Local ablative therapies and the effect on antitumor immune responses in pancreatic cancer - A review.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, projected to rank as the second most prevalent cause of cancer-related mortality by 2030. Despite significant progress in advances in surgical techniques and chemotherapy protocols, the overall survival (OS) remains to be less than 10 % for all stages combined. In recent years, local ablative techniques have been introduced and utilized as additional therapeutic approaches for locally advanced pancreatic cancer (LAPC), with promising results with respect to local tumor control and OS. In addition to successful cytoreduction, there is emerging evidence that local ablation induces antitumor immune activity that could prevent or even treat distant metastatic tumors. The enhancement of antitumor immune responses could potentially make ablative therapy a therapeutic option for the treatment of metastatic PDAC. In this review, we summarize current ablative techniques used in the management of LAPC and their impact on systemic immune responses.

The Impact of Age in the Treatment of Non-comorbid Patients with Rectal Cancer: Survival Outcomes from the National Cancer Database.

BACKGROUND: Multimodal therapy has improved survival outcomes for rectal cancer (RC) significantly with an exemption for older patients. We sought to assess whether older non-comorbid patients receive substandard oncological treatment for localized RC referring to the National Comprehensive Cancer Network (NCCN) guidelines and whether it affects survival outcomes. METHODS: This is a retrospective study using patient data from the National Cancer Data Base (NCDB) for histologically confirmed RC from 2002 to 2014. Non-comorbid patients between ≥50 and ≤85 years and defined treatment for localized RC were included and assigned to a younger (<75 years) and an older group (≥75 years). Treatment approaches and their impact on relative survival (RS) were analyzed using loess regression models and compared between both groups. Furthermore, mediation analysis was performed to measure the independent relative effect on age and other variables on RS. Data were assessed using the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist. RESULTS: Of 59,769 included patients, 48,389 (81.0%) were assigned to the younger group (<75 years). Oncologic resection was performed in 79.6% of the younger patients compared to 67.2% of the older patients (p < 0.001). Chemotherapy (74.3% vs. 56.1%) and radiotherapy (72.0% vs. 58.1%) were provided less often in older patients, respectively (p < 0.001). Increasing age was associated with enhanced 30- and 90-day mortality with 0.6% and 1.1% in the younger and 2.0% and 4.1% in the elderly group (p < 0.001) and worse RS rates [multivariable adjusted HR: 1.93 (95% CI 1.87-2.00), p < 0.001]. Adherence to standard oncological therapy resulted in a significant increase in 5-year RS (multivariable adjusted HR: 0.80 (95% CI 0.74-0.86), p < 0.001). Mediation analysis revealed that RS was mainly affected by age itself (84%) rather than the choice of therapy. CONCLUSIONS: The likelihood to receive substandard oncological therapy increases in the older population and negatively affects RS. Since age itself has a major impact on RS, better patient selection should be performed to identify those that are potentially eligible for standard oncological care regardless of their age.

Trends in pancreatic surgery in Switzerland: a survey and nationwide analysis over two decades.

BACKGROUND: Centralisation of highly specialised medicine (HSM) has changed practice and outcome in pancreatic surgery (PS) also in Switzerland. Fewer hospitals are allowed to perform pancreatic surgery according to nationally defined cut-offs. OBJECTIVE: We aimed to examine trends in PS in Switzerland. First, to assess opinions and expected trends among Swiss pancreatic surgeons in regard of PS practice and second, to assess the evolution of PS performance in Switzerland by a nationwide retrospective analysis. METHODS: First, a 26-item survey among all surgeons who performed PS in 2016 in Switzerland was performed. Then, nationwide data from 1998 to 2018 from all hospitals performing PS was analysed including centre volume, perioperative morbidity and mortality, surgical indications and utilisation of minimally invasive pancreatic surgery (MIPS). The national cut-off for regulatory accredited volume centres (AVC) was ≥ 12. Additionally, an international benchmark definition for high volume (≥ 20 surgeries/year) was used. RESULTS: Among 25 surgeons from 15 centres (response rate 51%), the survey revealed agreement that centralisation is important to improve perioperative outcomes. Respondents agreed on a minimum case load per surgeon or centre. Within the nationwide database, 8534 pancreatic resections were identified. Most resections were performed for pancreatic ductal adenocarcinoma (58.9%). There was a significant trend towards centralisation of PS with fewer non-accredited volume centres (nAVC) (36 in 1998 and 17 in 2018, p < 0.001) and more AVC (2 in 1998 and 18 in 2018, p < 0.001). A significantly higher adjusted mortality after pancreatoduodenectomy (PD) was observed in low-volume compared to high-volume hospitals (OR 1.45 [95% CI 1.15-1.84], p = 0.002) and a similar trend compared among AVC and nAVC (OR 1.25 [95% CI 0.98-1.60], p = 0.072), while mortality after distal pancreatectomy (DP) was not influenced by centre volume. CONCLUSIONS: Over the last two decades, centralisation of PS towards higher-volume centres was observed in Switzerland with a decrease of mortality after PD and low mortality after DP. Further centralisation is supported by most pancreatic surgeons. However, the ideal metric and outcome measures for the allocation of highly specialised medicine need further discussion to allow a fair and outcome-focused allocation.

Evaluation of the Introduction of a Colorectal Bundle in Left Sided Colorectal Resections (EvaCol): Study Protocol of a Multicentre, Observational Trial.

Purpose: Overall complication and leak rates in colorectal surgery showed only minor improvements over the last years and remain still high. While the introduction of the WHO Safer Surgery Checklist has shown a reduction of overall operative mortality and morbidity in general surgery, only minor attempts have been made to improve outcomes by standardizing perioperative processes in colorectal surgery. Nevertheless, a number of singular interventions have been found reducing postoperative complications in colorectal surgery. The aim of the present study is to combine nine of these measures to a catalogue called colorectal bundle (CB). This will help to standardize pre-, intra-, and post-operative processes and therefore eventually reduce complication rates after colorectal surgery. Methods: The study will be performed among nine contributing hospitals in the extended north-western part of Switzerland. In the 6-month lasting control period the patients will be treated according to the local standard of each contributing hospital. After a short implementation phase all patients will be treated according to the CB for another 6 months. Afterwards complication rates before and after the implementation of the CB will be compared. Discussion: The overall complication rate in colorectal surgery is still high. The fact that only little progress has been made in recent years underlines the relevance of the current project. It has been shown for other areas of surgery that standardization is an effective measure of reducing postoperative complication rates. We hypothesize that the combination of effective, individual components into the CB can reduce the complication rate. Trial registration: Registered in ClinicalTrials.gov on 11/03/2020; NCT04550156. Highlights: Purpose: Overall complications in colorectal surgery remain still highStandardizing can reduce overall operative mortality and morbidityOnly minor attempts have been made to standardize perioperative processes in colorectal surgerySingular interventions have been found reducing postoperative complicationsThe aim is to combine nine of these measures to a colorectal bundle (CB)The CB will help to reduce complication rates after colorectal surgery Methods: The observational study will be performed among nine hospitals in SwitzerlandSix month the patients will be treated according to the local standardsAfterwards patients will be treated according to the CB for another six monthsComplication rates before and after the implementation of the CB will be compared Discussion: Only little progress has been made to reduce complication rate in colorectal surgeryStandardization is an effective measure of reducing complication ratesThe combination of effective, individual components into the CB can reduce the complication rate.

Early detection of pancreatic tumors by advanced EUS imaging.

The early detection of pancreatic ductal adenocarcinoma (PDAC) dramatically improves outcome. All available state-of-the-art imaging methods allow early detection with EUS being the best technique for exclusion of PDAC and detection of very early PDAC. Etiological differentiation of small SPL is important to guide individually tailored patients' management including radical surgery in resectable PDAC, medical (neoadjuvant or palliative intended) treatment in patients with non-resectable malignancy, pancreatic parenchyma saving strategies in some non-PDAC, and follow-up in particular in low-grade PanNEN or other small benign lesions. Multimodality EUS imaging including B-Mode assessment, elastography, contrast-enhancement and EUS-guided sampling is the most appropriate technique for diagnosis and risk assessment of small SPL. We present a review discussing modern (endoscopic) ultrasound imaging techniques including contrast enhanced ultrasound and elastography for the early detection and characterization of solid pancreatic lesions.

Hospital-level compliance with the commission on cancer's quality of care measures and the association with patient survival.

BACKGROUND: Quality measurement has become a priority for national healthcare reform, and valid measures are necessary to discriminate hospital performance and support value-based healthcare delivery. The Commission on Cancer (CoC) is the largest cancer-specific accreditor of hospital quality in the United States and has implemented Quality of Care Measures to evaluate cancer care delivery. However, none has been formally tested as a valid metric for assessing hospital performance based on actual patient outcomes. METHODS: Eligibility and compliance with the Quality of Care Measures are reported within the National Cancer Database, which also captures data for robust patient-level risk adjustment. Hospital-level compliance was calculated for the core measures, and the association with patient survival was tested using Cox regression. RESULTS: Seven hundred sixty-eight thousand nine hundred sixty-nine unique cancer cases were included from 1323 facilities. Increasing hospital-level compliance was associated with improved survival for only two measures, including a 35% reduced risk of mortality for the gastric cancer measure G15RLN (HR 0.65, 95% CI 0.58-0.72) and a 19% reduced risk of mortality for the colon cancer measure 12RLN (HR 0.81, 95% CI 0.77-0.85). For the lung cancer measure LNoSurg, increasing compliance was paradoxically associated with an increased risk of mortality (HR 1.14, 95% CI 1.08-1.20). For the remaining measures, hospital-level compliance demonstrated no consistent association with patient survival. CONCLUSION: Hospital-level compliance with the CoC's Quality of Care Measures is not uniformly aligned with patient survival. In their current form, these measures do not reliably discriminate hospital performance and are limited as a tool for value-based healthcare delivery.

What does liver elastography measure? Technical aspects and methodology.

Elastography can be thought as an extension of the ancient technique of palpation. After giving a short introduction to the history of elastography, the different technologies that are nowadays available and the physics behind them, the article focuses on the assessment of liver stiffness in patients with diffuse liver disease using shear wave elastography (SWE). Practical advices on how to perform the SWE techniques and on the factors that should be considered for a correct interpretation of the results are given. This paper aimed to provide a practical guide for beginners and advanced clinical users to better understand technical aspects, methodologies and terminology.

Role of lymphadenectomy in resectable pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) remains one of the most devastating malignant diseases, predicted to become the second leading cause of cancer-related death by 2030. Despite advances in surgical techniques and in systemic therapy, the 5-year relative survival remains a grim 9% for all stages combined. The extent of lymphadenectomy has been discussed intensively for decades, given that even in early stages of PC, lymph node (LN) metastasis can be detected in approximately 80%. PURPOSE: The primary objective of this review was to provide an overview of the current literature evaluating the role of lymphadenectomy in resected PC. For this, we evaluated randomized controlled studies (RCTs) assessing the impact of extent of lymphadenectomy on OS and studies evaluating the prognostic impact of anatomical site of LN metastasis and the impact of the number of resected LNs on OS. CONCLUSIONS: Lymphadenectomy plays an essential part in the multimodal treatment algorithm of PC and is an additional therapeutic tool to increase the chance for surgical radicality and to ensure correct staging for optimal oncological therapy. Based on the literature from the last decades, standard lymphadenectomy with resection of at least ≥ 15 LNs is associated with an acceptable postoperative complication risk and should be recommended to obtain local radicality and accurate staging of the disease. Although radical surgery including appropriate lymphadenectomy of regional LNs remains the only chance for long-term tumor control, future studies specifically assessing the impact of neoadjuvant therapy on extraregional LNs are warranted.

Role of lymphadenectomy, adjuvant chemotherapy, and treatment at high-volume centers in patients with resected pancreatic cancer-a distinct view on lymph node yield.

PURPOSE: While the importance of lymphadenectomy is well-established for patients with resectable pancreatic cancer, its direct impact on survival in relation to other predictive factors is still ill-defined. METHODS: The National Cancer Data Base 2006-2015 was queried for patients with resected pancreatic adenocarcinoma (stage IA-IIB). Patients were dichotomized into the following two groups, those with 1-14 resected lymph nodes and those with ≥ 15. Optimal number of resected lymph nodes and the effect of lymphadenectomy on survival were assessed using various statistical modeling techniques. Mediation analysis was performed to differentiate the direct and indirect effect of lymph node resection on survival. RESULTS: A total of 21,912 patients were included; median age was 66 years (IQR 59-73), 48.9% were female. Median number of resected lymph nodes was 15 (IQR 10-22), 10,163 (46.4%) had 1-14 and 11,749 (53.6%) had ≥ 15 lymph nodes retrieved. Lymph node positivity increased by 4.1% per lymph node up to eight examined lymph nodes, and by 0.6% per lymph node above eight. Five-year overall survival was 17.9%. Overall survival was better in the ≥ 15 lymph node group (adjusted HR 0.91, CI 0.88-0.95, p < 0.001). On a continuous scale, survival improved with increasing LNs collected. Patients who underwent adjuvant chemotherapy and were treated at high-volume centers had improved overall survival compared with their counterparts (adjusted HR 0.59, CI 0.57-0.62, p < 0.001; adjusted HR 0.86, CI 0.83-0.89, p < 0.001, respectively). Mediation analysis revealed that lymphadenectomy had only 18% direct effect on improved overall survival, while 82% of its effect were mediated by other factors like treatment at high-volume hospitals and adjuvant chemotherapy. DISCUSSION: While higher number of resected lymph nodes increases lymph node positivity and is associated with better overall survival, most of the observed survival benefit is mediated by chemotherapy and treatment at high-volume centers.

Is There a Role for Surgery in Patients with Neuroendocrine Tumors of the Esophagus? A Contemporary View from the NCDB.

BACKGROUND: Esophageal neuroendocrine tumors (eNETs) are exceedingly rare, aggressive and have a poor prognosis. Treatment guidelines are ill-defined and mainly based on evidence from case reports and analogous experiences drawn from similar disease sites. METHODS: The NCDB was reviewed for histologically confirmed stage I-III, primary eNETs from 2006 to 2014. Patients were grouped into whether or not they underwent primary tumor resection. Univariate, multivariable, and full bipartite propensity score (PS) adjusted Cox regression analyses were used to assess overall and relative survival differences. RESULTS: A total of 250 patients were identified. Mean age was 65.0 (standard deviation [SD] 11.9) years, and 174 (69.6%) patients were male. Most patients had stage III disease (n = 136, 54.4%), and the most common type of NET was small cell eNET (n = 111, 44.4%). Chemotherapy was used in 186 (74.4%), radiation therapy in 178 (71.2%), and oncological resection was performed in 69 (27.6%) patients. Crude 2-year survival rates were higher in the operated (57.3%) compared with the nonoperated group (35.2%; p < 0.001). The survival benefit held true after multivariable adjustment (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.32-0.69, p < 0.001). After full bipartite PS adjustment analysis, survival was longer for patients who received a surgical resection compared with those who did not (HR 0.48, 95% CI 0.31-0.75, p = 0.003) with a corresponding 2-year overall survival rate of 63.3% (95% CI 52.0-77.2) versus 38.8% (95% CI 30.9-48.8), respectively. CONCLUSIONS: Multimodal treatment that includes surgery is associated with better overall survival for eNETs. Additional research is needed to more definitively identify patients who benefit from esophagectomy and to establish an appropriate treatment algorithm.

No Difference in Survival between Neo-Adjuvant Chemotherapy and Neo-Adjuvant Chemoradiation Therapy in Gastric Cardia Cancer Patients: A Contemporary View from the National Cancer Database.

INTRODUCTION: Both neo-adjuvant chemoradiation therapy (NACRT) and neo-adjuvant chemotherapy (NAC), in addition to surgical resection of gastric cardia cancer, improves survival outcomes. We assessed whether NACRT or NAC had superior overall survival (OS) and relative survival (RS) outcomes using the National Cancer Database (NCDB). METHODS: The NCDB from 2006 to 2014 was reviewed to identify non-metastatic adult gastric cardia cancer patients who underwent surgical resection and received NACRT or NAC. Advanced statistical models were applied to assess survival outcomes. RESULTS: Of the 5,371 patients included, 4,520 (84.2%) were male, the mean age was 61.2 years (SD 10.0), 4,229 (78.7%) underwent NACRT, and 1,142 (21.3%) underwent NAC. NACRT patients more often had an R0 resection compared to NAC (91.4 vs. 86.6%, p < 0.001, respectively). Univariate 5-year OS rates were 40.0% (95% CI 38.2-41.8) for NACRT and 40.1% (37.0-43.6) for NAC (p = 0.302). No differences in OS for NAC vs. NACRT were found after multivariable analysis (hazard ratio [HR] 0.95, 95% CI 0.86-1.05, p = 0.290). There were no survival differences after stepwise, propensity score, RS analyses, nor after near-far-matching (HR 0.94, 95% CI 0.82-1.07, p = 0.332). CONCLUSIONS: NAC or NACRT yield the same survival outcome for patients with resectable gastric cardia cancer. These data support the need for randomized controlled trials comparing the 2 regimens head-to-head.

Incidence of Ductal Carcinoma In Situ in the United States, 2000-2014.

BACKGROUND: In absence of definitive molecular risk markers, clinical management of patients diagnosed with ductal carcinoma in situ (DCIS) remains largely guided by patient and tumor characteristics. In this study, we analyzed recent trends in DCIS incidence and compared them against trends in mammography use. METHODS: The Surveillance, Epidemiology, and End Results registry was queried for patients diagnosed with DCIS from 2000 to 2014 (18 registries). Joinpoint regression analyses were used to compute age- and race-stratified trends in age-adjusted incidence of DCIS. The patterns of DCIS incidence were compared against mammography utilization data from the National Health Interview Survey. RESULTS: Between 2000 and 2014, overall DCIS incidence in the U.S. population was stable (P = 0.24). Among age groups 20 to 44 years and 45 to 55 years, DCIS incidence increased by 1.3% (P = 0.001) and 0.6% (P = 0.02) per year, respectively. Although stable among white women, DCIS incidence increased among black women and women of other races by 1.6% (P < 0.001) and 1.0% (P = 0.002) per year, respectively. Mammography uptake correlated well with DCIS incidence, with the exception of women ages 40 to 49 years and black women who experienced an increase in DCIS incidence despite stagnating and decreasing mammography uptake, respectively. CONCLUSIONS: Overall DCIS incidence rates have remained stable between 2000 and 2014. However, subgroup analyses revealed an increase in incidence among both younger women and black women. IMPACT: DCIS incidence trends did not correlate with the mammography uptake patterns, suggesting that etiologic factors other than screening may be leading to an increased DCIS incidence in these groups.

Cancer Outcomes in DCIS Patients Without Locoregional Treatment.

BACKGROUND: The vast majority of women diagnosed with ductal carcinoma in situ (DCIS) undergo treatment. Therefore, the risks of invasive progression and competing death in the absence of locoregional therapy are uncertain. METHODS: We performed survival analyses of patient-level data from DCIS patients who did not receive definitive surgery or radiation therapy as recorded in the US National Cancer Institute's Surveillance, Epidemiology, and End Results program (1992-2014). Kaplan-Meier curves were used to estimate the net risk of subsequent ipsilateral invasive cancer. The cumulative incidences of ipsilateral invasive cancer, contralateral breast cancer, and death were estimated using competing risk methods. RESULTS: A total of 1286 DCIS patients who did not undergo locoregional therapy were identified. Median age at diagnosis was 60 years (inter-quartile range = 51-74 years), with median follow-up of 5.5 years (inter-quartile range = 2.3-10.6 years). Among patients with tumor grade I/II (n = 547), the 10-year net risk of ipsilateral invasive breast cancer was 12.2% (95% confidence interval [CI] = 8.6% to 17.1%) compared with 17.6% (95% CI = 12.1% to 25.2%) among patients with tumor grade III (n = 244) and 10.1% (95% CI = 7.4% to 13.8%) among patients with unknown grade (n = 495). Among all patients, the 10-year cumulative incidences of ipsilateral invasive cancer, contralateral breast cancer, and all-cause mortality were 10.5% (95% CI = 8.5% to 12.4%), 3.9% (95% CI = 2.6% to 5.2%), and 24.1% (95% CI = 21.2% to 26.9%), respectively. CONCLUSION: Despite limited data, our findings suggest that DCIS patients without locoregional treatment have a limited risk of invasive progression. Although the cohort is not representative of the general population of patients diagnosed with DCIS, the findings suggest that there may be overtreatment, especially among older patients and patients with elevated comorbidities.

Plasma Levels of K18 Fragments Do Not Correlate with Alcoholic Liver Fibrosis.

Background/Aims: Noninvasive markers of liver fibrosis in alcoholic liver disease (ALD) are crucial to establish early intervention. Previous studies have suggested that plasma levels of cleaved keratin-18 (K18; M30) fragments can predict the severity of liver disease. The aim of this study was to correlate plasma M30 levels with stages of liver fibrosis in ALD. Methods: Patients with ALD (n=139, 79.1% males) and liver histology were included, and plasma samples were collected to quantify plasma M30 levels. Patients were stratified into five groups by fibrosis stage (F0=14; F1=15; F2=35; F3=17; and F4=58) according to the Kleiner score. Differences between groups were evaluated using the chi-square test or analysis of variance. Trends by fibrosis stage were calculated by logistic regression analysis, and sensitivity, specificity and positive and negative predictive values were determined. Results: There were no significant differences in M30 levels among fibrosis stages. The correlation between plasma M30 levels and fibrosis was poor (Pearson's correlation coefficient= 0.13, Spearman rho=0.20 [p=0.02]), and M30 levels did not correlate with alcohol-specific histological features. However, significant correlations of M30 levels with aspartate aminotransferase (Spearman rho=0.653, p<0.001) and alanine aminotransferase (spearman rho=0.432, p<0.001) were found. m30 levels of>200 U/L reveal a sensitivity for predicting cirrhosis of 84.5% with a negative predictive value of 73.5%. Conclusions: Plasma M30 levels are often elevated in ALD and correlate with serum transaminases but do not reflect fibrosis. The usefulness as a prognostic marker awaits evaluation in prospective studies.