Head-to-head comparison of treatment sequences in advanced pancreatic cancer-Real-world data from the prospective German TPK clinical cohort study.

There are no clear guidelines regarding the optimal treatment sequence for advanced pancreatic cancer, as head-to-head phase III randomised trials are missing. We assess real-world effectiveness of three common sequential treatment strategies by emulating a hypothetical randomised trial. This analysis included 1551 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer receiving FOLFIRINOX (n = 613) or gemcitabine/nab-paclitaxel (GEMNAB; n = 938) as palliative first-line treatment. We used marginal structural modelling to compare overall survival (OS) and time to deterioration (TTD) of health-related quality of life (HRQoL) between three common first- to second-line treatment sequences, adjusting for time-varying potential confounding. The sequences were: FOLFIRINOX→GEMNAB, GEMNAB→FOLFOX/OFF and GEMNAB→nanoliposomal irinotecan (NALIRI) + 5-fluorouracil. Outcome was also calculated stratified by patients' prognostic risk according to the Pancreatic Cancer Score. Median OS and TTD of HRQoL independent of risk were 10.7 [8.9, 11.9] and 6.4 [4.8, 7.7] months for FOLFIRINOX→GEMNAB, 8.4 [7.4, 9.7] and 5.8 [4.6, 7.1] months for GEMNAB→FOLFOX/OFF and 8.9 [7.8, 10.4] and 4.6 [4.1, 6.1] months for GEMNAB→NALIRI+5-fluorouracil. Compared to FOLFIRINOX→GEMNAB, OS and TTD were worse for poor-risk patients with GEMNAB→FOLFOX/OFF (OS: HR 2.09 [1.47, 2.98]; TTD: HR 1.97 [1.19, 3.27]) and those with GEMNAB→NALIRI+5-fluorouracil (OS: HR 1.35, [0.76, 2.39]; TTD: HR 2.62 [1.56, 4.42]). Brackets denote 95%-confidence intervals. The estimated real-world effectiveness of the three treatment sequences evaluated were largely comparable. Poor-risk patients might benefit from intensified treatment with FOLFIRINOX→GEMNAB in terms of clinical and patient-reported outcomes. Future randomised trials on sequential treatments in advanced pancreatic cancer are warranted.

K-ras mutation detected by peptide nucleic acid-clamping polymerase chain reaction, Ki-67, S100P, and SMAD4 expression can improve the diagnostic accuracy of inconclusive pancreatic EUS-FNB specimens.

OBJECTIVES: We aimed to assess the diagnostic utility of an immunohistochemical panel including calcium-binding protein P, p53, Ki-67, and SMAD family member 4 and K-ras mutation for diagnosing pancreatic solid lesion specimens obtained by endoscopic ultrasound-guided fine-needle biopsy and to confirm their usefulness in histologically inconclusive cases. METHODS: Immunohistochemistry and peptide nucleic acid-clamping polymerase chain reaction for K-ras mutation were performed on 96 endoscopic ultrasound-guided fine-needle biopsy specimens. The diagnostic efficacy of each marker and the combination of markers was calculated. The diagnostic performances of these markers were evaluated in 27 endoscopic ultrasound-guided fine-needle biopsy specimens with histologically inconclusive diagnoses. A classification tree was constructed. RESULTS: K-ras mutation showed the highest accuracy and consistency. Positivity in more than two or three of the five markers showed high diagnostic accuracy (94.6 % and 93.6 %, respectively), and positivity for more than three markers showed the highest accuracy for inconclusive cases (92.0 %). A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 showed high diagnostic performance, with only two misclassifications in inconclusive cases. CONCLUSIONS: K-ras mutation detection via peptide nucleic acid-clamping polymerase chain reaction is a stable and accurate method for distinguishing between pancreatic ductal adenocarcinoma and non-pancreatic ductal adenocarcinoma lesions. A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 helps increase the diagnostic accuracy of cases that are histologically difficult to diagnose.

Small protein blockers of human IL-6 receptor alpha inhibit proliferation and migration of cancer cells.

BACKGROUND: Interleukin-6 (IL-6) is a multifunctional cytokine that controls the immune response, and its role has been described in the development of autoimmune diseases. Signaling via its cognate IL-6 receptor (IL-6R) complex is critical in tumor progression and, therefore, IL-6R represents an important therapeutic target. METHODS: An albumin-binding domain-derived highly complex combinatorial library was used to select IL-6R alpha (IL-6Rα)-targeted small protein binders using ribosome display. Large-scale screening of bacterial lysates of individual clones was performed using ELISA, and their IL-6Rα blocking potential was verified by competition ELISA. The binding of proteins to cells was monitored by flow cytometry and confocal microscopy on HEK293T-transfected cells, and inhibition of signaling function was examined using HEK-Blue IL-6 reporter cells. Protein binding kinetics to living cells was measured by LigandTracer, cell proliferation and toxicity by iCELLigence and Incucyte, cell migration by the scratch wound healing assay, and prediction of binding poses using molecular modeling by docking. RESULTS: We demonstrated a collection of protein variants called NEF ligands, selected from an albumin-binding domain scaffold-derived combinatorial library, and showed their binding specificity to human IL-6Rα and antagonistic effect in HEK-Blue IL-6 reporter cells. The three most promising NEF108, NEF163, and NEF172 variants inhibited cell proliferation of malignant melanoma (G361 and A2058) and pancreatic (PaTu and MiaPaCa) cancer cells, and suppressed migration of malignant melanoma (A2058), pancreatic carcinoma (PaTu), and glioblastoma (GAMG) cells in vitro. The NEF binders also recognized maturation-induced IL-6Rα expression and interfered with IL-6-induced differentiation in primary human B cells. CONCLUSION: We report on the generation of small protein blockers of human IL-6Rα using directed evolution. NEF proteins represent a promising class of non-toxic anti-tumor agents with migrastatic potential.

Deep learning-based assessment of CT markers of sarcopenia and myosteatosis for outcome assessment in patients with advanced pancreatic cancer after high-intensity focused ultrasound treatment.

OBJECTIVES: To evaluate the prognostic value of CT-based markers of sarcopenia and myosteatosis in comparison to the Eastern Cooperative Oncology Group (ECOG) score for survival of patients with advanced pancreatic cancer treated with high-intensity focused ultrasound (HIFU). MATERIALS AND METHODS: For 142 retrospective patients, the skeletal muscle index (SMI), skeletal muscle radiodensity (SMRD), fatty muscle fraction (FMF), and intermuscular fat fraction (IMFF) were determined on superior mesenteric artery level in pre-interventional CT. Each marker was tested for associations with sex, age, body mass index (BMI), and ECOG. The prognostic value of the markers was examined in Kaplan-Meier analyses with the log-rank test and in uni- and multivariable Cox proportional hazards (CPH) models. RESULTS: The following significant associations were observed: Male patients had higher BMI and SMI. Patients with lower ECOG had lower BMI and SMI. Patients with BMI lower than 21.8 kg/m2 (median) also showed lower SMI and IMFF. Patients younger than 63.3 years (median) were found to have higher SMRD, lower FMF, and lower IMFF. In the Kaplan-Meier analysis, significantly lower survival times were observed in patients with higher ECOG or lower SMI. Increased patient risk was observed for higher ECOG, lower BMI, and lower SMI in univariable CPH analyses for 1-, 2-, and 3-year survival. Multivariable CPH analysis for 1-year survival revealed increased patient risk for higher ECOG, lower SMI, lower IMFF, and higher FMF. In multivariable analysis for 2- and 3-year survival, only ECOG and FMF remained significant. CONCLUSION: CT-based markers of sarcopenia and myosteatosis show a prognostic value for assessment of survival in advanced pancreatic cancer patients undergoing HIFU therapy. CLINICAL RELEVANCE STATEMENT: The results indicate a greater role of myosteatosis for additional risk assessment beyond clinical scores, as only FMF was associated with long-term survival in multivariable CPH analyses along ECOG and also showed independence to ECOG in group analysis. KEY POINTS: • This study investigates the prognostic value of CT-based markers of sarcopenia and myosteatosis for patients with pancreatic cancer treated with high-intensity focused ultrasound. • Markers for sarcopenia and myosteatosis showed a prognostic value besides clinical assessment of the physical status by the Eastern Cooperative Oncology Group score. In contrast to muscle size measurements, the myosteatosis marker fatty muscle fraction demonstrated independence to the clinical score. • The results indicate that myosteatosis might play a greater role for additional patient risk assessments beyond clinical assessments of physical status.

Evaluation of pancreatic cancer specimens for comprehensive genomic profiling.

Inadequate specimen quality or quantity hinders comprehensive genomic profiling in identifying actionable mutations and guiding treatment strategies. We investigated the optimal conditions for pancreatic cancer specimen selection for comprehensive genomic profiling. We retrospectively analyzed 213 pancreatic cancer cases ordered for comprehensive genomic profiling and compared results from pancreatic biopsy, liver biopsy of pancreatic cancer metastases, pancreatectomy, liquid, and nonliver metastatic organ specimens. We examined preanalytical conditions, including cellularity (tumor cell count/size). The successfully tested cases were those that underwent comprehensive genomic profiling tests without any issues. The successfully tested case ratio was 72.8%. Pancreatic biopsy had the highest successfully tested case ratio (87%), with a high tumor cell percentage, despite the small number of cells (median, 3425). Pancreatic biopsy, liver biopsy of pancreatic cancer metastases, and non-liver metastatic organ had higher successfully tested case ratios than that for pancreatectomy. Liver biopsy of pancreatic cancer metastases and pancreatectomy cases with tumor size (mm2) × tumor ratio (%) > 150 and >3000, respectively, had high successfully tested case ratios. The success of comprehensive genomic profiling is significantly influenced by the tumor cell ratio, and pancreatic biopsy is a potentially suitable specimen for comprehensive genomic profiling.

PW06 suppresses cancer cell metastasis in human pancreatic carcinoma MIA PaCa-2 cells via the inhibitions of p-Akt/mTOR/NF-κB and MMP2/MMP9 signaling pathways in vitro.

PW06 [(E)-3-(9-ethyl-9H-carbazol-3-yl)-1-(2,5-dimethoxyphenyl) prop-2-en-1-one], a kind of the carbazole derivative containing chalcone moiety, induced cell apoptosis in human pancreatic carcinoma in vitro. There is no investigation to show that PW06 inhibits cancer cell metastasis in human pancreatic carcinoma in vitro. Herein, PW06 (0.1-0.8 µM) significantly exists in the antimetastatic activities of human pancreatic carcinoma MIA PaCa-2 cells in vitro. Wound healing assay shows PW06 at 0.2 µM suppressed cell mobility by 7.45 and 16.55% at 6 and 24 hours of treatments. PW06 at 0.1 and 0.2 µM reduced cell mobility by 14.72 and 21.8% for 48 hours of treatment. Transwell chamber assay indicated PW06 (0.1-0.2 µM) suppressed the cell migration (decreased 26.67-35.42%) and invasion (decreased 48.51-68.66%). Atomic force microscopy assay shows PW06 (0.2 µM) significantly changed the shape of cell morphology. The gelatin zymography assay indicates PW06 decreased MMP2's and MMP9's activities at 48 hours of treatment. Western blotting assay further confirms PW06 reduced levels of MMP2 and MMP9 and increased protein expressions of EGFR, SOS1, and Ras. PW06 also increased the p-JNK, p-ERK, and p-p38. PW06 increased the expression of PI3K, PTEN, Akt, GSK3α/ß, and E-cadherin. Nevertheless, results also show PW06 decreased p-Akt, mTOR, NF-κB, p-GSK3ß, ß-catenin, Snail, N-cadherin, and vimentin in MIA PaCa-2 cells. The confocal laser microscopy examination shows PW06 increased E-cadherin but decreased vimentin in MIA PaCa-2 cells. Together, our findings strongly suggest that PW06 inhibited the p-Akt/mTOR/NF-κB/MMPs pathways, increased E-cadherin, and decreased N-cadherin/vimentin, suppressing the migration and invasion in MIA PaCa-2 cells in vitro.

FOLFIRINOX or gemcitabine/nab-paclitaxel in advanced pancreatic adenocarcinoma: A novel validated prognostic score to facilitate treatment decision-making in real-world.

There is no prospective, randomised head-to-head trial comparing first-line FOLFIRINOX and gemcitabine/nab-paclitaxel in advanced pancreatic cancer. We assess real-world effectiveness and quality of life (QoL) of both regimens using a new prognostic score. This analysis includes 1540 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer separated into learning (n = 1027) and validation sample (n = 513). The Pancreatic Cancer Score (PCS) was developed using multivariate Cox regression. We compared overall survival (OS) and time to deterioration (TTD) for longitudinal QoL between first-line FOLFIRINOX (n = 407) and gemcitabine/nab-paclitaxel (n = 655) according to patients' prognostic risk, after inverse probability of treatment weighting (IPTW) by propensity score analysis. The PCS includes nine independent prognostic factors for survival: female sex, BMI ≥24/unknown, ECOG performance status ≥1, Charlson comorbidity index ≥1, tumour staging IV/unknown at primary diagnosis, liver metastases, bilirubin >1.5× upper limit of normal (ULN), leukocytes >ULN and neutrophil-to-lymphocyte ratio ≥4. Median OS of the validation sample was 11.4 (95% confidence interval [CI]: 10.4-14.4), 8.5 (95% CI: 6.8-9.6) and 5.9 months (95% CI: 4.0-7.4) for favourable- (0-3 risk factors), intermediate- (4-5 factors) and poor-risk group (6-9 factors), respectively. After IPTW, only poor-risk patients had significantly longer median OS and TTD of overall QoL with FOLFIRINOX (OS: 6.9 months, 95% CI: 3.9-13.3; TTD: 10.6 months, 95% CI: 2.0-14.1) vs gemcitabine/nab-paclitaxel (OS: 4.0 months, 95% CI: 2.8-4.8; TTD: 4.1 months, 95% CI: 2.4-4.5). Our novel PCS may facilitate treatment decisions in clinical routine of advanced pancreatic cancer, since only poor-risk, but not favourable-risk patients, seem to benefit from intensified treatment with FOLFIRINOX.

Current state of radiomic research in pancreatic cancer: focusing on study design and reproducibility of findings.

OBJECTIVES: To critically appraise methodology and reproducibility of published studies on CT radiomics of pancreatic ductal adenocarcinoma (PDAC). METHODS: PRISMA literature search of MEDLINE, PubMed, and Scopus databases was conducted from June to August 2022 relating to CT radiomics human research articles pertaining to PDAC diagnosis, treatment, and/ or prognosis, utilising Image Biomarker Standardisation Initiative-compliant (IBSI) radiomic software. Keyword search included [pancreas OR pancreatic] AND [radiomic OR [quantitative AND imaging] OR [texture AND analysis]]. Analysis included cohort size, CT protocol used, radiomic feature (RF) extraction, segmentation, and selection, software used, outcome correlation, and statistical methodology, with focus on reproducibility. RESULTS: Initial search yielded 1112 articles; however, only 12 articles met all inclusion/exclusion criteria. Cohort sizes ranged from 37 to 352 (median = 106, mean = 155.8). CT slice thickness varied among studies (4 using ≤ 1 mm, 5 using > 1 to 3 mm, 2 using > 3 to 5 mm, 1 not specifying). CT protocol varied (5 using a single portal-venous (pv)-phase, 5 using a pancreas protocol, 1 study using a non-contrast protocol). RF extraction and segmentation were heterogeneous (RF extraction: 5 using pv-phase, 2 using late arterial, 4 using multi-phase, 1 using non-contrast phase; RF selection: 3 pre-selected, 9 software-selected). 2D/3D RF segmentation was diverse (2D in 6, 3D in 4, 2D and 3D in 2 studies). Six different radiomics software were used. Research questions and cohort characteristics varied, ultimately leading to non-comparable outcome results. CONCLUSION: The current twelve published IBSI-compliant PDAC radiomic studies show high variability and often incomplete methodology resulting in low robustness and reproducibility. CLINICAL RELEVANCE STATEMENT: Radiomics research requires IBSI compliance, data harmonisation, and reproducible feature extraction methods for non-invasive imaging biomarker discoveries to be valid. This will ensure a successful clinical implementation and ultimately an improvement of patient outcomes as part of precision and personalised medicine. KEY POINTS: • Current state of radiomics research in pancreatic cancer shows low software compliance to the Image Biomarker Standardisation Initiative (IBSI). • IBSI-compliant radiomics studies in pancreatic cancer are heterogeneous and not comparable, and the majority of study designs showed low reproducibility. • Improved methodology and standardisation of practice in the emerging field of radiomics has the potential of this non-invasive imaging biomarker in the management of pancreatic cancer.

Diffusion-weighted imaging for determining response to neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis.

OBJECTIVES: To determine the role of diffusion-weighted imaging (DWI) for predicting response to neoadjuvant therapy (NAT) in pancreatic cancer. MATERIALS AND METHODS: MEDLINE, EMBASE, and Cochrane Library databases were searched for studies evaluating the performance of apparent diffusion coefficient (ADC) to assess response to NAT. Data extracted included ADC pre- and post-NAT, for predicting response as defined by imaging, histopathology, or clinical reference standards. ADC values were compared with standardized mean differences. Risk of bias was assessed using the Quality Assessment of Diagnostic Studies (QUADAS-2). RESULTS: Of 337 studies, 7 were included in the analysis (161 patients). ADC values reported for the pre- and post-NAT assessments overlapped between responders and non-responders. One study reported inability of ADC increase after NAT for distinguishing responders and non-responders. A correlation with histopathological response was reported for pre- and post-NAT ADC in 4 studies. DWI's diagnostic performance was reported to be high in three studies, with a 91.6-100% sensitivity and 62.5-94.7% specificity. Finally, heterogeneity and high risk of bias were identified across studies, affecting the domains of patient selection, index test, reference standard, and flow and timing. CONCLUSION: DWI might be useful for determining response to NAT in pancreatic cancer. However, there are still too few studies on this matter, which are also heterogeneous and at high risk for bias. Further studies with standardized procedures for data acquisition and accurate reference standards are needed. CLINICAL RELEVANCE STATEMENT: Diffusion-weighted MRI might be useful for assessing response to neoadjuvant therapy in pancreatic cancer. However, further studies with robust data are needed to provide specific recommendations for clinical practice. KEY POINTS: •The role of DWI with ADC measurements for assessing response to neoadjuvant therapy in pancreatic cancer is still unclear. •Pre- and post-neoadjuvant therapy ADC values overlap between responders and non-responders. •DWI has a reported high diagnostic performance for determining response when using histopathological or clinical reference standards; however, studies are still few and at high risk for bias.

Accuracy of models to prognosticate survival after surgery for pancreatic cancer in the era of neoadjuvant therapy.

BACKGROUND: Outcomes for pancreatic adenocarcinoma (PDAC) remain difficult to prognosticate. Multiple models attempt to predict survival following the resection of PDAC, but their utility in the neoadjuvant population is unknown. We aimed to assess their accuracy among patients that received neoadjuvant chemotherapy (NAC). METHODS: We performed a multi-institutional retrospective analysis of patients who received NAC and underwent resection of PDAC. Two prognostic systems were evaluated: the Memorial Sloan Kettering Cancer Center Pancreatic Adenocarcinoma Nomogram (MSKCCPAN) and the American Joint Committee on Cancer (AJCC) staging system. Discrimination between predicted and actual disease-specific survival was assessed using the Uno C-statistic and Kaplan-Meier method. Calibration of the MSKCCPAN was assessed using the Brier score. RESULTS: A total of 448 patients were included. There were 232 (51.8%) females, and the mean age was 64.1 years (±9.5). Most had AJCC Stage I or II disease (77.7%). For the MSKCCPAN, the Uno C-statistic at 12-, 24-, and 36-month time points was 0.62, 0.63, and 0.62, respectively. The AJCC system demonstrated similarly mediocre discrimination. The Brier score for the MSKCCPAN was 0.15 at 12 months, 0.26 at 24 months, and 0.30 at 36 months, demonstrating modest calibration. CONCLUSIONS: Current survival prediction models and staging systems for patients with PDAC undergoing resection after NAC have limited accuracy.

The role of natural killer cell activity as a milestone in oncologic outcome after curative resection of pancreatic adenocarcinoma.

BACKGROUND: The objective of this study was to investigate differences in oncologic outcomes of patients with pancreas cancer according to natural killer cell activity (NKA). METHODS: A total of 118 patients who underwent curative resection for primary pancreas cancer in two hospitals were analyzed. NKA change pattern was analyzed. Difference in disease-free survival or overall survival was investigated by dividing subjects into two groups based on a normal NKA value for each period. RESULTS: NKA value decreased after surgery compared to the value measured at admission. It recovered to normal levels at 5 weeks postoperatively. The low NKA (less than 250 pg/mL) group at admission, 5 weeks postoperatively, and before 1st chemotherapy had significantly poorer disease-free survival than the normal NKA group. In multivariate analysis, NKA values less than 250 pg/mL at admission (odds ratio = 2.267, p = 0.023) and N 1 or N2 category (odds ratio = 2.478, p = 0.023) were significant factors associated with recurrence after curative resection. CONCLUSIONS: NKA in patients with pancreatic cancer demonstrated noticeable changes after surgery. Immunologically predisposed patients with a low NKA value had a high risk of early recurrence and a poor prognosis, although pancreatic cancer was surgically removed.

Design and synthesis of sulfonamides incorporating a biotin moiety: Carbonic anhydrase inhibitory effects, antiproliferative activity and molecular modeling studies.

Sulfonamides constitute an important class of classical carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Herein we have accomplished the conjugation of biotin with an ample number of sulfonamide motifs with the aim of testing them in vitro as inhibitors of the human carbonic anhydrase (hCA) isoforms I and II (cytosolic isozymes), as well as hCA IX and XII (transmembrane, tumor-associated enzymes). Most of these newly synthesized compounds exhibited interesting inhibition profiles, with activities in the nanomolar range. The presence of a 4-F-C6H4 moiety, also found in SLC-0111, afforded an excellent selectivity towards the tumor-associated hypoxia-induced hCA isoform XII with an inhibition constant (KI) of 4.5 nM. The 2-naphthyl derivative was the most potent inhibitor against hCA IX (KI = 6.2 nM), 4-fold stronger than AAZ (KI = 25 nM) with very good selectivity. Some compounds were chosen for antiproliferative activity testing against a panel of 3 human tumor cell lines, one compound showing anti-proliferative activity on glioblastoma, triple-negative breast cancer, and pancreatic carcinoma cell lines.

Overexpression of laminin-5 gamma-2 promotes tumorigenesis of pancreatic ductal adenocarcinoma through EGFR/ERK1/2/AKT/mTOR cascade.

Pancreatic ductal adenocarcinoma (PDAC) is correlated with poor outcomes because of limited therapeutic options. Laminin-5 gamma-2 (LAMC2) plays a critical role in key biological processes. However, the detailed molecular mechanism and potential roles of LAMC2 in PDAC stay unexplored. The present study examines the essential role and molecular mechanisms of LAMC2 in the tumorigenesis of PDAC. Here, we identified that LAMC2 is significantly upregulated in microarray cohorts and TCGA RNA sequencing data of PDAC patients compared to non-cancerous/normal tissues. Patients with higher transcript levels of LAMC2 were correlated with clinical stages; dismal overall, as well as, disease-free survival. Additionally, we confirmed significant upregulation of LAMC2 in a panel of PDAC cell lines and PDAC tumor specimens in contrast to normal pancreatic tissues and cells. Inhibition of LAMC2 significantly decreased cell growth, clonogenic ability, migration and invasion of PDAC cells, and tumor growth in the PDAC xenograft model. Mechanistically, silencing of LAMC2 suppressed expression of ZEB1, SNAIL, N-cadherin (CDH2), vimentin (VIM), and induced E-cadherin (CDH1) expression leading to a reversal of mesenchymal to an epithelial phenotype. Interestingly, co-immunoprecipitation experiments demonstrated LAMC2 interaction with epidermal growth factor receptor (EGFR). Further, stable knockdown of LAMC2 inhibited phosphorylation of EGFR, ERK1/2, AKT, mTOR, and P70S6 kinase signaling cascade in PDAC cells. Altogether, our findings suggest that silencing of LAMC2 inhibited PDAC tumorigenesis and metastasis through repression of epithelial-mesenchymal transition and modulation of EGFR/ERK1/2/AKT/mTOR axis and could be a potential diagnostic, prognostic, and therapeutic target for PDAC.

Health-related quality of life scores of metastatic pancreatic cancer patients responsive to first line chemotherapy compared to newly derived EORTC QLQ-C30 reference values.

BACKGROUND: Metastatic pancreatic cancer (mPC) and its treatments significantly impact health-related quality of life (HRQoL). POLO, a randomized, double-blind, placebo-controlled phase 3 trial evaluated the efficacy of olaparib as maintenance therapy in germline BRCA mutated mPC patients who had not progressed during ≥16 weeks of first-line platinum-based chemotherapy. HRQoL was assessed using the EORTC QLQ-C30. To enhance score interpretation, we derived reference values for treatment-naïve mPC patients from the literature. METHODS: A targeted literature review identified EORTC QLQ-C30 baseline values in treatment-naïve mPC patients. Reference values were calculated by deriving means from studies meeting inclusion criteria, with scores from 0 to 100 (higher scores indicate better QoL/functioning but worse symptoms). For POLO patients, means were calculated using pooled baseline data across study arms. RESULTS: Four studies met inclusion criteria. Depending on the specific scale, sample sizes ranged from n = 466 to n = 639. Compared to newly derived reference values, POLO patients reported markedly better HRQoL scores at baseline across most scales, with eight scales showing differences of ≥10 points. POLO patients' HRQoL scores were often close to or better than general population norm data. CONCLUSIONS: This is the first study to systematically derive EORTC QLQ-C30 reference values for mPC. POLO patients had better HRQoL scores than those in the literature and similar to general population data. Comparatively high HRQoL of POLO patients are likely due to effects of prior first-line treatment and resolution of chemotherapy-related symptoms, response shift, or a combination. Newly derived reference values can enhance interpretation of mPC patients' HRQoL. TRIAL REGISTRATION: The POLO trial was registered on 9 July 2014 with ClinicalTrials.gov as NCT02184195.

CT-diagnosed extra-pancreatic extension of pancreatic ductal adenocarcinoma is a more reliable prognostic factor for survival than pathology-diagnosed extension.

OBJECTIVES: To determine the correlation between CT-diagnosed extra-pancreatic extension of pancreatic ductal adenocarcinoma (PDAC), pathology-diagnosed extra-pancreatic extension, and survival in patients with PDAC. METHODS: This retrospective study included 87 patients with resected PDAC. Two radiologists evaluated negative ((i) tumours surrounded by the pancreatic parenchyma and (ii) tumours contacting the pancreatic surface) or positive ((iii) tumours with peri-pancreatic strand appearances and/or with expansive growth) CT-diagnosed extra-pancreatic extension. Clinical, pathological, and CT imaging characteristics predicting disease-free survival (DFS) and overall survival (OS) were assessed using Cox proportional-hazards models. Diagnostic accuracy for pathology-diagnosed extra-pancreatic extension was also assessed. RESULTS: CT-diagnosed extra-pancreatic extension (42/87 tumours, 48.3%; κ = 0.82) had a higher hazard ratio (HR) for the DFS (HR, 5.30; p < 0.01) and OS (HR, 5.31; p < 0.01) rates than pathology-diagnosed extension in univariable analyses. It was also an independent prognostic factor for the DFS (HR, 4.22; p < 0.01) and OS (HR, 4.38; p < 0.01) rates in multivariable analyses. Of 45 tumours without CT-diagnosed extra-pancreatic extension, pathology-diagnosed extra-pancreatic extension was observed in 2/8 (25.0%) and 32/37 (86.5%) tumours with CT categories (i) and (ii), respectively. However, the differences in the survival rates between patients with CT categories (i) and (ii) were insignificant, although those in the latter category had significantly better survival rates than those with CT-diagnosed extra-pancreatic extension (category (iii)). CONCLUSIONS: CT-diagnosed extra-pancreatic extension was a better prognostic factor than pathology-diagnosed extension and considered an independent factor for the postoperative DFS and OS rates with reasonable frequency and high reproducibility, despite the low diagnostic accuracy for predicting pathology-diagnosed extra-pancreatic extension. KEY POINTS: • A CT-diagnosed extra-pancreatic extension had a higher hazard ratio for both disease-free survival and overall survival compared to pathology-diagnosed extension in univariable survival analyses. • A CT-diagnosed extra-pancreatic extension was a significant independent predictor of both disease-free survival and overall survival, as observed in multivariable survival analyses. • Patients with tumours contacting with the pancreatic surface on CT images (CT category (ii)) showed similar survival rates to those whose tumours were surrounded by the pancreatic parenchyma (CT category (i)), although many tumours with CT category (ii) extended pathologically beyond the pancreas.

Branch-duct intraductal papillary mucinous neoplasm (IPMN): Are cyst volumetry and other novel imaging features able to improve malignancy prediction compared to well-established resection criteria?

OBJECTIVES: Current guidelines base the management of intraductal papillary mucinous neoplasms (IPMN) on several well-established resection criteria (RC), including cyst size. However, malignancy may occur in small cysts. Since branch-duct (BD) IPMN are not perfect spheres, volumetric and morphologic analysis might better correlate with mucin production and grade of dysplasia. Nonetheless, their role in malignancy (high-grade dysplasia/invasive cancer) prediction has been poorly investigated. Previous studies evaluating RC also included patients with solid-mass-forming pancreatic cancer (PC), which may affect the RC yield. This study aimed to assess the role of volume, morphology, and other well-established RC in malignancy prediction in patients with BD- and mixed-type IPMN after excluding solid masses. METHODS: Retrospective ethical review-board-approved study of 106 patients (2008-2019) with histopathological diagnosis of BD- and mixed-type IPMN (without solid masses) and preoperative MRI available. Standard imaging and clinical features were collected, and the novel imaging features cyst-volume and elongation value [EV = 1 - (width/length)] calculated on T2-weighted images. Logistic regression analysis was performed. Statistical significance set at two-tails, p < 0.05. RESULTS: Neither volume (odds ratio (OR) = 1.01, 95% CI: 0.99-1.02, p = 0.12) nor EV (OR = 0.38, 95% CI: 0.02-5.93, p = 0.49) was associated with malignancy. Contrast-enhancing mural nodules (MN), main pancreatic duct (MPD) ≥ 5 mm, and elevated carbohydrate antigen (CA) 19-9 serum levels (> 37 µmol/L) were associated with malignancy (MN OR: 4.32, 95% CI: 1.18-15.76, p = 0.02; MPD ≥ 5 mm OR: 4.2, 95% CI: 1.34-13.1, p = 0.01; CA19-9 OR: 6.72; 95% CI: 1.89 - 23.89, p = 0.003). CONCLUSIONS: Volume and elongation value cannot predict malignancy in BD- and/or mixed-type IPMN. Mural nodules, MPD ≥ 5 mm and elevated CA19-9 serum levels are associated with higher malignancy risk even after the exclusion of solid masses. KEY POINTS: • Novel and well-established resection criteria for IPMN have been evaluated after excluding solid masses. • BD-IPMN volume and elongation value cannot predict malignancy. • Main pancreatic duct ≥ 5 mm, mural nodules, and elevated carbohydrate antigen 19-9 levels are associated with malignancy.

Exosome-mediated lncRNA SNHG11 regulates angiogenesis in pancreatic carcinoma through miR-324-3p/VEGFA axis.

Pancreatic carcinoma (PC) is one of the most common and deadly human malignancies worldwide. LncRNAs play significant roles in the occurrence and development of various cancers. LncRNA SNHG11 (SNHG11) has been found to display high expression in serum of PC patients, which implies that dysregulated SNHG11 may be related to the development of PC. However, there is still a knowledge gap concerning the specific function and molecular mechanism of SNHG11 in PC. After conducting experiments with constructed models in vitro or in vivo, we found that exosomal SNHG11 promoted cell proliferation, migration, and angiogenesis but impeded cell apoptosis in PC in vitro, and additionally, it facilitated tumor growth in vivo. Exosome-mediated SNHG11 regulated the expression of VEGFA through sponging miR-324-3p. Rescue assays validated that the inhibitory effect of SNHG11 depletion on cell proliferation, migration, and angiogenesis could be reversed by miR-324-3p downregulation or VEGFA upregulation, and the promoting effect of SNHG11 silence on cell apoptosis could be rescued by transfection of miR-324-3p inhibitor or pcDNA3.1-VEGFA. To conclude, exosomal-mediated SNHG11 could regulate PC progression via miR-324-3p/VEGFA axis. Our findings may provide a novel insight for understanding PC, which might contribute to the development of potential PC biomarker.

Gender-specific side effects of chemotherapy in pancreatic cancer patients.

Pancreatic carcinoma incidence showed a significant increase in men over the last few years and the prognosis remains poor. Patients are treated with different pharmacological plans with no evidence about gender-specific adverse effects. We aimed to investigate differences in the incidence of chemotherapy side effects in the treatment of pancreatic cancer, to provide insights toward a personalized assistance based in individual needs. The sample population is composed of 207 patients. Regression model highlighted the predictive role of female gender for alopecia, constipation, hand-foot syndrome, and epigastric pain. Also, considering single therapeutic schemes, gender differences have been reported. Moreover, evaluating the effect of age, a general reduced risk of toxicity has been reported in younger patients. To personalize chemotherapy and increase patient survival rate and life quality during the therapy, gender medicine and pharmacology studies are recommended.

Synthesis and biological evaluation of cajaninstilbene acid and amorfrutins A-D as cytotoxic agents against human pancreatic carcinoma PANC-1 cells.

A concise synthesis of cajaninstilbene acid was achieved in 7 steps from (E)-3,5-dimethoxystilbene in 8.6% overall yield via the Claisen rearrangement of an aryl reverse-prenyl ether as the key step. Cytotoxic activities against human pancreatic carcinoma PANC-1 cells of cajaninstilbene acid and amorfrutins A-D were also evaluated.

Orbital metastasis as the primary manifestation of pancreatic carcinoma: a case report and literature review.

BACKGROUND: Orbital metastasis from pancreatic tumors is extremely rare, and its clinical characteristics are still unclear. CASE PRESENTATION: Our case was a 73-year-old female who noticed diplopia on right gaze 3 months before referral to us. Imaging studies demonstrated a mass involving the lateral rectus muscle in the right orbit. The results of pathological examination of an excised specimen corresponded to poorly differentiated adenocarcinoma. Systemic work-up revealed pancreatic carcinoma with peritoneal metastasis. The patient underwent chemotherapy. We reviewed literature on similar cases and found 19 reported cases of pancreatic tumors metastasizing to the orbit. The results of our review indicate a tendency for formation of solitary mass without bony erosion, delayed detection of the primary pancreatic carcinoma, and poorer prognosis of such tumors, compared to metastatic orbital tumors from other lesions. CONCLUSIONS: We report a rare case of metastatic orbital tumor from an unknown primary pancreatic carcinoma. Clinical characteristics of cases with metastatic pancreatic tumors seem to be different from those with metastatic tumors from the other lesions. Pancreatic tumors are frequently asymptomatic in an early stage, leading to delayed detection of the primary pancreatic carcinoma and poorer prognosis.