bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of malnutrition at diagnosis with survival among older adults with pancreatic cancer.
Authors: Doshi Apoorva , Martin Landon , Williams Grant Richard , Giri Smith
Published: January 2025

680

Background:
Malnutrition is common among older adults newly diagnosed with pancreatic cancer. However, the implications of malnutrition among this vulnerable population are poorly understood. We sought to understand the association between malnourishment at diagnosis and overall survival (OS) among older adults with pancreatic cancer.
Methods:
We included adults aged ≥ 60 years with newly diagnosed pancreatic cancer, who were enrolled in the University of Alabama at Birmingham (UAB) Cancer and Aging Resilience Evaluation (CARE) registry between October 2017 and April 2024. To assess nutritional status, we administered an abridged version of the Patient-Generated Subjective Global Assessment (abPG-SGA) to patients at baseline prior to receiving chemotherapy. Using abPGSGA scores, we categorized patients as either normal (score ≤ 5) or malnourished (score ≥ 6). All participants were followed until death or until the cutoff date of July 10, 2024. We employed Kaplan-Meier survival analysis to estimate overall survival (OS) for both malnourished and non-malnourished groups and compared them using log-rank test. Additionally, we built multivariable Cox proportional hazards models to test the association between malnutrition and OS, while controlling for age at diagnosis, sex, race/ethnicity, and cancer stage.
Results:
A total of 274 patients were included; the median age at diagnosis was 70 (interquartile range, IQR: 65-75) years with 52% males, 75% non-Hispanic White and 52% with Stage IV disease at diagnosis. At baseline, 59% of patients were malnourished, and the median abPGSGA score was 8 (IQR 4-14). Patients who were malnourished had a similar demographic and clinical characteristics as compared to those without malnutrition. Over a median follow up of 36 months, a total of 202 patients (74 %) died. The median overall survival (OS) was significantly lower for malnourished patients at 13 months compared to 21 months for non-malnourished patients (log-rank test, p < .001). After adjusting for potential age, sex, race/ethnicity and cancer stage, malnutrition at diagnosis remained independently associated with worse survival outcomes (adjusted HR: 1.762; 95% CI: 1.316–2.358; p < .001).
Conclusions:
Our study reports that malnutrition at baseline is significantly associated with worse overall survival in older adults with pancreatic cancer. These findings underscore the importance of early nutritional assessment and intervention to enhance outcomes in this population.
Redefining the use of a first-line FOLFIRINOX-like regimen in older patients with metastatic pancreatic cancer.
Authors: Winer Arthur , Ioffe Dina , Ruth Karen J , Ross Eric A. , Bynum Katrina , Mikkelsen Eli , Astsaturov Igor A. , Cann Christopher G , Vijayvergia Namrata , Wookey Vanessa , Cannon Timothy Lewis , Wadlow Raymond Couric , Huynh Jasmine , Lee Yoomi , Dotan Efrat
Published: January 2025

681

Background:
Prospective elderly-specific data for treating pancreatic cancer are scarce. First-line treatment with triplet chemotherapy (e.g., FOLFIRINOX) is often too toxic for older adults (OA). An alternating regimen of FOLFOX and FOLFIRI (aFOLFIRINOX) has demonstrated efficacy and decreased toxicity in patients with colon cancer. This ongoing multicenter phase II trial evaluates the tolerability and efficacy of aFOLFIRINOX in OA with metastatic pancreatic adenocarcinoma (mPDAC). Herein we report the interim safety analysis results.
Methods:
Eligible patients (goal n=37) ≥65 years old with measurable untreated mPDAC, ECOG PS 0-2, receive standard doses of FOLFOX alternating with FOLFIRI every 2 weeks for up to 6 months. Patients can continue treatment thereafter at the discretion of their physician. The primary endpoint is rate of treatment-limiting grade ≥3 adverse events (TLAE) per CTCAE v5.0 in the first 8 weeks of therapy. These toxicities are defined as treatment-related grade 3 non-hematologic AE persisting > 2 weeks despite best supportive care, grade 3 anemia or thrombocytopenia, grade >3 neuropathy, or any grade > 4 AE. The study is powered to detect a 20% improvement in grade ≥3 TLAE: null vs alternate: 45% vs 65% of patients without TLAE at 8 weeks. Secondary endpoints include progression free & overall survival (PFS & OS) and objective response rate (ORR). FACT-G and PROMIS-10 quality of life (QOL) surveys and geriatric assessments are collected and will be correlated with treatment outcomes.
Results:
21 eligible patients were included in the interim safety analysis: 11 male, 10 female; median age:73 (range 65-82); 18 patients had ECOG PS 0-1. 16 (76%) patients did not experience TLAE as defined above. TLAE included neutropenia, thromboembolism, and hypokalemia, and are similar to reported toxicity with FOLFOX and FOLFIRI in this patient population. One patient died of their disease within 8 weeks of treatment initiation and another within 2 weeks due to pulmonary embolism deemed unrelated to treatment. Of the 18 patients evaluable for response, ORR was 11% (partial response: n =2), Disease Control Rate was 89% (stable disease: n =14). 7 patients completed 6 months of treatment on study.
Conclusions:
The interim safety analysis of this clinical trial fulfilled the predefined futility rule without excess treatment-limiting or unexpected toxicity among OA with mPDAC treated with first-line aFOLFIRINOX, suggesting this may be a reasonable treatment option in this patient population. Trial is ongoing for evaluation of efficacy data of this regimen.
Clinical trial information: NCT05360732
.
Optimizing clinical trial design to mitigate racial disparities in pancreatic cancer clinical trial enrollment.
Authors: Pu Tracey , Gustafson Alexandra M. , Coleman Kendra N , Russell Nicole , Eng Oliver , Snyder Rebecca A
Published: January 2025

682

Background:
Participation in pancreatic ductal adenocarcinoma (PDAC) clinical trials remains dismal among patients from minoritized groups. This study aimed to investigate if clinical trial design, including eligibility criteria, affects representation of minoritized populations.
Methods:
United States Phase I-IV PDAC clinical trials between 2000-2020 were extracted from the ClinicalTrials.gov database. The Surveillance, Epidemiology, and End Results (SEER) database was used to determine cancer incidence linked with years of trial enrollment. Enrollment fraction (EF) was defined as the number of trial participants divided by the incidence of PDAC in each racial and ethnic group. Representation Quotient (RQ) was defined as the proportion of trial participants divided by proportion of PDAC incidence for each subgroup, where underrepresentation was RQ <1.0.
Results:
8451 patients from 228 unique PDAC clinical trials were analyzed. 55.7% (n=128) and 44.3% (n=102) trials reported racial and ethnic demographic data, respectively. Non-Hispanic Black (NHB), Non-Hispanic Asian/Pacific Islander (NHAPI), Non-Hispanic American Indian/Alaskan Native (NHAIAN), and Hispanic patients were underrepresented (Table). NHB patients were more likely to be underrepresented in trials for metastatic PDAC disease (89.4% vs. 73.8% of trials, p=0.035). NHB patients demonstrated an increase in median RQ (0.28 vs. 0.48) in trials from 2000-2010 vs. 2011-2020, while Hispanic patients had a decreased median RQ (0.36 vs. 0.25). Trials with renal insufficiency exclusion criteria without cutoffs or explicit methodology were more likely to accrue NHB patients (RQ 0.88 vs. 0.46, p=0.02), whereas trials that used a creatinine cutoff or the modified Cockcroft-Gault (CG) formula did not significantly affect RQ. Other eligibility criteria including cardiac history, HIV, Hepatitis B/C, and receipt of neoadjuvant therapy did not significantly affect RQ for any racial or ethnic group. Trial location and funding source did not affect RQ for any group.
Conclusions:
Systemic barriers persist in minority enrollment in PDAC clinical trials. Clinical trial design optimizing inclusive eligibility requirements is a first feasible step in increasing minority clinical trial enrollment.

Racial and ethnic representation in pancreatic ductal adenocarcinoma clinical trials.

Enrollment Fraction (Median, IQR)
Representation Quotient (Median, IQR)

NHW
0.28 (0.12-0.62)
1.17 (1.09-1.24)

NHB
0.15 (0-0.33)
0.47 (0-0.87)

NHAPI
0 (0-0.23)
0 (0-0.45)

NHAIAN
0 (0-0)
0 (0-0)

Hispanic
0.07 (0-0.21)
0.26 (0-0.68)

*Abbreviations: Interquartile Range (IQR), Non-Hispanic Black (NHB), Non-Hispanic Asian/Pacific Islander (NHAPI), Non-Hispanic American Indian/Alaskan Native (NHAIAN).
Impact of intrathecal targeted drug delivery (ITDD) on oral morphine equivalents and pain scores in advanced pancreatic cancer pain.
Authors: Eye Nicole , Metz Tim , Arneson Francine , McKean Heidi Ann
Published: January 2025

686

Background:
Pancreatic cancer accounts for approximately 3% of all cancers and affects ~64,000 adults in the United States each year. Seventy five percent of patients present with abdominal pain, leading to diagnosis. This is one of the most painful cancers, with pain severity strongly correlating to prognosis. Severe intractable abdominal pain negatively impacts quality of life. Traditionally, opioids have been used as the first line agent for the treatment of severe abdominal pain. However, opioids carry significant risk and often unwarranted side effects. With escalating doses to treat refractory pain there is also potential for unintentional overdose. Intrathecal targeted drug delivery (ITDD) provides pain medications directly to the intrathecal space limiting systemic side effects. Our study aimed to determine the impact ITDD has on pain scores as well as the amount of systemic opioid needed in patients with advanced pancreatic cancer.
Methods:
A retrospective review was conducted on 217 advanced cancer patients that underwent ITDD placement from March 2019 through July 2024. Thirty- five patients with a diagnosis of pancreatic cancer met inclusion criteria. Pain scores and oral morphine equivalent (OME) use was evaluated at baseline (prior to ITDD), at 1 month and 3 months post ITDD implant. A numeric scale of 0-10 was used to determine pain scores, while a comprehensive chart review and patient response was used to determine OME use.
Results:
We found that post ITDD placement, pain scores were reduced on average by 4.55 points at 1month and 4 points at 3-months after implantation. This was statistically significant with a two-paired t-test analysis (p <0.05). Post ITDD placement, there was a 96.7% reduction in OME at 1-month (p <0.005) and 98.1% reduction in OME at 3 months (p <0.04).
Conclusions:
Despite the small sample size of patients, ITDD showed a significant reduction in pain scores and OME use compared to baseline with systemic opioid use only in patients with advanced pancreatic cancer. This reduction appeared to be maintained for 3 months post ITDD placement. Further studies conducted on a larger sample size would be beneficial to demonstrate statistical outcomes of ITDD therapy on pain scores and OME use.
Clinical outcomes of immunotherapy in metastatic pancreatic carcinoma: A systematic review and meta-analysis.
Authors: Shahzad Moazzam , Vyas Abhinav , Dave Prashil , Irfan Sohaib , Khan Abat , Chaudhry Ahtshamullah , Qasim Hana , Khizer Umair , Khalid Muhammad Fareed , Shabbir Muhammad , Jaglal Michael Vishal
Published: January 2025

688

Background:
Metastatic pancreatic carcinoma is one of the most challenging malignancies to treat. Traditional treatment modalities such as chemotherapy and radiation therapy have shown limited efficacy. This meta-analysis aims to investigate immunotherapy as a potential therapeutic option for metastatic pancreatic carcinoma.
Methods:
PubMed, Cochrane, Embase, and Clinicaltrials.gov were searched as per PRISMA guidelines. Data extraction was conducted independently by two reviewers, and any discrepancies were resolved through discussion. Pooled analysis was performed using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2).
Results:
834 patients from the 17 studies reporting immunotherapy outcomes in metastatic pancreatic carcinoma were included in this systematic review and meta-analysis. The studies included (There were) were 4 phase I (23.5%), 2 phase Ib (11.8%), 1 phase Ib/II (5.9%), and 5 phase II (29.4%), 1 retrospective study (5.9%) and 4 prospective studies (23.5%). The median age of the patients was 61 years and 55.6% (398/716) were male. Immunotherapies included were GVAX, tremelimumab, Mesothelin-specific Chimeric Antigen Receptor T cells, durvalumab, pembrolizumab, canerpaturev, Sotigalimab, nivolumab, CO-1.01, allogeneic natural killer cell immunotherapy, Anti-EGFR chimeric antigen receptor-modified T cells, bispecific antibody armed T cells, and clivatuzumab tetraxetan. The median follow-up duration was 17.8 months. The median overall survival was 7.9 months, and the median progressive-free survival was 4.6 months. The pooled overall response rate was calculated at 16% (95% CI 0.09-0.26, I2=70, p<0.01, n= 426) and the pooled partial response rate was 13% (95% CI 0.09-0.26, I2= 67%, p<0.01, n= 272). The pooled stable disease was calculated to be 28% (95% CI, 0.2-0.39, I2= 59%, p<0.01, n=277). The pooled progressive disease was 36% (95% CI, 0.23-0.52, I2=34%, p=0.22, n=68). The most common overall adverse effects were anemia, diarrhea, and thrombocytopenia.
Conclusions:
This meta-analysis demonstrates that novel immunotherapies have promising results on metastatic pancreatic cancer. Future new clinical trials with a follow-up on current early-phase results are needed.
A multi-institutional retrospective study evaluating clinical outcomes and prognostic factors in patients with metastatic appendiceal adenocarcinoma.
Authors: Fukuda Koshiro , Takashima Atsuo , Osumi Hiroki , Awatsu Takahito , Ooki Akira , Hirano Hidekazu , Fukuoka Shota , Udagawa Shohei , Wakatsuki Takeru , Shoji Hirokazu , Chin Keisho , Fujishiro Mitsuhiro , Kato Ken , Boku Narikazu , Yamaguchi Kensei , Shinozaki Eiji
Published: January 2025

69

Background:
Appendiceal adenocarcinoma (AA), a rare cancer, has been reported to have high incidences of mucinous type histology, peritoneal metastasis, and relatively good prognosis. However, its chemotherapeutic efficacy and prognostic factors is not well known.
Methods:
We collected patients with metastatic AA treated with chemotherapy between February 2005 and March 2023 in two high volume cancer centers in Japan. We retrospectively analyzed the clinical outcomes of the chemotherapy of patients with metastatic AA and the clinical factors associated with treatment efficacy and prognosis by multivariate analysis.
Results:
A total of 66 patients with a median age of 54 years, were enrolled. 40 patients (60.6%) received an oxaliplatin-based regimen in combination with bevacizumab. The response rate was 22.0% and the disease control rate was 87.8%. With median follow-up period was 15.5 months [1.9-103.1], median progression-free survival (PFS) was 10.9 months [95% CI: 7.2-15.2] and median overall survival (OS) was 23.0 months [95% CI: 19.6-35.8]. 77.4% of patients received subsequent chemotherapy. In multivariate analysis, pretreatment carcinoembryonic antigen (CEA) and/or carbohydrate antigen 19-9 (CA19-9) were associated with significantly shorter PFS (HR: 2.93,
P
= 0.0049). Presence of primary tumor (HR:2.50,
P
= 0.015), ECOG performance status (PS) ≥1 (HR: 2.67,
P
= 0.0091), moderate to massive ascites (HR: 3.06,
P
= 0.0043) and high tumor marker levels (HR: 2.46,
P
= 0.026) were associated with significantly shorter OS. Classifying the patients by number of these prognostic factors for OS into three groups (0, 1-2, and 3-4), the group with prognostic factors (1-2 or 3-4) had a significantly shorter prognosis compared to the group without any these factors (0 vs 1-2: HR: 4.70,
P
= 0.038, 0 vs 3-4: HR: 17.6,
P
< 0.01). In addition, the group with 3-4 prognostic factors had relatively lower rate of subsequent chemotherapy ratio than the group without these factors (66.7% vs 100%,
P
= 0.25).
Conclusions:
We confirmed our treatment outcomes were consistent with previous studies and elevation of tumor markers presence of primary tumor, ECOG PS ≥1, moderate to massive ascites were significantly associated with survival in patients with metastatic AA.
Overall survival (OS) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line (1L) FOLFIRINOX (FFX): Bridging the gap between the NAPOLI 3 trial and real-world practice.
Authors: Cockrum Paul , Chang Rose , Yu Louise Huafeng , Xu Chunyi , Duh Mei Sheng , Kim George P.
Published: January 2025

690

Background:
NALIRIFOX (liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin) demonstrated significantly improved OS compared to 1L gemcitabine + nab-paclitaxel in the phase 3 NAPOLI 3 trial (NCT04083235). The median OS (95% CI) in the NALIRIFOX intention-to-treat population (N= 383) was 11.1 (10.0, 12.1) months. However, the relative efficacy of NALIRIFOX versus FFX (irinotecan + 5-fluorouracil/leucovorin + oxaliplatin), another standard of care for 1L treatment of mPDAC, has not been studied. To further contextualize findings from NAPOLI 3 trial, the current study described OS among patients treated with 1L FFX in the real-world setting.
Methods:
Three cohorts of patients with mPDAC treated with 1L FFX were identified from the Flatiron Health database. The all-comer cohort included all adult patients with mPDAC treated with 1L FFX since January 2014. Among them, the trial-aligned cohort included patients with mPDAC treated with 1L FFX between January 1, 2020 and July 31, 2022 (to align with the time period of NAPOLI 3 trial) who met the eligibility criteria of NAPOLI 3. Finally, a subgroup of patients in the trial-aligned cohort who received modified FFX (mFFX) regimen composed the trial-aligned mFFX cohort. OS was assessed using Kaplan-Meier analysis.
Results:
The all-comer cohort consisted of 3,271 patients. The trial-aligned cohort included 219 patients, of whom 154 (70%) were treated with mFFX. The distribution of baseline characteristics was similar across three cohorts (Table). The median age of the trial-aligned cohort was 65 years old, with 46% of patients being female, 67% being White, and 47% having ECOG score of 1. The median OS (95% CI) in the all-comer cohort and trial-aligned cohort was 9.0 (8.5, 9.3) months and 9.1 (7.8, 10.9) months, respectively; the median OS (95% CI) was 8.6 (7.3, 10.5) months in the trial-aligned mFFX cohort.
Conclusions:
NALIRIFOX regimen in the NAPOLI 3 trial showed numerically improved OS compared to FFX, including mFFX, in the real-world setting. Analysis adjusting for baseline characteristics are warranted and will provide further insights for the comparative efficacy of the two regimens.

Characteristics of real-world FOLFIRINOX cohorts.

All-comer cohort(N=3,271)
Trial-aligned cohort(N=219)
Trial-aligned mFFX cohort (N=154)

Baseline characteristics

Age, years, mean (SD)
63.5 (9.0)
64.6 (8.2)
65.1 (8.5)

Female, n (%)
1,377 (42.1)
100 (45.7)
68 (44.2)

White, n (%)
2,118 (64.8)
146 (66.7)
100 (64.9)

ECOG score = 1, n (%)
1,327 (48.9)*
103 (47.0)
77 (50.0)

Endpoint

Median OS, months (95% CI)
9.0 (8.5, 9.3)
9.1 (7.8, 10.9)
8.6 (7.3, 10.5)

Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; OS, overall survival; SD, standard deviation.

*Proportion calculated based on 2,711 patients with ECOG available at baseline.
Real-world excess costs associated with hematologic adverse events (hAEs) during first-line (1L) treatment of metastatic pancreatic adenocarcinoma (mPDAC) with FOLFIRINOX (FFX), FFX without 5FU bolus, and gemcitabine+nab-paclitaxel (GnP).
Authors: Dennen Syvart , Masek Marty , Cockrum Paul , Paluri Ravi Kumar
Published: January 2025

693

Background:
During 1L treatment of mPDAC with FFX and GnP, hAEs can harm patients (pts) and accrue excess costs to the health system, i.e., costs beyond those of a treated pt without the hAE. This study examined excess total cost of care (TCoC) and components (total inpatient; outpatient transfusion, granulocyte colony-stimulating factor [G-CSF], and thrombopoietic growth factor [TGF]) for three key hAEs (anemia, neutropenia, thrombocytopenia) during 1L FFX, FFX without 5FU bolus (FFXnb), and GnP.
Methods:
This retrospective observational study utilized Optum Market Clarity claims + EHR linked data. Inclusion criteria were: adult pts diagnosed with mPDAC between 1/1/2015 and 5/31/2023; initiated 1L FFX, FFXnb, or GnP within -14 to +90 days (index date); ≥6 months pre-index enrollment. hAEs during 1L were detected from lab values and grouped all grades combined. Pts were divided into “hAE groups” and “ref. groups” with and without any of the three hAEs of interest, respectively. Pts were matched 1:1 without replacement based on follow-up time. Costs were measured from the day a lab value indicated an hAE until 30 days later and during the corresponding times for ref. pts, then standardized to per-pt-per-month (PPPM). This study did not adjust for differences in pt characteristics.
Results:
Means and differences (95% CI) in TCoC following hAE detection for each regimen and hAE of interest are presented (Table). PPPM TCoC was greater for all three regimens and hAEs, driven by 1.6–4.9 times higher inpatient costs. Inpatient costs were $5,614 and $5,665 higher for FFX and FFXnb neutropenia pts vs. ref. groups. Use of outpatient G-CSF at any time during 1L was lower for FFX and FFXnb neutropenia pts, at 76% and 63% vs. 83% and 75% in the ref. groups, respectively. Outpatient TGF and transfusions were rare.
Conclusions:
All hAEs showed excess PPPM TCoC across regimens, driven by inpatient costs. FFX and FFXnb neutropenia pts had lower overall utilization of outpatient G-CSF but higher inpatient costs following detection of neutropenia, which may represent an opportunity for improved pt management.

Excess TCoC of hAEs.

AE (any grade)
FFX, hAE group(N=199, 127, 157)
FFX, ref. group(N=199, 127, 157)
Diff. (95% CI)
FFXnb, hAE group(N=202, 106, 137)
FFXnb, ref. group (N=202, 106, 137)
Diff. (95% CI)
GnP, hAE group (N=406, 268, 270)
GnP, ref. group (N=406, 268, 270)
Diff. (95% CI)

AnemiaTCoC, mean
30,561
22,310
8,251 (4,396–12,106)
31,866
23,380
8,487(4,007–12,966)
32,662
27,697
4,965(1,320–8,610)

NeutropeniaTCoC, mean
30,382
24,952
5,430(-31–10,891)
26,588
22,571
4,017(-1,288–9,322)
32,975
31,051
1,924(-4,629–8,477)

ThrombocytopeniaTCoC, mean
30,566
22,535
8,031 (3,895–12,166)
31,434
22,958
8,476(2,962–13,991)
33,863
30,751
3,113(-3,310–9,536)
Assessing impact of postoperative outcomes and quality of life on decisional regret after resection of pancreatic ductal adenocarcinoma.
Authors: Li Judy , Li Thomas M , Geffner Adam , Neugarten Sophie , Correa Camilo , Sarpel Umut , Labow Daniel M , Gunasekaran Ganesh , Schwartz Myron E. , Tabrizian Parissa , Hiotis Spiros P , Park James O , Cohen Noah A
Published: January 2025

699

Background:
Surgery is potentially curative for patients with localized pancreatic ductal adenocarcinoma (PDAC). Given the high rate of complications, decline in quality of life (QoL) postoperatively, and high rates of recurrence, clear preoperative communication and expectation setting is critical. This study investigates clinical outcomes that affect postoperative decisional regret (DR) in patients with PDAC.
Methods:
This mixed-methods study investigates the impact of clinical outcomes and QoL on the degree of DR in patients with PDAC who have undergone curative-intent resection at least 6 months prior to study recruitment. Patients completed validated surveys assessing DR and QoL by the European Organization for Research and Treatment of Cancer (EORTC). Groups are stratified by presence or absence of DR, assessed by the Decisional Regret Scale (DRS). Characteristics and survey scores were compared by chi-square, independent t-test, and median test. Narrative responses were thematically analyzed. Given significant findings, results of this interim analysis are reported below.
Results:
45 patients met inclusion criteria and completed all questionnaires. 19 (42.2%) patients expressed regret about their decision to pursue curative-intent surgery, with 5 patients expressing moderate to severe regret (DRS ≥ 25). There was no significant difference in median postoperative timing of survey completion between groups (56 months in DR group vs 34 months, P=0.465). Baseline characteristics, medical treatments, and operative approaches were similar. Both groups had similar recurrence rates at time of survey completion. While 30 and 90 day readmission rates were similar, a greater proportion of the DR group had 30 day complications (42.1% vs 15.4%, P=0.045). Those expressing regret reported poorer physical functional status (mean score 79.30 ± 18.84 vs 92.31 ± 10.27, P=0.011) and greater impact on social activities (mean score 67.54 ± 33.55 vs 84.67 ± 19.19, P=0.038). Thematic analysis of narrative responses revealed that a majority of patients expressed a strong desire to have a greater focus on potential QoL changes during preoperative discussions.
Conclusions:
Patients expressing postoperative DR experienced more 30 day complications, and still report lasting effects on their current physical status and social activities. This emphasizes the importance of thorough preoperative counseling on surgical risks and potential changes in postoperative QoL so that patients may make the best informed decision.
Real world characteristics and outcomes of patients with BRAFV600E-mutant metastatic colorectal cancer in Australia: The COALA project.
Authors: Hitchen Nadia , Wong Hui-Li , Wong Rachel , Shapiro Jeremy David , Burge Matthew E. , Nott Louise M. , Lee Belinda , Lim Stephanie Hui-Su , Wong Shu Fen , Caird Susan , Wong Vanessa , Rainey Natalie Heather , Khattak Adnan , Mandaliya Hiren A. , Hayes Theresa M. , Torres Javier , Jalali Azim , Campbell Angus , Gibbs Peter , Tie Jeanne
Published: January 2025

70

Background:
BRAFV600E-mutant metastatic colorectal cancer (mCRC) represents a unique molecular subset with poor prognosis and less responsiveness to chemotherapy. The BEACON CRC study demonstrated that encorafenib plus cetuximab (EC) significantly improved overall survival (OS) compared to FOLFIRI plus cetuximab in BRAF-mutant mCRC as 2
nd
or 3
rd
line therapy. This combination was reimbursed in Australia from January 2022.
Methods:
We analysed data from the Australian TRACC mCRC clinical registry, encompassing patients (pts) with BRAF-mutant mCRC diagnosed in Australia from 2009 to 2024 at 31 hospitals. We assessed baseline demographics, uptake of EC following reimbursement and efficacy analysis of progression-free survival (PFS) and OS for pts that received EC and those who did not. Pts receiving EC on a clinical trial were excluded.
Results:
Among 2,800 pts with known BRAF mutation status, 365 (13%) were BRAF mutated. The BRAF mutant cohort had a median age of 63 years, with a significantly higher mutation rate in the 20-39 age group than other age groups (age 20-39, 25.5%; age 40-59, 10%; age 60+, 13.2%; P<0.001); 54.5% were female, 58% right-sided tumours, 64% with synchronous metastatic disease and 21.7% deficient mismatch repair (dMMR). Overall, 314 (86%) pts with BRAF mutant tumours and 2,079 (85%) BRAF wild-type (WT) tumours received 1
st
line treatment, and 156 (43%) BRAF mutant and 1,144 (47%) BRAF WT pts received 2
nd
line therapy. The median OS from diagnosis was 17.3 months for BRAF mutant pts versus 34.7 months for BRAF WT pts (p < 0.0001). All dMMR BRAF mutant pts received 1
st
line pembrolizumab since its reimbursement in August 2021. Among 41 BRAF mutant pts progressing on 1
st
line therapy since January 2022,(32 pMMR, 9 dMMR), 33 (80%) were subsequently treated with EC, and 4 (10%) did not receive further treatment. OS from the start of 2
nd
line therapy was 9.6 months (95% CI: 7.2-12.5) for pts who received EC and 7.1 months (95% CI: 6.4-8.6) for those who received other systemic treatment. Median PFS for pts receiving EC was 4.6 months (95% CI: 3.4-5.8) and 3.3 months (95% CI: 2.5-5.3) for other 2
nd
line treatments.
Conclusions:
mCRC pts younger than 40 have a high rate of BRAF mutation, where 1 in 4 tumours harbour the mutation. BRAF mutant mCRC has a poorer outcome than BRAF WT despite a similar proportion receiving 1
st
and 2
nd
line treatment. The majority of eligible BRAF mutant mCRC pts received EC following reimbursement in Australia, with PFS and OS outcomes consistent with the BEACON CRC trial.
Disease-free survival as a surrogate endpoint for overall survival in adults with early-stage pancreatic cancer: A trial-level surrogacy analysis.
Authors: Leite da Silva Luís Felipe , Almeida Luiz F. Costa , Noronha Mariana Macambira , da Conceição Lucas Diniz , Belotto Marcos , Megid Thais Baccili Cury , Peixoto Renata D'Alpino
Published: January 2025

708

Background:
In early-stage cancer, overall survival (OS) is the gold-standard endpoint for assessing therapeutic efficacy. However, long follow-up periods make OS challenging and costly to measure in clinical trials. Disease-free survival (DFS), which captures the time to recurrence or death, has been proposed as a surrogate endpoint for OS in early-stage pancreatic cancer (PC). This surrogacy relationship could allow for a more rapid assessment of treatment benefits, but its validity requires robust analysis across clinical trials. Understanding the trial-level correlation between DFS and OS is crucial to optimizing trial design and grant accelerated drug approval.
Methods:
We conducted a systematic search of Embase, PubMed, and Cochrane databases through August 2024, identifying randomized controlled trials (RCTs) that evaluated adjuvant or neoadjuvant systemic therapies in adult patients with PC. Included studies reported both OS and DFS outcomes. Hazard ratios for DFS (HR_DFS) were analyzed as surrogate endpoints for OS (HR_OS). Statistical analyses utilized linear regression models, weighted by trial sample sizes, to determine the strength of the correlation. Surrogacy strength was categorized by the coefficient of determination (R²), with R² ≥ 0.7 indicating a strong correlation, 0.69–0.5 a moderate correlation, and values < 0.5 indicating weak correlation.
Results:
Out of 3,048 studies screened, 30 RCTs met the inclusion criteria, comprising 5,275 patients in adjuvant therapy trials and 557 patients in neoadjuvant therapy trials. The median follow-up duration ranged from 16 to 53.5 months, with 12 phase II trials included. Overall, DFS showed strong surrogacy for OS in adjuvant trials (R² = 0.70; 95% CI, 0.50–0.91). Subgroup analysis indicated strong correlation in phase III trials (R² = 0.71; 95% CI, 0.46–0.96) and moderate correlation in phase II trials (R² = 0.67; 95% CI, 0.21–1.00). The strongest surrogacy was observed in studies incorporating adjuvant radiation therapy (R² = 0.81; 95% CI, 0.52–1.00). In the analysis of neoadjuvant trials, HR-DFS also presented strong correlation with OS (R² = 0.90; 95% CI, 0.56–1.00).
Conclusions:
There is a strong trial-level correlation between DFS and OS in both adjuvant and neoadjuvant therapy trials for early-stage pancreatic cancer, particularly in phase III studies and trials incorporating adjuvant radiation therapy. However, the strength of this surrogacy varies depending on the treatment setting and trial design.
Optimal preoperative treatment strategy for conversion surgery in unresectable locally advanced pancreatic cancer: A project study by the Japanese Society of Hepato-Biliary-Pancreatic Surgery.
Authors: Yasuda Satoshi , Satoi Sohei , Takami Hideki , Hirano Satoshi , Akita Hirofumi , Takahahshi Yu , Matsumoto Ippei , Unno Michiaki , Ninomiya Riki , Kawai Manabu , Nagakwa Yuichi , Sugiura Teiichi , Yamamoto Naoto , Nagai Minako , Uemura Kenichiro , Imamura Masafumi , Ozu Naoki , Nakamura Masafumi , Ohtsuka Masayuki , Sho Masayuki
Published: January 2025

718

Background:
Conversion surgery (CS) for unresectable locally advanced pancreatic cancer (UR-LAPC) has been widely accepted when feasible. However, optimal preoperative treatment strategies remain unclear. To determine the most effective preoperative approach for UR-LAPC in the current treatment landscape, we conducted a project study in the Japanese Society of Hepato-Biliary-Pancreatic Surgery.
Methods:
We analyzed 465 UR-LAPC patients who underwent CS following chemotherapy with FOLFIRINOX (FFX), gemcitabine plus nab-paclitaxel (GnP), or modified regimens between 2015 and 2020 across 84 Japanese board-certified training institutions. Overall survival (OS) was the primary endpoint. We used the Kaplan-Meier method for estimating survival analyses, the Cox proportional hazards model for multivariate analyses, and Maximally Selected Rank Statistics to determine the optimal preoperative treatment duration.
Results:
Median OS was 43.8 months, with a 5-year survival rate of 37.2%. The optimal preoperative treatment duration was 6.1 months. Patients receiving >6 months of preoperative treatment (n=350) showed significantly better median OS and recurrence-free survival (RFS) compared to ≤6 months (n=115) (50.4 vs 29.7 months and 15.6 vs 9.1 months, respectively; both
P<0.001
). FFX-based regimens (n=116) showed better OS and RFS than GnP-based regimens (n=349) (65.0 vs 36.5 months and 19.3 vs 12.4 months, respectively; both
P<0.01
). Multivariate analysis identified preoperative treatment >6 months (HR 0.53, 95% CI 0.407-0.697,
P<0.001
) and initial FFX-based regimens (HR 0.63, 95% CI 0.464-0.843,
P=0.002
) as independent prognostic factors. Additional favorable factors included normal CA19-9 and CEA levels, PNI>45 before CS, adjuvant chemotherapy, R0 resection, and Evans grade III/IV.
Conclusions:
This large-scale retrospective study has demonstrated that preoperative treatment duration >6 months and the use of FFX-based regimens as initial treatment were associated with improved survival outcomes in UR-LAPC patients undergoing CS. These findings provide critical information for considering CS in UR-LAPC patients, especially in current clinical practice.
Neoadjuvant therapy in borderline resectable and resectable pancreatic cancer.
Authors: Dhamija Kriti , Awuah Kojo-Frimpong B. , Marwaha Alexander , Kharoud Harmeet , Monga Dulabh K.
Published: January 2025

735

Background:
To improve clinical outcomes in borderline resectable and resectable pancreatic cancer patients, preoperative chemotherapy with or without radiation can be administered. According to NCCN, there is limited evidence to recommend a specific neoadjuvant chemotherapy regimen. The Dutch randomized phase III PREOPANC trial showed that preoperative chemoradiotherapy led to improved disease free survival. We compared overall survival (OS) between two chemotherapy regimens; mFOLFIRINOX (mFOL) and Gemcitabine/nabPaclitaxel (Gem/nabP).
Methods:
We performed a retrospective analysis of biopsy-proven pancreatic cancer patients from 1/1/2019 to 2/1/2024. We included borderline resectable and resectable pancreatic cancer patients who received neoadjuvant chemotherapy and then underwent pancreatic resection. We divided them into two cohorts: those receiving mFOL and those receiving Gem/nabP. Kaplan-Meier and multivariate Cox regression analyses were performed to analyze OS and rates of R
0
resection amongst the two groups. A p-value < 0.05 was deemed statistically significant.
Results:
From January 2019 to January 2024, 85 pancreatic cancer patients received preoperative chemotherapy prior to pancreatic resection. 50 patients received mFOL and 35 patients received Gem/nabP. The mean overall survival (OS) for the mFOL group was 1,137 days, while for the Gem/nabP group it was 876 days. The hazard ratio was estimated as 1.692 (confidence interval 0.901- 3.177, p-value 0.10). After matching for pathological stage and grade, preoperative radiation, postoperative chemotherapy, and presence of perineural and lymphovascular invasion, the hazard ratio was 1.981 (p-value 0.065). The R
0
resection rate was 92.1% for mFOL and 82.2% for Gem/nabP. The odds ratio for having negative margins with mFOL compared to Gem/nabP was 2.005 with a p-value of 0.37.
Conclusions:
Preoperative chemotherapy with mFOL did not demonstrate improved OS compared to Gem/nabP. The probability of achieving negative margins was also similar amongst the two groups. The SWOG S1505 which is a randomized phase II trial comparing perioperative chemotherapy with mFOL versus Gem/nabP in resectable pancreatic cancer patients has also shown similar OS and progression free survival in both groups.
Chidamide plus envafolimab combined with S-1 as second-line treatment in advanced and metastatic pancreatic cancer (P-henomS/SCOG-P002): A single-arm, exploratory, multicenter, phase 2 trial—Interim report.
Authors: Li Wei , Chen Kai , Du Juan , Chen Xiaofeng , Wang Deqiang , He Kang , Xu Caihua , Wu Mengyao , Xu Mengdan , Wang Bingyi
Published: January 2025

740

Background:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with poor prognosis worldwide. Chidamide, a subtype-selective histone deacetylase (HDAC) inhibitor, has significant anti-tumor effects and extensive synergistic effects with immunotherapy. Envafolimab is a light-chain deficient PD-L1 antibody. Here we conducted a single-arm, multicenter, prospective phase Ⅱ clinical study (ChiCTR2200058431) to evaluate the efficacy and safety of Chidamide plus Envafolimab combined with S-1 as second-line treatment in advanced and metastatic pancreatic cancer.
Methods:
Patients with metastatic PDAC receive Envafolimab (400 mg, on day 1), Chidamide (20 mg orally twice weekly, on days 0, 3, 7, and 10), and S-1 (40-60 mg according to body surface area, orally twice daily from day 1 to 14) every 3 weeks until disease progression, unacceptable toxicity, or patient refusal. The primary end points are safety and ORR. The secondary endpoints were PFS, OS, DCR, QoL and nutrition score.
Results:
Recruitment completed with 16 patients as of September 2023 and the data cut-off for analysis was August 2024, 13 were evaluable. Median age was 66 (range 59 - 80), with 5 males and 11 females. After a median follow-up of 8.5 months, the ORR and DCR by RECIST v1.1 were 30.77% and 76.92%, respectively. Median PFS was 5.83 months (95%CI 2.592-9.068) and median OS was not reached. No new safety signals were observed. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 31.25% of patients. The most common TRAEs were anemia (12.5%), decreased platelet count (6.25%) and neutropenia (12.5%). No treatment-related deaths occurred.
Conclusions:
Preliminary data suggest that Chidamide and Envafolimab in combination with S-1 may be an effective second-line treatment with a manageable safety profile for patients with PDAC.
Clinical trial information: ChiCTR2200058431
.

Efficacy evaluation.

Efficacy Evaluation
AII (N = 13) n(%)

Best efficacy evaluation

Partial Response (PR)
4（30.77%）

Stable Disease (SD)
6（46.15%）

Progressive Disease (PD)
3（23.08%）

Objective response rate (ORR)
30.77%

95%CI
9.09-61.43

Disease control rate (DCR)
76.92%

95%CI
46.19-94.96

mPFS（95%CI）
5.83（2.592-9.068）

mOS（95%CI）
-（NR）
Implication of the novel microtubule targeting agent, AUS_001, in pancreatic cancer cellular signaling.
Authors: Koutsioumpa Marina , Lelie Herman , Lee Pony Yu-Ling , Lin Kun-Yuan
Published: January 2025

748

Background:
Pancreatic cancer (PanCa) is considered a major therapeutic challenge due to its poor prognosis, high mortality rate and resistance to most therapies, underlining the need for new treatment approaches. Our previous investigations revealed that the prenylated hydroxy-stilbene, AUS_001, inhibits β-tubulin polymerization via its unique binding to the colchicine site of tubulin. A cell-based profiling platform identified sensitivity of 12 out of 13 PanCa lines to AUS_001 with a median concentration causing 50% growth inhibition of 0.227µM. The goal of the current study was to elucidate the signaling activity and cellular responses following treatment with AUS_001 and explore the prospect of the latter in PanCa treatment.
Methods:
A series of functional and biochemical assays were performed to delineate the effect of AUS_001 on the growth, colony formation ability, invasive capacity and oxidative status of PanCa cells. Tumor growth was evaluated in PANC-1 implanted CB.17 SCID mice and MIA PaCa-2 implanted nude mice upon intraperitoneal administration of AUS_001 once weekly. Metabolic profiling was carried out using the Seahorse XF Analyzer. RNA silencing and adenovirus-mediated overexpression of the Dominant-Negative Mutant of c-Jun were employed to explore the link of c-Jun activation and AUS_001-induced cytotoxicity.
Results:
The potential of AUS_001 to disrupt PanCa cell functions was established
in vitro
and
in vivo
. Viability and compromised membrane integrity were multiplexed and resulted in half maximal effective concentration agreement indicating drug-induced cytotoxicity. AUS_001-treated cells underwent apoptosis followed by secondary necrosis, exerted diminished anchorage-independent growth and metastatic potential
in vitro
. Importantly, tumor growth was significantly reduced in PanCa murine xenograft models by AUS_001 as a monotherapy. Pretreatment with N-acetyl-l-cysteine did not alter cellular sensitivity to AUS_001, suggesting that the time-dependent induction of reactive oxygen species upon AUS_001 exposure is not the primary cause of cytotoxicity. Notably, the oxygen consumption rate, extracellular acidification rate and function of all mitochondrial complexes (I-IV) of live MIA PaCa_2 cells were significantly impaired in both glucose- and galactose-containing media 48h after AUS_001 administration. Integration of transcriptomic and proteomic data originating from AUS_001-challenged cells uncovered the dramatic induction of c-Jun and FosB stress responders. Further studies demonstrated that c-Jun transcriptional activation acts as a partial mediator of AUS_001-induced cytotoxicity.
Conclusions:
Collectively, our findings provide critical insights into the molecular events triggered by AUS_001 in PanCa cells and serve as supporting data for future exploration of AUS_001 as a novel PanCa therapeutic agent.
CD8
+
T cell proximity analysis of the tumor microenvironment (TME) in patients with pancreatic ductal adenocarcinoma (PDAC) and associated clinical outcomes.
Authors: Ebia Matthew , Abbas Anser Ali , Dotson Suzanne , Elmadbouh Omer H.M. , Davelaar John , Hendifar Andrew Eugene , Osipov Arsen
Published: January 2025

754

Background:
Immunosuppressive cells (cancer-associated fibroblasts [CAFs], tumor associated neutrophils [TANs], M2/M1 macrophages) can influence CD8
+
T cell infiltration in the PDAC TME. The spatial proximity of these cells to CD8
+
T cells and association with clinical outcomes is not well known. We hypothesize the cell distances between CD8
+
T cells and these phenotypes: CXC chemokine receptor 4 (CXCR4)
+
TANs, CAFs, focal adhesion kinase (FAK)
+
tumor cells, FAK
+
M2 and M1 macrophages will correlate with survival outcomes.
Methods:
Twenty-two stage I/II PDAC patients who consented for tissue collection were stratified into two groups: standard responders (n=11) with overall survival (OS) >2 years and poor responders (n=11) with OS ≤ 2 years. Multiplex IHC was performed on specimens using multiple biomarkers (CD8, CXCR4, CD66b, FAK, FAP, CD68, CSF1R, CD163, EPCAM) to identify cell phenotypes. Comprehensive spatial analysis with HALO software was used to measure mean cell distance between CD8
+
T cells and other cells. The mean cell-to-cell distance among evaluable specimens was determined by phenotype. Patients were divided into two groups with average cell distance below or above the mean by phenotype. OS of each subgroup was compared using Kaplan-Meier method.
Results:
Median OS for standard and poor responders was 47.6 months vs 13.1 months (p<.0001), respectively. There was a higher % of CD8
+
T cells closer (<50 µm) to CXCR4
+
TANs in standard responders (56% vs 28%, p<.0001). There were no significant differences in CD8
+
T cell distance to other phenotypes. Longer survival was seen with average cell distance below the mean when comparing CD8
+
T cells to FAK
+
tumor cells (1274 d vs 742 d, p=.306), to CXCR4
+
TANs (854 d vs 442 d, p=.947) and to FAP
+
FAK
+
CAFs (890.5 d vs 672 d, p=.662). In contrast, longer survival was seen with a distance above the mean comparing CD8
+
T cells to M2 (622 d vs 1274 d, p=.732) and to M1 (613 d vs 1397 d, p=.517) macrophages.
Conclusions:
Our study shows clinical outcomes may be correlated with spatial distance among TME immune cells in PDAC. Longer survival was seen when CD8
+
T cells were closer to FAK
+
tumor cells, CXCR4
+
TANs, and CAFs and further away from M2 and M1 macrophages. Larger cohort analyses may better elucidate the prognostic and biological significance of cell distance among TME phenotypes, which may have potential implications for response to immunotherapy.
Impact of pancreatic tumour biomechanics on diagnosis and post-operative complications.
Authors: O'Dowling Aidan , Fox Michelle , Hanly Micheal , Rodriguez Brian , O'Toole Dermot , Donnellan Fergal , Swan Niall , Thorpe Stephen , Gallagher Tom
Published: January 2025

756

Background:
Around 600 people are diagnosed with pancreatic cancer in Ireland each year, with 90% of these having pancreatic ductal adenocarcinoma (PDAC). Five-year survival for PDAC is around 10%. PDAC upregulates stromal collagen formation which contributes to tissue stiffness. Stiffer pancreatic tumours have worse oncological outcomes due to faster progression and increased chemoresistance. Softer pancreata, conversely, are more likely to develop post-operative pancreatic fistulae (POPF), a significant post-pancreatectomy complication. While incorporated in risk scores, softness is currently determined by subjective intra-operative observation.
Methods:
Atomic force microscopy (AFM) is the gold standard technique used to measure biomechanics at a cellular length scale. We obtained fine needle biopsies (FNBs) of pancreatic tumours during diagnostic endoscopic ultrasound. This is the first time tissue biomechanics have been measured from pancreatic biopsies. Separately, we applied this technique to pancreatic tumours and adjacent normal tissue following resection. We also assessed collagen organisation in these pancreatic tumours to understand its contribution to the observed mechanical properties.
Results:
Of the patients with PDAC who underwent FNB, those presenting with metastatic disease had significantly stiffer tumours than those without, 1,490 Pa (SD 2,048.03 Pa) vs 250 Pa (SD 555.06 Pa) (p<0.0001). Neuroendocrine tumours exhibited larger variance compared to PDAC (p < 0.0001), SD 5,885.97 Pa vs SD 1,797.23 Pa. Regarding tumours which have undergone curative resection, tumour stroma is significantly stiffer than both cancer and benign epithelium. The collagen strands in this stroma are straighter, more numerous, and more packed than epithelial tissues. Pancreata which develop post-operative pancreatic fistulae (POPF) are softer than those which do not 96.42 Pa (SD 691.14 Pa) vs 343.99 Pa (SD 1,678.37 Pa).
Conclusions:
We describe a novel technique to measure the biomechanical properties of pancreatic biopsies. Using this technique, we now have the opportunity to measure these properties for the first time on all pancreatic tumours, including those presenting with unresectable disease. It is possible to distinguish between different types of tumour based on the biomechanical profile of biopsies. Previous ex vivo studies have linked stiffer tumours to a higher metastatic potential, and our results are the first to suggest that this may be true in a human population. In resected tumours, we confirm the anecdotal belief that softer pancreata are associated with POPF. Overall, this research demonstrates that tissue biomechanics has potential diagnostic and prognostic applications in pancreatic cancer.