Introduction

In our recent multicentre prospective study (AXIOMA), the effectiveness of lumen-apposing metal stents (LAMS) in endoscopic transluminal drainage of infected necrosis was comparable to that of double-pigtail plastic stents(1). The use of LAMS did not reduce the need for additional drainage procedures and resulted in similar patient outcomes compared to double-pigtails plastic stents. However, long-term follow-up data (>6 months) from prospective studies were still lacking for comparison of the stents.

Aims & Methods

We examined the long-term outcomes of patients with infected necrotizing pancreatitis enrolled in two prospective studies. Patients were treated with endoscopic transluminal drainage with LAMS (n=52) as part of a multicentre prospective cohort in 16 hospitals, or with double-pigtail plastic stents (n=48) as part of the endoscopic step-up arm of a randomized multicentre trial (TENSION) in 19 hospitals(2, 3). The protocol of both studies, including in- and exclusion criteria, were identical except for the type of transluminal stent. The primary endpoint was the proportion of patients requiring additional endoscopic, percutaneous or surgical drainage procedures due to (recurrence of) symptomatic or infected (peri-)pancreatic collections. Secondary endpoints included the individual components of the primary endpoint, major complications, mortality, number of (pancreatitis-related) readmissions and interventions, length of hospital stay, pancreatic function and quality of life.

Results

The median follow-up period was 4 years. By the end of this period, 77 out of 100 patients were still alive. Among the 47 surviving patients treated with LAMS, 9 were lost to follow-up after the initial 6-month study. An additional percutaneous, endoscopic or surgical drainage or necrosectomy procedure was needed in 37 patients (77%) in the plastic stent group and 40 patients (77%) in the LAMS group (RR 1.002 95% CI 0.809-1.242). The median number of interventions did not differ during overall follow-up (2 [IQR, 1–5] vs 2 [IQR, 1.5–7.5], respectively, P = 0.66). Overall, there was no significant difference in mortality rates (12 patients (25%) vs. 11 (21%) respectively; RR 1.18 95% CI 0.576–2.42), and there was no difference in new mortality after the initial follow-up (3 patients (8%) vs. 6 (13%) respectively; RR 0.603 95% CI 0.16–2.254). No deaths during long-term follow-up were related to pancreatitis. The plastic stents group and LAMS group had a similar rate of pancreatitis-related readmissions (2 [IQR, 0–2] vs 1 [IQR, 0–3], P = 0.67) and associated length of hospital stay (9 [IQR, 0–20.75] vs 6 [IQR, 0–19.75], P = 0.58).

Conclusion

During the long-term follow-up of the AXIOMA study participants, we found no differences in mortality, major complications, readmissions or the need for additional interventions between double-pigtails plastic stents and LAMS. These long-term results are consistent with our prior findings, suggesting that double-pigtail plastic stents and LAMS have comparable clinical outcomes and adverse events in the endoscopic step-up approach for infected necrotizing pancreatitis.

References

1. Boxhoorn L, Verdonk R, Besselink M, Boermeester M, Bollen T, Bouwense S, et al. Comparison of lumen-apposing metal stents versus double-pigtail plastic stents for infected necrotising pancreatitis. Gut. 2023;72(1):66.
2. van Brunschot S, van Grinsven J, van Santvoort HC, Bakker OJ, Besselink MG, Boermeester MA, et al. Endoscopic or surgical step-up approach for infected necrotising pancreatitis: a multicentre randomised trial. Lancet. 2018;391(10115):51-8.
3. Onnekink AM, Boxhoorn L, Timmerhuis HC, Bac ST, Besselink MG, Boermeester MA, et al. Endoscopic Versus Surgical Step-Up Approach for Infected Necrotizing Pancreatitis (ExTENSION): Long-term Follow-up of a Randomized Trial. Gastroenterology. 2022;163(3):712-22.e14.

Disclosure

MGB reports grants from Intuitive, grants from Ethicon Endo-Surgery, grants from Medtronic, outside the submitted work; MBr reports grants and personal fees from Boston Scientific, grants and personal fees from Cook Medical, grants from Pentax Medical, grants from Mylan, grants from 3M, grants from InterScope, outside the submitted work; PF reports personal fees from Cook Medical, personal fees from Olympus, personal fees from Ethicon Endo-Surgery, outside the submitted work; J-WP reports personal fees and other from Cook Endoscopy, personal fees and other from Boston Scientific, personal fees and other from Pentax Medical, outside the submitted work; JEvH reports personal fees from Olympus Endoscopy, grants from Cook Medical, personal fees from Boston Scientific, personal fees from Medtronic, outside the submitted work; FV reports grants from Boston Scientific, outside the submitted work; RPV reports grants and personal fees from Boston Scientific, grants from Zambon, outside the submitted work.

Introduction

The prognostic significance of the preoperative C-reactive protein-albumin-lymphocyte (CALLY) index has been reported in various cancer types; however, its role in pancreatic cancer remains unclear.

Aims & Methods

A cohort of 339 patients with resectable pancreatic cancer (RPC) who underwent curative surgery between July 2012 and December 2019 was analyzed. The CALLY　index was defined as (albumin × lymphocytes)/ (C-reactive protein × 10⁴). The cutoff value of the CALLY index was determined according to　receiver operating characteristics analysis using survival status　at the 3-year　follow-up. 　We investigated the association　 between the CALLY index with disease-free survival (DFS) and overall survival (OS) using univariate and multivariate analyses.

Results

The median CALLY index was 4.1, with an interquartile range of 1.4–11.7. The cutoff value of the CALLY index was set at 3.0, dividing the patients into the CALLY-high group (> 3.0; n = 198) and the CALLY-low group (≤ 3.0; n = 141). The DFS and OS in the CALLY-low group were significantly worse than those in the CALLY-high group (p < 0.001 and p < 0.001, respectively). Multivariate analysis, using the preoperative clinicopathological variables, indicated that the CALLY index ≤ 3.0 was an independent prognostic factor for DFS (Hazard Ratio [HR] 1.53, p = 0.008) and for OS (HR 1.69, p = 0.002).

Conclusion

In RPC, survival outcomes were significantly stratified by the CALLY index = 3.0, with < 3 being a significantly poor prognostic factor for DFS and OS. The CALLY index may be useful in predicting the long-term survival of patients with RPC.

Introduction

Acute pancreatitis is a multifactorial condition which despite showing a mild disease course in the majority of patients can be associated with significant morbidity and occasional fatality. Until lately, aggressive fluid expansion has been an undisputed aspect about managing the early stages of acute pancreatitis. Evidence produced by recent studies including the WATERFALL trial [1] supports a more conservative approach of fluid resuscitation given the fact that patients face significantly higher odds of relevant fluid overload while experiencing no benefit of their underlying condition. However, owing to strict inclusion criteria, results obtained from the WATERFALL trial only apply to patients with non-severe pancreatitis.

Aims & Methods

This retrospective monocentric study is thought to shed light on fluid-related complications in pancreatitis patients with any degree of severity. Altogether, n = 129 patients with all-cause acute pancreatitis including moderately severe and severe courses were enrolled and divided into 3 groups based on their cumulative fluid administration within the first 24 hrs (restrictive: < 3 L, moderate: 3 – 6 L, aggressive: > 6 L). Vital sign records and laboratory values were reported at defined time points (baseline, t = 48 hrs, t = 7 days). Fluid replacement was guided by institutional protocols with an initial bolus of 10 ml/kg, followed by a high-volume infusion rate of 4 ml/kg/h (< 24 hrs). Clinical response to fluid administration was monitored by changes in mean arterial pressure (> 65 mmHg), urine output (> 0,5 ml/kg/h), hematocrit (< 44 %), and blood urea nitrogen (< 25 mg/dl) at t = 12 and 24 hrs, respectively.

Results

The majority of patients were allocated to the group of moderate fluid resuscitation (n = 76, 58,9 %). At baseline, patients did not differ in systemic disease severity as indicated by SIRS and SOFA scores. Compared with a restrictive and moderate fluid regime, a significantly higher proportion of patients with moderately severe or severe pancreatitis associated with an acute peripancreatic fluid collection had previously been administered > 6 L fluids (> 6 L: 17/33, 52 % vs. < 3 L: 2/20, 10 % and 3 – 6 L: 24/76, 32 % vs., p = 0,001). Patients receiving > 6 L fluids were significantly more likely to show at least one radiological feature of pulmonary fluid overload (> 6 L: 15/33, 45 % vs. < 3 L: 2/10, 10 % and 3 – 6 L: 16/76, 21 %, p = 0.006), be transferred to intensive care unit (> 6 L: 18/33, 55 % vs. < 3 L: 2/20, 10 % and 3 – 6 L: 21/76, 28 %, p = 0,002), and require extended in-patient care (8, 6 – 11 days vs. 6, 4 – 7 days and 6, 4 – 10 days, p = 0,025). In addition, within 72 hrs after admission these patients had a significantly lower Horovitz ratio compared with restrictive and moderate group (> 6 L: 285, 239 – 337 vs. < 3 L: 360, 319 – 360 and 3 – 6 L: 337, 304 – 390, respectively, p = 0,003). At t = 48 hrs, C-reactive protein levels were significantly higher in patients with > 6 L (> 6 L: 164, 74 – 260 mg/l vs. < 3 L: 58, 4 – 162 mg/l and 3 – 6 L: 95, 13 – 183 mg/l) while serum albumin levels were significantly decreased (> 6 L: 30, 27 – 32 g/l vs. 3 6 L: 34, 31 – 36.5 g/l and 36, 33,5 – 41,5 g/l, p = 0,001).

Conclusion

Besides conferring a significantly higher risk of pulmonary edema, excessive fluid replacement is significantly associated with moderately severe or severe disease courses of acute pancreatitis, prolonged hospitalization, and need for intensive care. Although the retrospective design does not allow conclusions on causal relationships, results imply that excessive fluid resuscitation not only increases the risk of iatrogenic fluid overload but may additionally aggravate pancreatic inflammation. Our data suggest that further investigation on the appropriate fluid management in patients with moderate and severe acute pancreatitis is required.

References

[1] de-Madaria E, Buxbaum JL, Maisonneuve P, García García de Paredes A, Zapater P, Guilabert L, Vaillo-Rocamora A, Rodríguez-Gandía MÁ, Donate-Ortega J, Lozada-Hernández EE, Collazo Moreno AJR, Lira-Aguilar A, Llovet LP, Mehta R, Tandel R, Navarro P, Sánchez-Pardo AM, Sánchez-Marin C, Cobreros M, Fernández-Cabrera I, Casals-Seoane F, Casas Deza D, Lauret-Braña E, Martí-Marqués E, Camacho-Montaño LM, Ubieto V, Ganuza M, Bolado F; ERICA Consortium. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis. N Engl J Med. 2022 Sep 15;387(11):989-1000. doi: 10.1056/NEJMoa2202884. PMID: 36103415.

Disclosure

All authors confirm that they have no conflict of interest.

Introduction

The complex biology of pancreatic ductal adenocarcinoma (PDAC) remains a significant challenge and limits overcoming its dismal prognosis. The tumor microenvironment (TME), shaped by dynamic interactions between cancer-associated fibroblasts (CAFs), immune and tumor cells, plays a crucial role in PDAC pathogenesis. Our investigation into homologous recombination deficiency (HRD), caused by mutations in genes like ATM, revealed its role in promoting PDAC aggressiveness and triggering a pronounced desmoplastic reaction, suggesting a unique TME programing. We have shown that the loss of ATM in the neoplastic epithelium reprograms CAFs through the TGFβ signaling to promote cancer aggressiveness. Additionally, preliminary data revealed distinct immune profiles in ATM-deficient and proficient tumors.

Aims & Methods

To capture the immune profiles of ATM-deficient PDACs, and decipher specific oncogenic tumor–stroma interactions, we first conducted single cell-resolved multiomics analyses of murine ATM and/or P53-depleted PDACs. Histopathological analyses and validation using publicly available human datasets were performed to further characterize ATM loss-specific immune patterns in pancreatic cancer.

Results

Mouse tumor analyses, using single-nucleus multiomics RNA/ATAC sequencing and multiplex immunostainings, revealed alterations in immune cell contents, e.g. reduced macrophage populations and reduced M2 polarization in ATM-deficient tumors. ATM loss-specific immune molecular signatures were further investigated and correlated with human PDAC RNA sequencing data (TCGA, PanCancer Atlas). Molecular signatures and cell-cell communication inference revealed ATM-specific tumor–TME interactions and identified the TGFβ signaling as a core driver of the interplay between CAFs, immune cells, and a particularly aggressive EMT-like tumor cell subpopulation overrepresented in ATM-depleted tumors. Strikingly, we also observed distinct communication patterns between CAFs and immune cells. Finally, a combinatorial therapy targeting the TGFβ-driven tumor–stroma dialog reversed the cancer-promoting TME remodeling and exacerbated the therapeutic response to FOLFIRINOX in vivo, exclusively in ATM-deficient HRD PDACs.

Conclusion

Through single cell-resolved multiomics analyses of ATM-deficient PDACs, and validation in human cases, we unveil transcriptional, translational, and secretory regulatory events, shed light on the intricate interplay between tumor genetics and PDAC microenvironment, and pave the way for the elaboration of novel personalized therapies.

Introduction

The combination of standard chemotherapy and phophorus-32 (³²P) microparticle intra-tumoural implantation has revealed encouraging results for patients with locally advanced pancreatic cancer (LAPC). As no direct comparison has been made, our aim was to compare FOLFIRINOX alone and FOLFIRINOX with ³²P implantation in a propensity-score weighted analysis.

Aims & Methods

We conducted a retrospective cohort study comparing LAPC patients with combination chemotherapy and ³²P implantation at 2 centres with patients with chemotherapy only (discussed at hepatobiliary multidisciplinary team meetings or underwent diagnostic endoscopic ultrasound for pancreatic cancer) from a single centre, from August 2017 to January 2023. Landmark analysis was used to overcome immortal time bias. Propensity score weighting was further performed to minimise baseline confounders. Primary outcome was overall survival.

Results

104 patients were considered. The landmark date was designated as 3 months after initiation of chemotherapy. After excluding patients who died before the landmark, 101 patients were included in the propensity-score weighted analysis (35 with ³²P implantation and chemotherapy, 66 with chemotherapy only). The restricted mean survival time (RMST) within 24 months after initiation of chemotherapy was estimated to be 112 days longer for patients with ³²P implantation and chemotherapy (459 days, 95%CI 393-536) compared to patients with chemotherapy only (347 days, 95% CI 308-392). The restricted mean local progression free time within 24 months after initiation of chemotherapy is estimated to be 112 days (95% CI 36-187) longer for patients with ³²P implantation and chemotherapy compared to patients with chemotherapy only. Average tumour size at 6 months was 12.8mm smaller (95% CI 4.69-20.9, p=0.002) with combination therapy than with chemotherapy only. The probability of downstaging if all patients were to be treated with combination therapy was 22.3% higher (95% CI 5.12%, 39.5%, p=0.03) than the probability with chemotherapy only.

Conclusion

This first comparative study between standard chemotherapy and chemotherapy with additional ³²P microparticles implantation has demonstrated significant survival, disease control and downstaging benefits of combination therapy with chemotherapy and ³²P microparticle implantation.

Disclosure

Nil

Introduction

Hormonal exposure influences cancer initiation and progression in several organs, including the pancreas. The association between gynecological factors and the onset of pancreatic adenocarcinoma (PDAC) is conflicting, with some studies showing a reduced risk of PDAC with the use of hormonal replacement therapy (HRT) or with having had a late-onset menopause. Nonetheless, the association between gynecological factors and disease prognosis has not yet been investigated. Our objective was to evaluate whether gynecological/reproductive factors affect PDAC prognosis.

Aims & Methods

This was a single-center retrospective analysis of a prospectively maintained database of PDAC patients. Risk factors were assessed via questionnaires regarding gynecologic/reproductive factors (age at menarche, menopause, years of fertility, breastfeeding, pregnancy, miscarriages, use of oral contraceptives (OC) or HRT), medical history, and prognosis were evaluated with follow-up visits and/or telephonic calls. Continuous variables were investigated using the Mann–Whitney test, and factors associated with survival probability were evaluated using Cox's proportional hazards model, adjusting for potential confounders.

Results

228 PDAC women were analyzed, with mean age at diagnosis being 68. The most frequent stages were borderline resectable (35.9%) and locally advanced (25.4%), with a median overall survival (OS) of 14 months. The age of PDAC onset for patients with previous use of OC was significantly lower than that of non-users (63 years vs. 72; p<0.0001), and OC use was associated with a trend toward increased survival (HR 0.6; 95%CI: 0.35-1.03; p=0.06). In addition, previous use of HRT was associated with a reduced risk of recurrence or progression (HR, 0.4; 95%CI: 0.26-0.99; p=0.001). No differences in survival or progression-free probability were observed with the other factors.

Conclusion

This is the first study to evaluate whether gynecological/reproductive factors are associated with the prognosis of PDAC patients, with the use of OC and HRT being the most relevant factors. Previous OC users had a significantly lower onset age for PDAC and a borderline significant association was seen with increased survival. Additionally, HRT use is associated with a reduced risk of tumor recurrence or progression. These data need to be confirmed, and the potential mechanisms need to be elucidated.

Introduction

Diabetes mellitus (DM) is a substantial risk factor for pancreatic cancer (PC). Concurrently, aspirin has been implicated to have chemopreventive effect against cancer of digestive system. However, studies regarding the effect of aspirin on mitigating PC risk among DM populations remain scant.

Aims & Methods

We aimed to examine whether regular use of aspirin was associated with a reduced risk of PC after adjusting for known risk factors among type 2 diabetes (T2D) patients.

This was a territory-wide, retrospective cohort study of newly diagnosed T2D patients between 2001 and 2015 in Hong Kong. Exclusion criteria included <18 years old, history of PC, pancreatic neuroendocrine tumor, serous cystadenoma, chronic or acute pancreatitis, and pancreatic cyst. The outcome of interest was pancreatic cancer. Adjusted hazard ratios (aHRs) for outcomes associated with aspirin use were calculated using multivariable Cox regression models. Aspirin use was treated as a time-varying covariates (≥180 days use at each yearly interval) in the analysis to address and minimize immortal-time bias.

Results

We identified 342,920 T2D patients (52.2% male, mean age: 58.8±11.6 years), including 43,634 (12.7%) aspirin users. During a mean follow-up of 11.1±4.2 years, 1,114 (0.3%) patients developed PC, with an incidence rate of 2.92 per 10,000 person-years. Aspirin use was associated with a reduced PC risk (HR 0.55, 95%CI 0.46-0.66). When compared with the reference group (never use), a lower risk was observed with increasing frequency, with the exception of daily use. In addition, longer durations of aspirin use were associated with a progressively lower PC risks (HR 0.83, 95%CI 0.71-0.96, for less than five years of use; HR 0.56, 95%CI 0.45-0.69, for five to ten years of use; and HR 0.27, 95%CI 0.20-0.36, for ten or more years of use. Both frequency and duration of aspirin use demonstrated statistically significant trends (P_trend <0.001) (Table 1).

Table 1. HRs and 95% CIs for the association between frequency and duration of aspirin use and risk of pancreatic cancer

Aspirin use	No. of patients (n=342,920)	No. of PC (n=1,114)	HR (95% CI)	P*	Ptrend*
Frequency Never user	219,674	736	ref	-	<0.001
<Monthly use	13,809	52	0.66 (0.50-0.88)	0.004
Monthly to <weekly use	13.274	44	0.59 (0.43-0.80)	<0.001
Weekly to <daily use	73,232	201	0.54 (0.46-0.63)	<0.001
Daily use	22,931	81	0.90 (0.69-1.16)	0.401
Duration (years) Never user	219,674	736	ref	-	<0.001
<5	54,029	223	0.83 (0.71-0.96)	0.015
5 - <10	40,003	99	0.56 (0.45-0.69)	<0.001
≥10	29,214	56	0.27 (0.20-0.36)	<0.001

*Cox proportional hazards model was used to calculate the P values. Adjusted covariates included age, sex, lifestyle factors (body mass index, smoking, and alcohol use), metabolic disorders (dyslipidemia and hypertension), time-weighted mean HbA1c, DM complications, cardiovascular diseases, other anti-diabetic medications, non-aspirin non-steroidal anti-inflammatory drugs, and statins.
Abbreviation: CI, confidence interval; HR, hazard ratios; PC, pancreatic cancer; ref, reference

Conclusion

Aspirin use was associated with a reduction in PC risk among T2D patients, which was dependent on both frequency and duration of use. Notably, this trend was observed with increased frequency of use, with the exception of daily use. Further studies are warranted to assess long-term effects and potential risks.