hygiene and personal protection equipment signage, as well as monitoring in high-risk CDI areas; improved diagnostic stewardship by an electronic best practice advisory to reduce inappropriate CDI testing; education through surgical grand rounds; and routine data feedback via NSQIP and National Healthcare Safety Network CDI reports. RESULTS: The observed rate of CDIs decreased from 1.27% in 2016 to 0.91% in 2017. Cefoxitin and fluoroquinolone use decreased. Clostridium difficile infection testing for patients on laxatives decreased. Terminal cleaning with ultraviolet light increased. Handwashing compliance increased. Data feedback to stakeholders was established. CONCLUSIONS: Our multidisciplinary CDI reduction program has demonstrated significant reductions in CDIs. It is effective, straightforward to implement and monitor, and can be generalized to high-outlier institutions.

Reduced Impact of Smoking Status on 30-Day Complication and Readmission Rates After Elective Spinal Fusion (≥3 Levels) for Adult Spine Deformity: A Single Institutional Study of 839 Patients.

BACKGROUND: Smoking status has been shown to affect postoperative outcomes after surgery. The aim of this study was to determine whether patients' smoking status impacts 30-day complication and readmission rates after elective complex spinal fusion (≥3 levels). METHODS: The medical records of 839 adult spinal deformity patients undergoing elective complex spinal fusion (≥3 levels) at a major academic institution from 2005 to 2015 were reviewed. We identified 124 (14.8%) smokers and 715 (85.2%) nonsmokers. Patient demographics, comorbidities, intraoperative and postoperative complications, and 30-day readmission rates were collected for each patient. The primary outcome investigated in this study was the rate of 30-day postoperative complication and readmission rates. RESULTS: Patient demographics and comorbidities were similar between both groups, including age, sex, and body mass index. Median [interquartile] number of fusion levels and operative time were similar between the cohorts (smoker: 5 [4-7] vs. nonsmoker: 5 [4-8], P = 0.58) and (smoker: 309.6 ± 157.9 minutes vs. nonsmoker: 287.5 ± 131.7 minutes, P = 0.16), respectively. Both cohorts had similar postoperative complication rates and lengths of hospital stay. There was no significant difference in 30-day readmission between the cohorts (smoker: 12.9% vs. nonsmoker: 10.8%, P = 0.48). There were no observed differences in 30-day complication rates, including pain (P = 0.46), UTI (P = 0.54), hardware failure (P = 0.36), wound dehiscence (P = 0.29), and wound drainage (P = 0.86). Smokers had greater rates of 30-day cellulitis (smoker: 1.6% vs. nonsmoker: 0.3%, P = 0.05) and DVT (smoker: 0.8% vs. nonsmoker: 0.0%, P = 0.02). CONCLUSIONS: Our study suggests that smoking does not significantly affect 30-day readmission rates after complex spinal surgery requiring ≥3 levels of fusion. Further studies are necessary to corroborate our findings.

Impact of surgical approach on complication rates after elective spinal fusion (≥3 levels) for adult spine deformity.

BACKGROUND: While there are variations in techniques and surgical approaches to spinal fusion, there is not a defined consensus on a recommended surgical approach. The aim of this study is to determine if there was a difference in intra- and post-operative complication rates between different surgical approaches after elective spinal fusion (≥3 levels) for adult spine deformity. METHODS: The medical records of 443 adult spine deformity patients undergoing elective spinal fusion (≥3) at a major academic institution from 2005 to 2015 were reviewed. We identified 96 (21.7%) anterior only, 225 (50.8%) posterior only, and 122 (27.5%) combined anterior/posterior approaches taken for spinal fusion (anterior: n=96; posterior: n=225). Patient demographics, comorbidities, anatomical location, and complication rates were collected for each patient. The primary outcome investigated in this study was the rate of intra- and post-operative complications. RESULTS: Patient demographics and comorbidities were similar between all groups. The posterior approach had significantly higher EBL (P<0.0001) and number of PRBC blood transfusions (P<0.002), while the combined approach had a higher operative time (P<0.0001). The posterior approach had a significantly higher rate of intraoperative durotomies than anterior and combined (anterior: 0% vs. posterior: 11.1% vs. combined: 4.1%, P<0.0001). There was no significant difference in the rate 30-day readmissions between the cohorts (anterior: 10.4% vs. posterior: 12.8% vs. combined: 13.1%, P=0.80). CONCLUSIONS: Our study suggests that posterior approaches to spinal fusion may lead to a higher incidence of complications compared to anterior or combined anterior/posterior approaches.

Impact of Race on 30-Day Complication Rates After Elective Complex Spinal Fusion (≥5 Levels): A Single Institutional Study of 446 Patients.

OBJECTIVE: Racial disparities have been shown to affect surgical outcomes. However, the effect of race on complex spinal fusion outcomes remains understudied. The aim of this study is to determine if patient race affects 30-day complication rates after elective complex spinal fusion (≥5 levels). METHODS: The medical records of 490 adult patients with spinal deformity undergoing elective complex spinal fusion (≥5 levels) at a major academic institution from 2005 to 2015 were reviewed. We identified 52 black patients (11.7%) and 438 white patients (88.3%). Patient demographics, comorbidities, and intraoperative and 30-day postoperative complication and readmission rates were collected. The primary outcome investigated in this study was the rate of 30-day postoperative complications. RESULTS: Patient demographics and comorbidities were similar between both groups, including age, gender, and body mass index. Median (interquartile range) number of fusion levels and operative time were similar between the cohorts (black, 6.5 [5-9] vs. white, 7 [5-9]; P = 0.55; and black, 307.3 ± 120.2 minutes vs. white, 321.3 ± 135.3 minutes; P = 0.45, respectively). Both cohorts had similar postoperative complications and lengths of hospital stay (black, 7.2 ± 5.4 days vs. white: 6.5 ± 4.9; P = 0.37). There was no significant difference in 30-day readmission between the cohorts (black, 9.6% vs. white, 12.8%; P = 0.66). There were no observed differences in 30-day complication rates, including: pain (P = 0.74), urinary tract infection (P = 0.68), hardware failure (P = 0.36), wound dehiscence (P = 0.29), and drainage (P = 0.86). CONCLUSIONS: Our study suggests that there is no difference between races in 30-day complication and readmission rates after complex spinal surgery requiring ≥5 levels of fusion.

Impact of Age on Change in Self-Image 5 Years After Complex Spinal Fusion (≥5 Levels).

BACKGROUND: Spinal deformities that require ≥5 fusion levels are difficult and challenging for both the surgeon and patient. Corrections of moderate to severe deformities have been shown to improve patient-reported outcomes (PROs), and provide patients with a better quality of life. Self-image is an important PRO because it sheds insight into the patient's perception of health, as well as serving as a proxy of satisfaction for patients with spine deformity undergoing corrective surgery. However, with an aging population, the impact of age on long-term change in self-image is unknown. The aim of this study is to determine the effects of age on self-image 5 years after undergoing an elective complex spinal fusion (≥5 levels). METHODS: This was a retrospective analysis of prospectively collected data of 55 adult patients (≥18 years old) undergoing ≥5 levels of spinal fusion to the sacrum with iliac fixation from January 2002 to December 2008. Patients were grouped by age: young (<60 years old) and older (≥60 years old). Patient demographics, comorbidities, preoperative variables (sagittal and Cobb angles) and postoperative complication rates were collected. All patients had prospectively collected outcome measures and a minimum of 5 years follow-up. PRO instrument SRS-22r (function, self-image, mental health, and pain) was completed before surgery then at follow-up (at least 5 years after surgery). The primary outcome investigated in this study was the change in self-image after surgery. RESULTS: Baseline characteristics and preoperative variables were similar in both cohorts. There were no significant differences in intraoperative variables, including the mean ± standard deviation number of fusion levels between the cohorts (young, 11.2 ±4.3 vs. older, 12.1 ± 4.0; P = 0.42). Complication rates were similar between the cohorts, with no significant differences in the types of complications (young, 29.63% vs. older, 25.0%; P = 0.77). There were no significant differences in preoperative and follow-up PROs between the cohorts. The mean ± standard deviation preoperative and follow-up self-image scores were (young, 2.35±0.58 vs. older, 2.68 ± 0.64; P = 0.51) and (young, 3.82 ± 0.63 vs. older, 3.51 ± 0.94), respectively. There were no significant differences in the change of function, mental health, or pain between the cohorts. However, the younger cohort experienced a significantly greater overall change in self-image than did the older cohort (young, 1.49 ± 0.87 vs. older, 0.70±1.14; P = 0.01). CONCLUSIONS: Our study suggests that age significantly affects the perception of self-image after deformity correction surgery; with younger patients reporting a greater change from baseline in self-image after surgery. Further studies are necessary to corroborate our observed findings.