Adjuvant Chemoradiation in Resected Biliary Adenocarcinoma: Evaluation of SWOG S0809 with a Large National Database.

BACKGROUND: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer. METHODS: Using the National Cancer Database, we selected patients from 2004 to 2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching. RESULTS: Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p = 0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77-0.95; p = 0.004). CONCLUSION: Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers.

Existing and emerging biomarkers in hepatocellular carcinoma: relevance in staging, determination of minimal residual disease, and monitoring treatment response: a narrative review.

Background and Objective: With the development of novel active systemic therapies, the landscape of hepatocellular carcinoma (HCC) management is rapidly changing. However, HCC lacks sensitive and specific biomarkers to predict prognosis, monitor for minimal residual disease after locoregional therapy, and predict treatment response. In this review, we aim to summarize the best supporting evidence for refining existing, and development of novel biomarkers for staging, prognosis, determination of minimal residual disease and monitoring treatment response in HCC, focusing on those with evidence in clinical trials. Methods: PubMed and Embase databases were searched using the keywords; hepatocellular carcinoma, biomarker, minimal residual disease, surveillance, prognosis, staging, alpha-fetoprotein (AFP), liquid biopsy, treatment response, adjuvant, immunotherapy. Relevant clinical studies were included. Key Content and Findings: AFP remains the major workhorse as the most widely used biomarker in HCC, however, its lack of wide applicability due to the high proportion of patients with HCC who are AFP negative, limits its value throughout all stages of HCC management. Significant work has been done to combine AFP with other clinical and serologic factors to increase its accuracy and utility as a biomarkers. However, it is likely that other more novel biomarkers such as those obtained through liquid biopsy will provide the prognostic power necessary for applications such as detecting recurrence and predicting treatment response. Liquid biopsy provides not only a wealth of potential biomarkers including circulating tumor cells and cell-free RNA/DNA, but also the ability to examine the mutational characteristics of the tumor with next generation sequencing. While early evidence supports the potential impact of many new biomarkers, validation in large clinical trials is lacking. Conclusions: This review highlights the paucity of sensitive and specific, widely applicable biomarkers, throughout all phases of management of HCC and summarizes evidence on biomarkers currently in use, as well as those in development and validation. Inclusion of biomarker analysis through clinical trials in HCC is critical to development of optimal therapeutic regimens, and improve patient outcomes.

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.

Surgical Management of Retroperitoneal Sarcoma.

Surgery is the cornerstone of treatment for retroperitoneal sarcoma (RPS). Surgery should be performed by a surgical oncologist with sub-specialization in this disease and in the context of a multidisciplinary team of sarcoma specialists. For primary RPS, the goal of surgery is to achieve the complete en bloc resection of the tumor along with involved organs and structures to maximize the clearance of the disease. The extent of resection also needs to consider the risk of complications. Unfortunately, the overarching challenge in primary RPS treatment is that even with optimal surgery, tumor recurrence occurs frequently. The pattern of recurrence after surgery (e.g., local versus distant) is strongly associated with the specific histologic type of RPS. Radiation and systemic therapy may improve outcomes in RPS and there is emerging data studying the benefit of non-surgical treatments in primary disease. Topics in need of further investigation include criteria for unresectability and management of locally recurrent disease. Moving forward, global collaboration among RPS specialists will be key for continuing to advance our understanding of this disease and find more effective treatments.

Effect of Thoracic Surgery Regionalization on 1- and 3-Year Survival after Cancer Esophagectomy.

OBJECTIVE: The aim of this study was to investigate whether our previously reported improvements in short-term cancer esophagectomy outcomes after large-scale regionalization in the United States translated to longer-term survival benefit. BACKGROUND: Regionalization is associated with better early postoperative outcomes following cancer esophagectomy; however, data regarding its effect on long-term survival are mixed. METHODS: We retrospectively reviewed 461 patients undergoing cancer esophagectomy before (2009-2013, N = 272) and after (2014-2016, N = 189) regionalization. Kaplan-Meier curves and chi-square tests were used to describe 1- and 3-year survival in each era. Hierarchical logistic regression models examined the adjusted effect of regionalization on mortality. RESULTS: Compared to pre-regionalization patients, post-regionalization patients had significantly higher 1-year survival (83.1% vs 73.9%, P = 0.02) but not 3-year survival (52.9% vs 58.2%, P = 0.26).Subgroup analysis by cancer stage revealed that 1-year survival benefit was only significant among mid-stage (IIB-IIIB) patients, whereas differences in 3-year survival only approached significance among early-stage (IA-IIA) patients.In multivariable analysis, only regionalization was a predictor of lower mortality at 1 year [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.29-1.00], and only thoracic specialty at 3years (OR 0.62, 95% CI 0.38-0.99). Older age, more advanced stage, and complications were associated with higher 1- and 3-year mortality. Comorbidity, minimally invasive approach, surgeon volume, facility volume, and neoadjuvant treatment were not significant in this model. CONCLUSIONS: Regionalization was associated with improved 1-year survival after cancer esophagectomy, independent of factors such as morbidity or volume in our adjusted models. This survival benefit did not persist at 3 years, likely due to the aggressive nature of the disease.

Comparable Esophagectomy Outcomes by Surgeon Specialty: A NSQIP Analysis.

BACKGROUND: A few observational studies have found that outcomes after esophagectomies by thoracic surgeons are better than those by general surgeons. METHODS: Non-emergent esophagectomy cases were identified in the 2016-2017 American College of Surgeons NSQIP database. Associations between patient characteristics and outcomes by thoracic versus general surgeons were evaluated with univariate and multivariate logistic regression. RESULTS: Of 1,606 cases, 886 (55.2%) were performed by thoracic surgeons. Those patients differed from patients treated by general surgeons in race (other/unknown 19.3% vs 7.8%; P<.001) but not in other baseline characteristics (age, sex, BMI, and comorbidities). Thoracic surgeons performed an open approach more frequently (48.9% vs 30.8%, P<.001) and had operative times that were 30 minutes shorter (P<.001). General surgeons had lower rates of reoperation (11.8% vs 17.2%; P=.003) and were more likely to treat postoperative leak with interventional means (6.3% vs 3.4%, P=.01). Thoracic surgeons were more likely to treat postoperative leak with reoperation (5.9% vs 3.6%, P=.01). There were no other differences in univariate comparison of outcomes between the two groups, including leak, readmission, and death. General surgery specialty was associated with lower risk of reoperation. Our multivariable model also found no relationship between general surgeon and risk of any complication (odds ratio 1.10; 95% CI .86 to 1.42). DISCUSSION: In our large, national database study, we found that outcomes of esophagectomies by general surgeons were comparable with those by thoracic surgeons. General surgeons managed postoperative leaks differently than thoracic surgeons.

Pancreaticogastrostomy as a fistula mitigating strategy for a high-risk pancreatic anastomosis following pancreaticoduodenectomy.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD) has been associated with soft gland texture and/or small pancreatic duct. We hypothesized that selective use of pancreaticogastrostomy (PG) over pancreaticojejunostomy (PJ) in those scenarios would decrease the rate of CR-POPF. METHODS: Review of prospective database of all PD's performed at a single institution between 2009 and 2019 was performed. The pancreatic remnant was deemed "high risk" if soft gland and/or small duct were present. RESULTS: PJ was performed in 199 (147 "low-risk" and 52 "high-risk") cases, and 110 patients (all "high-risk") had a PG. Overall CR-POPF rate was 11.9% with no difference between the groups. Risk-stratified analysis within PJ group showed CR-POPF rate of 5.4% versus 36% in "low-risk" versus "high risk" scenarios, respectively; the use of PG significantly decreased CR-POPF rate (9.1%, p < 0.0001). Gastrointestinal bleeding was more likely to occur following PG than PJ. Soft gland texture and gastrointestinal bleeding were the strongest predictors of CR-POPF in PJ and PG groups, respectively. CONCLUSION: Selective use of PG after PD in "high-risk" scenarios mitigates the risk of CR-POPF. Increased rate of gastrointestinal bleeding calls for further refinement of the technique and heightened postoperative vigilance.

Intercostal nerve blockade with liposomal bupivacaine reduces length of stay after video assisted thoracic surgery (VATS) lobectomy.

BACKGROUND: Intercostal nerve blockade (INB) for thoracic surgery analgesia has gained popularity in practice, but evidence demonstrating its efficacy remains sparse and inconsistent. We investigated the effect of INB with standard bupivacaine (SB) with epinephrine versus liposomal bupivacaine (LB) versus a mixed solution of the two on postoperative pain control and outcomes in video assisted thoracoscopic lobectomy patients. METHODS: Since 2014, our practice has shifted from using INBs with SB with epinephrine, to LB, to a mix of the two as the central component of multimodal analgesia after video assisted thoracoscopic surgery. The blocks are performed in a standardized fashion under thoracoscopic visualization consecutively from two rib spaces above to two below the outermost incisions. We retrospectively compared all minimally invasive lobectomies performed at our institution between January 2014 and July 2018 by type of local anesthetic used for INB. We examined median length of stay (LOS), opioid utilization, and subjective pain scores [0-10]. RESULTS: Out of 302 minimally invasive lobectomy patients, 34 received SB with epinephrine, 222 received LB alone, and 46 received the mixed solution. LOS was almost a full day shorter in the LB group than in the SB group (34.8 vs. 56.5 hours, P=0.01). There was nearly 25% lower median total morphine equivalent utilization in the mixed solution cohort compared to the LB cohort (-7.1 mg, P=0.02). Additionally, IV morphine equivalent utilization was over 50% lower in the mixed solution group than in the SB with epinephrine group (-10.0 mg, P=0.03). CONCLUSIONS: Our study is by far the largest (N=302) to compare types of local anesthetic used for INB within a uniform case population. The reductions in LOS and opiate utilization observed in our study among patients receiving LB-based formulations were both statistically and clinically significant.

Age Determines Adjuvant Chemotherapy Use in Resected Stage II Colon Cancer.

BACKGROUND: The role of adjuvant chemotherapy in resected stage II colon cancer remains controversial. Treatment recommendations rely largely on the presence of certain high-risk features for recurrence. OBJECTIVE: We sought to define patient and clinicopathologic differences between early-onset and late-onset colorectal cancer and determine whether these differences impact treatment. We hypothesized that high-risk features in stage II colorectal cancer differed between age groups and would most strongly influence administration of adjuvant chemotherapy. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted at a Commission on Cancer designated hospital as well as the National Cancer Institute Intramural Research Program. PATIENTS: Patients with resected stage II colon cancer were identified in the National Cancer Database, and clinicopathologic characteristics were recorded. Patients were stratified into young (≤45), middle-aged (50-75), and older (>75) age groups. MAIN OUTCOME MEASURES: Incidence of high-risk clinicopathologic features and receipt of adjuvant chemotherapy were measured. RESULTS: A total of 14,966 patients met inclusion criteria. Young patients were found to have had at least one high-risk feature ( n = 489, 44%) slightly more often than both middle-aged ( n = 3734, 40%) and older patients ( n = 1890, 42%). A total of 332 (7%) older patients received adjuvant chemotherapy compared to 627 (56%) young patients and 2854 (30%) middle-aged patients. Age group was independently associated with receipt of adjuvant chemotherapy when controlling for relevant clinicopathologic factors. LIMITATIONS: This was a retrospective study without granular detail on treatment decisions. CONCLUSIONS: Young patients are frequently prescribed adjuvant chemotherapy for both high- and low-risk tumors despite questionable benefit in the latter. Older patients rarely receive adjuvant therapy. Both medical and surgical oncologists should be aware of disparities in cancer treatment and remain conscientious about making treatment decisions solely based on age. See Video Abstract at http://links.lww.com/DCR/B846 . LA EDAD DETERMINA EL USO DE QUIMIOTERAPIA ADYUVANTE EN EL CNCER DE COLON RESECADO EN ESTADIO II: ANTECEDENTES:El papel de la quimioterapia adyuvante en el cáncer de colon resecado en estadio II sigue siendo controversial . Las recobmendaciones para el tratamiento dependen en gran medida de la presencia de ciertas características de alto riesgo de recurrencia.OBJETIVO:Buscamos definir las diferencias clínico-patológicas del paciente entre el CCR de inicio temprano y tardío; y determinar si estas diferencias afectan el tratamiento. Hipotetizamos que las características de alto riesgo del cáncer colorrectal en estadio II difieren entre los grupos de edad y que influyen fuertemente en la administración de quimioterapia adyuvante.DISEÑO:Este fue un estudio de cohorte retrospectivo.ENTORNO CLINICO:El estudio se llevó a cabo en un hospital designado por la Comisión sobre el Cáncer, así como el Programa de Investigación Intramural del Instituto Nacional del Cáncer.PACIENTES:Se identificaron los pacientes con cáncer de colon resecado en estadio II en la Base de datos nacional del cáncer y se registraron las características clínico-patológicas. Los pacientes se estratificaron en grupos de edad jóvenes (≤45), de mediana edad (50-75) y mayores (> 75).PRINCIPALES MEDIDAS DE RESULTADO:Se estudiaron la incidencia de las características clínico-patológicas de alto riesgo y la recepción de quimioterapia adyuvante.RESULTADOS:Un total de 14.966 pacientes cumplieron con los criterios de inclusión. Se encontró que los pacientes jóvenes tenían al menos una característica de alto riesgo (n = 489, 44%) un poco más frecuente que los pacientes de mediana edad (n = 3734, 40%) y los pacientes mayores (n = 1890, 42%). Un total de 332 (7%) de los pacientes mayores recibieron quimioterapia adyuvante en comparación con 627 (56%) de los pacientes jóvenes y 2854 (30%) de los pacientes de mediana edad. El grupo de edad se asoció de forma independiente con la recepción de quimioterapia adyuvante al controlar los factores clínico-patológicos relevantes.LIMITACIONES:Este fue un estudio retrospectivo sin detalles granulares sobre las decisiones de tratamiento.CONCLUSIONES:A los pacientes jóvenes se les prescribe con frecuencia quimioterapia adyuvante para tumores de alto y bajo riesgo, a pesar de los cuestionables beneficios en estos últimos. Los pacientes de edad avanzada rara vez reciben terapia adyuvante. Tanto los oncólogos clínicos como los quirúrgicos deben ser conscientes de las disparidades en el tratamiento del cáncer y ser conscientes de tomar decisiones de tratamiento basadas únicamente en la edad. Consulte Video Resumen en http://links.lww.com/DCR/B846 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Effect of thoracic surgery regionalization on long-term survival after lung cancer resection.

OBJECTIVE: Existing evidence demonstrates some benefit of regionalization on early postoperative outcomes following lung cancer resection, but data regarding the persistence of this effect in long-term mortality are lacking. We investigated whether previously reported improvements in short-term outcomes translated to long-term survival benefit. METHODS: We retrospectively reviewed patients undergoing major pulmonary resection (lobectomy, bilobectomy, or pneumonectomy) for cancer within our integrated health care system before (2011-2013; n = 782) and after (2015-2017; n = 845) thoracic surgery regionalization. Overall survival was compared by Kaplan-Meier analysis, and 1- and 3-year mortality was compared by the by χ2 or Fisher exact test. Multivariable Cox regression models evaluated the effect of regionalization on mortality adjusted for relevant factors. RESULTS: Kaplan-Meier curves showed that overall survival was better among patients undergoing surgery postregionalization (log-rank test, P < .0001). Both 1- and 3-year mortality were decreased after regionalization: to 5.7% from 11.1% (P < .0001) for 1 year and to 17.0% from 25.5% (P = .0002) for 3 years. The multivariable adjusted Cox regression analysis revealed that only regionalization (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.42-0.76), age (HR, 1.03; 95% CI, 1.02-1.04), cancer stage (HR, 1.72, 1.83, and 2.56 for stages II, III, and IV, respectively), and Charlson comorbidity index (HR, 1.80 for 1-2; 2.05 for ≥3) were independent predictors of mortality. CONCLUSIONS: We found that overall mortality as well as 1- and 3-year mortality for lung cancer resection were lower after thoracic surgery regionalization. The association between regionalization and reduced mortality was significant even after adjusting for other related factors in a multivariable Cox analysis. Notably, surgeon volume, facility volume, surgeon specialty, neoadjuvant treatment, and video-assisted thoracoscopic surgery approach did not significantly affect mortality in the adjusted model.

Integration of adeno-associated virus (AAV) into the genomes of most Thai and Mongolian liver cancer patients does not induce oncogenesis.

BACKGROUND: Engineered versions of adeno-associated virus (AAV) are commonly used in gene therapy but evidence revealing a potential oncogenic role of natural AAV in hepatocellular carcinoma (HCC) has raised concerns. The frequency of potentially oncogenic integrations has been reported in only a few populations. AAV infection and host genome integration in another type of liver cancer, cholangiocarcinoma (CCA), has been studied only in one cohort. All reported oncogenic AAV integrations in HCC come from strains resembling the fully sequenced AAV2 and partly sequenced AAV13. When AAV integration occurs, only a fragment of the AAV genome is detectable in later DNA or RNA sequencing. The integrated fragment is typically from the 3' end of the AAV genome, and this positional bias has been only partly explained. Three research groups searched for evidence of AAV integration in HCC RNAseq samples in the Cancer Genome Atlas (TCGA) but reported conflicting results. RESULTS: We collected and analyzed whole transcriptome and viral capture DNA sequencing in paired tumor and non-tumor samples from two liver cancer Asian cohorts from Thailand (N = 147, 47 HCC and 100 intrahepatic cholangiocarcinoma (iCCA)) and Mongolia (N = 70, all HCC). We found only one HCC patient with a potentially oncogenic integration of AAV, in contrast to higher frequency reported in European patients. There were no oncogenic AAV integrations in iCCA patients. AAV genomic segments are present preferentially in the non-tumor samples of Thai patients. By analyzing the AAV genome positions of oncogenic and non-oncogenic integrated fragments, we found that almost all the putative oncogenic integrations overlap the X gene, which is present and functional only in the strain AAV2 among all fully sequenced strains. This gene content difference could explain why putative oncogenic integrations from other AAV strains have not been reported. We resolved the discrepancies in previous analyses of AAV presence in TCGA HCC samples and extended it to CCA. There are 12 TCGA samples with an AAV segment and none are in Asian patients. AAV segments are present in preferentially in TCGA non-tumor samples, like what we observed in the Thai patients. CONCLUSIONS: Our findings suggest a minimal AAV risk of hepatocarcinogenesis in Asian liver cancer patients. The partial genome presence and positional bias of AAV integrations into the human genome has complicated analysis of possible roles of AAV in liver cancer.

Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Intratumor molecular heterogeneity is a key feature of tumorigenesis and is linked to treatment failure and patient prognosis. Herein, we aimed to determine what drives tumor cell evolution by performing single-cell transcriptomic analysis. METHODS: We analyzed 46 hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) biopsies from 37 patients enrolled in interventional studies at the NIH Clinical Center, with 16 biopsies collected before and after treatment from 7 patients. We developed a novel machine learning-based consensus clustering approach to track cellular states of 57,000 malignant and non-malignant cells including tumor cell transcriptome-based functional clonality analysis. We determined tumor cell relationships using RNA velocity and reverse graph embedding. We also studied longitudinal samples from 4 patients to determine tumor cellular state and its evolution. We validated our findings in bulk transcriptomic data from 488 patients with HCC and 277 patients with iCCA. RESULTS: Using transcriptomic clusters as a surrogate for functional clonality, we observed an increase in tumor cell state heterogeneity which was tightly linked to patient prognosis. Furthermore, increased functional clonality was accompanied by a polarized immune cell landscape which included an increase in pre-exhausted T cells. We found that SPP1 expression was tightly associated with tumor cell evolution and microenvironmental reprogramming. Finally, we developed a user-friendly online interface as a knowledge base for a single-cell atlas of liver cancer. CONCLUSIONS: Our study offers insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers of tumor evolution in response to therapy. LAY SUMMARY: Intratumor molecular heterogeneity is a key feature of tumorigenesis that is linked to treatment failure and patient prognosis. In this study, we present a single-cell atlas of liver tumors from patients treated with immunotherapy and describe intratumoral cell states and their hierarchical relationship. We suggest osteopontin, encoded by the gene SPP1, as a candidate regulator of tumor evolution in response to treatment.

Contralateral Suppression Index Does Not Predict Clinical Cure in Patients Undergoing Surgery for Primary Aldosteronism.

BACKGROUND: Adrenal venous sampling (AVS) is recommended before adrenalectomy for patients with primary aldosteronism (PA) over 35 years old. The literature examining contralateral suppression (CoS) on AVS in predicting surgical outcomes is conflicting. We examined the presence of CoS in patients who underwent adrenalectomy while adjusting for clinical and biochemical factors associated with a clinical cure of hypertension (ccHTN). METHODS: We performed a retrospective review of patients with successful AVS who underwent unilateral adrenalectomy for PA at a quaternary referral center. Patients were excluded if they had overt cortisol co-secretion, or inadequate follow-up. We first evaluated the aldosterone resolution score (ARS) in predicting ccHTN in our cohort. Next, the receiver-operator characteristic analysis (ROC) was used to determine the optimal contralateral suppression index (CSI) cutoff to define CoS. We performed univariable and multivariable analyses of factors associated with ccHTN. The primary outcome was ccHTN defined as blood pressure less than 140/90 mmHg, and off blood pressure medications. RESULTS: Of the 102 patients on bivariable analysis, age, sex, duration of HTN, number of medications, preoperative systolic blood pressure, and creatinine level were associated with ccHTN. ROC analysis of ARS had an AUC of 0.850 (p < 0.001). On multivariable analysis, only ARS remained associated with ccHTN (OR 3.40, 95% CI 1.20-9.61, p = 0.021). CSI was not significantly associated with ccHTN on ROC, bivariable, or multivariable analyses. CONCLUSION: The presence of CoS was not useful in predicting ccHTN following unilateral adrenalectomy for PA in our cohort. After adjusting for clinical and biochemical factors, ARS remains a useful predictor for ccHTN.

Local excision and chemoradiation for clinical node-negative anal adenocarcinoma.

BACKGROUND: Given the lack of consensus in the surgical treatment of anal adenocarcinoma, practice-patterns demonstrate utilization of organ-preserving techniques. The adequacy of local excision compared to abdominoperineal resection (APR) as a surgical approach for stage II disease is unknown. Our study examines the utilization of local excision in the treatment of stage II anal adenocarcinoma, rates of R0 resection, and differences in overall survival compared to APR. MATERIALS AND METHODS: Using the National Cancer Database (2004-2016), we retrospectively analyzed patients diagnosed with clinical stage II anal adenocarcinoma who received chemoradiation and surgery. Patient cohorts were assigned based on the surgical procedure they received. Propensity score matching was used to offset selection bias and confounding factors. Treatment approach, pathologic margin status, and overall survival were assessed. RESULTS: Overall, 359 patients underwent resection of clinical stage II anal adenocarcinoma and received chemoradiation therapy. Of these patients, 87 (24%) underwent local excision, whereas 272 (76%) received an abdominoperineal resection. In a propensity score-matched cohort, patients who underwent local excision were less likely to achieve an R0 resection (40% vs 90%), and more likely to receive adjuvant instead of neoadjuvant chemoradiation. Overall survival was not significantly different between the propensity-matched groups. Surgical approach and pathologic margin status were not independently associated with overall survival. CONCLUSIONS: Among patients with clinical stage II anal adenocarcinoma who received chemotherapy and radiation, complete resection was significantly less likely with local excision compared to abdominoperineal resection, however, overall survival was not affected. Prospective studies of neoadjuvant chemoradiation followed by local excision are warranted.

Multivisceral Resection for Locally Advanced Gastric Cancer.

BACKGROUND: Locally advanced gastric cancer (LAGC) presents a therapeutic dilemma, particularly as it often involves adjacent organs through desmoplasia or true pathologic invasion. To obtain a margin-negative resection, these tumors require en bloc gastrectomy with multivisceral resection (G+MVR), and contention remains regarding its safety and oncologic benefit. METHODS: We used the National Cancer Database to retrospectively evaluate the short- and long-term outcomes of patients with LAGC treated in the USA between 2004 and 2016. Associations with margin status and perioperative outcomes were calculated using logistic regression. Survival was estimated using Cox proportional hazards regression and the Kaplan-Meier method. RESULTS: Overall, 785 pathologic stage T4b (pT4b) patients diagnosed with LAGC underwent gastrectomy (n = 438) or G+MVR (n = 347). There was no association between G+MVR and short- or long-term mortality. Positive resection margins (HR 1.68, 95% CI 1.40-2.03), the presence of nodal disease (HRs 1.46-1.50), treatment at a high-volume center (HR 0.76, 95% CI 0.68-0.85), and the receipt of adjuvant chemotherapy (HR 0.64, 95% CI 0.51-0.80) were independently associated with overall survival. Diffuse-type histology was associated with higher rates of an R1 resection (OR 3.60, 95% CI 2.20-5.87). Perioperative and long-term survival metrics were comparable between patients with pT4a and pT4b LAGC who underwent a margin-negative G+MVR. Undergoing a margin-negative G+MVR imparted a 6-month survival benefit over non-curative gastrectomy alone (p < 0.001). CONCLUSIONS: Our study demonstrates the safety and long-term feasibility of G+MVR for disease clearance in well-selected patients with LAGC, and we advocate for their referral to high-volume centers for optimal care.

Prognostic impact of lymphovascular invasion in pT1-T3 gallbladder adenocarcinoma.

BACKGROUND: Most gallbladder cancers are diagnosed after cholecystectomy for presumed benign disease, and nodal staging to inform subsequent treatment is therefore often lacking. We evaluated the association of lymphovascular invasion (LVI) with regional lymph node involvement in gallbladder adenocarcinoma and its impact on survival. METHODS: The National Cancer Database was queried to identify patients with resected gallbladder adenocarcinoma and with available staging and LVI status. Patients with pT4 and M1 disease were excluded. Univariable and multivariable regression identified factors associated with positive lymph nodes. Cox proportional hazards model was used to evaluate overall survival (OS). RESULTS: Of 1649 patients with available LVI status, 1142 (69.7%) had at least one positive lymph node and 765 (46.4%) had LVI. On multivariable regression, presence of LVI was the strongest predictor of positive lymph nodes (odds ratio, 3.69; P < .001). The positive predictive value of LVI for positive lymph nodes in pT2 and pT3 tumors was 80.1% and 90.5%, respectively. LVI was independently associated with decreased OS (hazard ratio, 1.21; P = .001), as were node-positive disease and increasing T stage. CONCLUSION: In patients with gallbladder adenocarcinoma, LVI is independently associated with regional lymph node metastases and abbreviated OS. LVI status may help risk-stratify patients following initial cholecystectomy and inform subsequent treatment.

Hepatic Stellate Cells and Hepatocarcinogenesis.

Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.

Characterization of alveolar soft part sarcoma using a large national database.

BACKGROUND: Alveolar soft part sarcoma is a rare, histologic subtype of soft tissue sarcoma that remains poorly defined. We aimed to describe patient characteristics and treatment patterns and to examine factors associated with survival for patients with alveolar soft part sarcoma. METHODS: After identifying patients with alveolar soft part sarcoma in the National Cancer Database, we recorded their clinicopathologic characteristics. Univariable log-rank survival analysis and Cox proportional hazards model were employed. For context, survival comparisons were included for patients with other sarcoma subtypes. RESULTS: Overall, 293 patients with alveolar soft part sarcoma were identified. Interestingly, patients with head and neck tumors were least likely to present with distant disease (40%, P = .025). The majority of patients underwent resection (n = 183, 63%). Among those, no predictors of lesser survival were identified other than the presence of metastases (hazard ratio 6.04, P ≤ .001). Patients with stage IV alveolar soft part sarcoma who underwent resections experienced improved survival relative to similar patients with more common subtypes of soft tissue sarcomas (P ≤ .001). CONCLUSION: Alveolar soft part sarcoma is exceedingly rare, and patients often present with metastases. Primary tumors can occur anywhere in the body, and location impacts the rates of metastases at presentation. Resection is associated with a favorable survival advantage when compared to other, more common histologic subtypes of soft tissue sarcomas.