Can we "prehabilitate" pancreatic cancer patients prior to surgery?A critical appraisal of the literature.

BACKGROUND: Enhancing a patient's functional capacity to withstand the surgical stress by means of multimodal (combined exercise, nutrition and psychological interventions) prehabilitation may potentially lead to improved outcomes in pancreatic cancer surgery. METHODOLOGY: A systematic review was undertaken searching PubMed, Google Scholar and Cochrane Library databases, exploring the impact of prehabilitation in pancreatic surgery. Outcomes of interest were adherence to the prehabilitation, functional capacity, overall complications and post-operative length of stay. Pooled analysis was performed using a random-effects model. RESULTS: Twelve studies comprising of 1497 patients were included in the review. Most of the studies seem to lack a multimodal approach. Less than 50 % of the studies reported adherence, which ranged between 27 to 100 %. Functional capacity, in terms of 6-minute walk test, showed improvement with prehabilitation. Among the post-operative outcomes, prehabilitation was associated with significant improvement in pulmonary complications (2.4 % versus 6.7 %, RR 0.36, CI 0.17-0.74, p= 0.01, I2= 28%). Prehabilitation was not effective in terms of length of stay or readmission rates. CONCLUSIONS: Larger studies with multimodal prehabilitation approaches may demonstrate more consistent and clinically meaningful benefits, which would lead to a firm appreciation of its role the management of pancreatic cancer patients undergoing surgery.

'IHPBA-APHPBA clinical practice guidelines': international Delphi consensus recommendations for gallbladder cancer.

BACKGROUND: The Delphi consensus study was carried out under the auspices of the International and Asia-Pacific Hepato-Pancreato-Biliary Associations (IHPBA-APHPBA) to develop practice guidelines for management of gallbladder cancer (GBC) globally. METHOD: GBC experts from 17 countries, spanning 6 continents, participated in a hybrid four-round Delphi consensus development process. The methodology involved email, online consultations, and in-person discussions. Sixty eight clinical questions (CQs) covering various domains related to GBC, were administered to the experts. A consensus recommendation was accepted only when endorsed by more than 75% of the participating experts. RESULTS: Out of the sixty experts invited initially to participate in the consensus process 45 (75%) responded to the invitation. The consensus was achieved in 92.6% (63/68) of the CQs. Consensus covers epidemiological aspects of GBC, early, incidental and advanced GBC management, definitions for radical GBC resections, the extent of liver resection, lymph node dissection, and definitions of borderline resectable and locally advanced GBC. CONCLUSIONS: This is the first international Delphi consensus on GBC. These recommendations provide uniform terminology and practical clinical guidelines on the current management of GBC. Unresolved contentious issues like borderline resectable/locally advanced GBC need to be addressed by future clinical studies.

Perinatal Famine Exposure and Young-Onset Cancer-Lessons from China Health and Nutrition Survey.

Background/Objectives: Perinatal exposure to malnutrition has been hypothesised to influence the development of young-onset cancer (≤50 years of age). This study aimed to determine if perinatal malnutrition in individuals exposed to the Great Famine of China increased their risk of developing young-onset cancer compared to other individuals born prior to the famine. Subjects/Methods: This cross-sectional study involved 7272 participants from the China Health and Nutrition Survey who were classified into four groups based on birth year: participants born between 1953 and 1955 (before the famine) were designated as the pre-famine group (unexposed); the remainder formed perinatal exposure groups comprised of those exposed during the famine (1959-1961), those exposed in the early post-famine period (1962-1964), and those exposed in the late post-famine period (1965-1967). Multivariable adjusted log-binomial regression models were used to calculate the RR and 95% CI of young-onset cancer (including genitourinary cancer) across four groups. Results: Perinatal exposure to early post-famine (RR 2.08; 95%CI 1.04, 4.34; p = 0.043) and the female sex (RR 15.6, 95%CI 4.54, 60.3; p < 0.001) were noted to have a significantly increased risk of young-onset cancer. In addition, the early (RR 13.8; 95%CI 2.68, 253; p = 0.012) and late post-famine (RR 12.3; 95%CI 2.16, 231; p = 0.020) cohorts demonstrated a significantly increased risk of young-onset genitourinary cancer. The latter was accompanied by an increased risk of hypertension (RR 3.30; 95%CI 1.28, 7.87; p = 0.009). Conclusions: Perinatal exposure to famine, especially in females, was associated with a higher risk of young-onset cancer. This was particularly evident for young-onset genitourinary cancers. These findings highlight the potential long-term impact of perinatal malnutrition on young-onset carcinogenesis.

Childhood Cancer Incidence and Survival in South Australia and the Northern Territory, 1990-2017, with Emphasis on Indigenous Peoples.

BACKGROUND & AIMS: Reports of a rise in childhood cancer incidence in Australia and globally prompted the investigation of cancer incidence and survival in South Australia (SA) and the Northern Territory (NT) over a 28-year period, with emphasis on Indigenous peoples. METHODS: This cross-sectional analysis of two prospective longitudinal databases, the SA and NT Cancer Registries (1990-2017), included all reported cases of childhood cancers. Poisson regression provided estimates of incidence rate ratios and survival was modelled using Cox proportional hazard models for children aged <5 and ≥5 years. RESULTS: A total of 895 patients across SA (N = 753) and the NT (N = 142) were ascertained. Overall and in the NT, childhood cancer incidence was higher in males compared with females (IRR 1.19 [1.04-1.35] and 1.43 [1.02-2.01], respectively). Lymphocytic leukemia was the most reported cancer type across all locations. With reference to the 1990-1999 era (181.67/100,000), cancer incidence remained unchanged across subsequent eras in the combined cohort (SA and NT) (2000-2009: 190.55/100,000; 1.06 [0.91-1.25]; 2010-2017: 210.00/100,000; 1.15 [0.98-1.35]); similar outcomes were reflected in SA and NT cohorts. Cancer incidence amongst non-Indigenous children significantly decreased from the 1990-1999 era (278.32/100,000) to the 2000-2009 era (162.92/100,000; 0.58 [0.35-0.97]). Amongst 39 Indigenous children in the NT, incidence rates remained unchanged across eras (p > 0.05). With reference to the 1990-1999 era, overall survival improved in subsequent eras in SA (2000-2009: HR 0.53 [0.38-0.73]; 2010-2017: 0.44 [0.28-0.68]); however, remained unchanged in the NT (2000-2009: 0.78 [0.40-1.51]; 2010-2017: 0.50 [0.24-1.05]). In the NT, overall survival of Indigenous patients was significantly lower compared with the non-Indigenous cohort (3.42 [1.92-6.10]). While the survival of Indigenous children with cancer significantly improved in the last two eras (p < 0.05), compared to the 1990-1999 era, no change was noted amongst non-Indigenous children in the NT (p > 0.05). CONCLUSIONS: The incidence of childhood cancers has remained unchanged over 28-years in SA and the NT. Encouragingly, improved survival rates over time were observed in SA and amongst Indigenous children of the NT. Nevertheless, survival rates in Indigenous children remain lower than non-Indigenous children.

The epidemiology of acute pancreatitis in Tasmania over a 12-year period: Is this a disease of disadvantage?

BACKGROUND: The global incidence of acute pancreatitis (AP) is increasing, but little information exists about trends in Australia. This study aimed to describe incidence trends, along with clinical and socio-demographic associations, in the state of Tasmania over a recent 12-year period. METHODS: The study cohort was obtained by linking clinical and administrative datasets encompassing the whole Tasmanian population between 2007 and 2018, inclusive. Pancreatitis case definition was based on relevant ICD-10 hospitalization codes, or elevated serum lipase or amylase in pathology data. Age-standardised incidence rates were estimated, overall and stratified by sex, aetiology, and Index of Relative Socio-economic Disadvantage (IRSD). RESULTS: In the study period, 4905 public hospital AP episodes were identified in 3503 people. The age-standardised person-based incidence rate across the entire period was 54 per 100,000 per year. Incidence was inversely related to IRSD score; 71 per 100,000 per year in the most disadvantaged quartile compared to 32 in the least disadvantaged. Biliary AP incidence was higher than that of alcohol-related AP, although the greatest incidence was in "unspecified" cases. There was an increase in incidence for the whole cohort (average annual percent change 3.23 %), largely driven by the two most disadvantaged IRSD quartiles; the least disadvantaged quartile saw a slight overall decrease. CONCLUSION: This is the first Australian study providing robust evidence that AP incidence is increasing and is at the upper limit of population-based studies worldwide. This increased incidence is greatest in socio-economically disadvantaged areas, meriting further research to develop targeted, holistic management strategies.

Neoadjuvant Therapy in Borderline Resectable Pancreatic Cancer.

In this perspective, we present our assessment of all of the known accumulated evidence on the role of neoadjuvant therapy in the management of borderline resectable pancreatic cancer highlighting the gaps in the data, the current regimens used and providing a brief insight into the way forward.

The burden of young-onset pancreatic cancer and its risk factors from 1990 to 2019: A systematic analysis of the global burden of disease study 2019.

OBJECTIVE: To investigate worldwide incidence, deaths, disability-adjusted life years (DALYs) and risk factors for young-onset pancreatic cancer (YOPC) using the Global Burden of Disease Study 2019-20 data. METHODS: We queried the Global Health Data Exchange tool for "pancreatic cancer" and "incidence", "deaths" as the "measure", and "DALYs" as the "cause" for the age group of 15-49 years to determine global, regional, and national trends in the incidence, deaths, and DALYs of YOPC. Sociodemographic index (SDI) was used to evaluate the associations between socioeconomic development and YOPC. Risk factors including smoking, tobacco use, hi2gh body mass index (BMI), and high fasting plasma glucose (FPG) were evaluated, and their attributable burden was estimated. RESULTS: Global incidence, death, and DALY rates of YOPC significantly increased from 1990 to 2019 ((0.30 (p = 0.001), 0.25 (p = 0.001), and 11.18 (p = 0.002), respectively). Regions with the highest and lowest incidence, death, and DALY rates of YOPC were Eastern Europe and Central Sub-Saharan Africa, respectively. Incidence, death, and DALY rates increased with increasing age and SDI. Leading risk factors for YOPC in 2019 were smoking and tobacco use. DALYs attributable to smoking and tobacco use decreased from 1990 to 2019, especially in females, while those attributable to high BMI and FPG increased during the same period. CONCLUSIONS: The global incidence, death and DALY rates of YOPC have significantly increased over 3 decades. Certain regions and nations are witnessing a higher increase in this trend. There is an urgent need for global efforts targeting preventable causes of YOPC.

Global Perceptions on ERAS® in Pancreatoduodenectomy.

BACKGROUND: Uptake of ERAS® pathways for pancreatic surgery have been slow and impacted by low compliance. OBJECTIVE: To explore global awareness, perceptions and practice of ERAS® peri-pancreatoduodenectomy (PD). METHODS: A structured, web-based survey (EPSILON) was administered through the ERAS® society and IHPBA membership. RESULTS: The 140 respondents included predominantly males (86.4%), from Europe (45%), practicing surgery (95%) at academic/teaching hospitals (63.6%) over a period of 10-20 years (38.6%). Most respondents identified themselves as general surgeons (68.6%) with 40.7% reporting an annual PD volume of 20-50 cases, practicing post-PD clinical pathways (37.9%), with 31.4% of respondents auditing their outcomes annually. Reduced medical complications, cost and hospital length of stay, and improved patient satisfaction were perceived benefits of compliance to enhancing-recovery. Multidisciplinary co-ordination was considered the most important factor in the implementation and sustainability of peri-PD ERAS® pathways, while reluctance to change among health care practitioners, difficulties in data collection and audit, lack of administrative support, and recruitment of an ERAS® dedicated nurse were reported to be important barriers. CONCLUSIONS: The EPSILON survey highlighted global clinician perceptions regarding the benefits of compliance to peri-PD ERAS®, the importance of individual components, perceived facilitators and barriers, to the implementation and sustainability of these pathways.

Fluid resuscitation in the early management of acute pancreatitis - evidence from a systematic review and meta-analysis.

BACKGROUND: Third space fluid loss is one of the hallmarks of the pathophysiology of acute pancreatitis (AP) contributing to complications, including organ failure and death. We conducted a systematic review of literature to determine the ideal fluid resuscitation in the early management of AP, primarily comparing aggressive versus moderate intravenous fluid resuscitation (AIR vs MIR). METHODS: A systematic review of major reference databases was undertaken. Meta-analysis was performed using random-effects model. Bias was assessed using Cochrane risk of bias and ROBINS-I tools for randomized and non-randomised studies, respectively. RESULTS: Twenty studies were included in the analysis. Though there was no significant difference in mortality between AIR and MIR groups (8.3% versus 6.0%; p = 0.3), AIR cohort had significantly higher rates of organ failure (p = 0.009), including pulmonary (p = 0.02) and renal (p = 0.01) complications. Similarly, there was no difference in mortality between normal saline (NS) and Ringer's lactate (RL) (3.17% versus 3.01%; p = 0.23), though patients treated with NS had a significantly longer length of hospital stay (LOS) (p = 0.009). CONCLUSIONS: Current evidence appears to support moderate intravenous resuscitation (level of evidence, low) with RL (level of evidence, moderate) in the early management of AP.

Impact of Unplanned Intra-Operative Conversions on Outcomes in Minimally Invasive Pancreatoduodenectomy.

BACKGROUND: Minimally-invasive pancreatoduodenectomy (MIPD) is fraught with the risk of complication-related deaths (LEOPARD-2), a significant volume-outcome relationship and a long learning curve. With rates of conversion for MIPD approaching 40%, the impact of these on overall patient outcomes, especially, when unplanned, are yet to be fully elucidated. This study aimed to compare peri-operative outcomes of (unplanned) converted MIPD against both successfully completed MIPD and upfront open PD. METHODS: A systematic review of major reference databases was undertaken. The primary outcome of interest was 30-day mortality. Newcastle-Ottawa scale was used to judge the quality of the studies. Meta-analysis was performed using pooled estimates, derived using random effects model. RESULTS: Six studies involving 20,267 patients were included in the review. Pooled analysis demonstrated (unplanned) converted MIPD were associated with an increased 30-day (RR 2.83, CI 1.62- 4.93, p = 0.0002, I2 = 0%) and 90-day (RR 1.81, CI 1.16- 2.82, p = 0.009, I2 = 28%) mortality and overall morbidity (RR 1.41, CI 1.09; 1.82, p = 0.0087, I2 = 82%) compared to successfully completed MIPD. Patients undergoing (unplanned) converted MIPD experienced significantly higher 30-day mortality (RR 3.97, CI 2.07; 7.65, p < 0.0001, I2 = 0%), pancreatic fistula (RR 1.65, CI 1.22- 2.23, p = 0.001, I2 = 0%) and re-exploration rates (RR 1.96, CI 1.17- 3.28, p = 0.01, I2 = 37%) compared upfront open PD. CONCLUSIONS: Patient outcomes are significantly compromised following unplanned intraoperative conversions of MIPD when compared to successfully completed MIPD and upfront open PD. These findings stress the need for objective evidence-based guidelines for patient selection for MIPD.

A core set of quality performance indicators for HPB procedures: a global consensus for hepatectomy, pancreatectomy, and complex biliary surgery.

BACKGROUND: Surgery for hepatopancreaticobiliary (HPB) conditions is performed worldwide. This investigation aimed to develop a set of globally accepted procedural quality performance indicators (QPI) for HPB surgical procedures. METHODS: A systematic literature review generated a dataset of published QPI for hepatectomy, pancreatectomy, complex biliary surgery and cholecystectomy. Using a modified Delphi process, three rounds were conducted with working groups composed of self-nominating members of the International Hepatopancreaticobiliary Association (IHPBA). The final set of QPI was circulated to the full membership of the IHPBA for review. RESULTS: Seven "core" indicators were agreed for hepatectomy, pancreatectomy, and complex biliary surgery (availability of specific services on site, a specialised surgical team with at least two certified HPB surgeons, a satisfactory institutional case volume, synoptic pathology reporting, undertaking of unplanned reintervention procedures within 90 days, the incidence of post-procedure bile leak and Clavien-Dindo grade ≥III complications and 90-day post-procedural mortality). Three further procedure specific QPI were proposed for pancreatectomy, six for hepatectomy and complex biliary surgery. Nine procedure-specific QPIs were proposed for cholecystectomy. The final set of proposed indicators were reviewed and approved by 102 IHPBA members from 34 countries. CONCLUSIONS: This work presents a core set of internationally agreed QPI for HPB surgery.

Extended distal pancreatectomy in pancreatic cancer: is it justified? A systematic review of literature.

Background: Extended distal pancreatectomy (EDP) is being increasingly performed for pancreatic cancers with suspected invasion into the adjacent organs. However, the perioperative safety and oncological efficacy of this procedure merit further elucidation. Methods: Major databases were searched for studies evaluating EDP, and a meta-analysis was performed using fixed- or random-effects models. Results: Fifteen studies were included in the analysis. EDP was found to be associated with significantly greater incidence of postoperative pancreatic fistula overall and with major complications, re-explorations, mortality and readmissions. However, on pooled analysis of 3- and 5-year survival, EDP was found to be noninferior to standard distal pancreatectomy. Conclusion: EDP is feasible and may offer equivalent survival in highly selected patients but carries a higher risk of perioperative morbidity and mortality.

Young-Onset Cancers-Early Steps in the Right Direction.

The global incidence of young-onset (YO) cancer is on the rise [...].

Overcoming the Fibrotic Fortress in Pancreatic Ductal Adenocarcinoma: Challenges and Opportunities.

An overabundance of desmoplasia in the tumour microenvironment (TME) is one of the defining features that influences pancreatic ductal adenocarcinoma (PDAC) development, progression, metastasis, and treatment resistance. Desmoplasia is characterised by the recruitment and activation of fibroblasts, heightened extracellular matrix deposition (ECM) and reduced blood supply, as well as increased inflammation through an influx of inflammatory cells and cytokines, creating an intrinsically immunosuppressive TME with low immunogenic potential. Herein, we review the development of PDAC, the drivers that initiate and/or sustain the progression of the disease and the complex and interwoven nature of the cellular and acellular components that come together to make PDAC one of the most aggressive and difficult to treat cancers. We review the challenges in delivering drugs into the fortress of PDAC tumours in concentrations that are therapeutic due to the presence of a highly fibrotic and immunosuppressive TME. Taken together, we present further support for continued/renewed efforts focusing on aspects of the extremely dense and complex TME of PDAC to improve the efficacy of therapy for better patient outcomes.

Mortality and costs related to severe acute pancreatitis in the intensive care units of Australia and New Zealand (ANZ), 2003-2020.

BACKGROUND AND OBJECTIVE: Comprehensive data on the burden of severe acute pancreatitis (SAP) in global intensive care units (ICUs) and trends over time are lacking. Our objective was to compare trends in hospital and ICU mortality, in-hospital and ICU length of stay, and costs related to ICU admission in Australia and New Zealand (ANZ) for SAP. METHODS: We performed a retrospective, observational, cohort study of ICU admissions reported to the ANZ Intensive Care Society Adult Patient Database over three consecutive six-year time periods from 2003 to 2020. RESULTS: 12,635 patients with SAP from 189 ICUs in ANZ were analysed. No difference in adjusted hospital mortality (11.4% vs 11.5% vs 11.0%, p = 0.85) and ICU mortality rates (7.5% vs 8.0% vs 8.1%, p = 0.73) were noted over the study period. Median length of hospital admission reduced over time (13.9 days in 2003-08, 13.1 days in 2009-14 and 12.5 days in 2015-20; p < 0.01). No difference in length of ICU stay was noted over the study period (p = 0.13). The cost of managing SAP in ANZ ICUs remained constant over the three time periods. CONCLUSIONS: In critically-ill SAP patients in ANZ, no change in mortality has been noted over nearly two decades. There was a slight reduction in hospital stay (1 day), while the length of ICU stay remained unchanged. Given the significant costs related to care of patients with SAP in ICU, these findings highlight the need to prioritise resource allocation for healthcare delivery and targeted clinical research to identify treatments aimed at reducing mortality.

Targeted therapy for intractable cancer on the basis of molecular profiles: An open-label, phase II basket trial (Long March Pathway).

Purpose: We evaluated he effects of molecular guided-targeted therapy for intractable cancer. Also, the epidemiology of druggable gene alterations in Chinese population was investigated. Materials and methods: The Long March Pathway (ClinicalTrials.gov identifier: NCT03239015) is a non-randomized, open-label, phase II trial consisting of several basket studies examining the molecular profiles of intractable cancers in the Chinese population. The trial aimed to 1) evaluate the efficacy of targeted therapy for intractable cancer and 2) identify the molecular epidemiology of the tier II gene alterations among Chinese pan-cancer patients. Results: In the first stage, molecular profiles of 520 intractable pan-cancer patients were identified, and 115 patients were identified to have tier II gene alterations. Then, 27 of these 115 patients received targeted therapy based on molecular profiles. The overall response rate (ORR) was 29.6% (8/27), and the disease control rate (DCR) was 44.4% (12/27). The median duration of response (DOR) was 4.80 months (95% CI, 3.33-27.2), and median progression-free survival (PFS) was 4.67 months (95% CI, 2.33-9.50). In the second stage, molecular epidemiology of 17,841 Chinese pan-cancer patients demonstrated that the frequency of tier II gene alterations across cancer types is 17.7%. Bladder cancer had the most tier-II alterations (26.1%), followed by breast cancer (22.4%), and non-small cell lung cancer (NSCLC; 20.2%). Conclusion: The Long March Pathway trial demonstrated a significant clinical benefit for intractable cancer from molecular-guided targeted therapy in the Chinese population. The frequency of tier II gene alterations across cancer types supports the feasibility of molecular-guided targeted therapy under basket trials.