Liquid-based cytology features of pancreatic acinar cell carcinoma: comparison with other non-ductal neoplasms of the pancreas.

BACKGROUND: Acinar cell carcinoma (ACC) is a rare malignant epithelial neoplasm, which shares many cytomorphological features with other non-ductal pancreatic neoplasms such as pancreatic neuroendocrine neoplasm (PanNEN) and solid-pseudopapillary neoplasm (SPN). Due to the relative rarity of these tumors, pathologists are less familiar with the cytological features, especially on liquid-based cytology (LBC) which has been relatively recently introduced for endoscopic ultrasound-guided fine needle aspiration specimens. METHODS: We evaluated the detailed cytological features of 15 histologically confirmed ACC (7 conventional smears [CS], 8 LBC), and compared them with the LBC features of SPN (n = 9) and PanNEN (n = 9). RESULTS: Compared with CS, LBCs of ACC demonstrated significantly less bloody background. All ACCs demonstrated prominent nucleoli and macronucleoli on LBC. On comparison with the LBC features of SPN and PanNEN, most ACCs demonstrated a necrotic background with apoptotic debris while PanNEN and SPN did not show these features. Acinar structures were predominantly observed in ACC, while frequent pseudopapillary structures were seen only in SPN. Prominent nucleoli and macronucleoli were only seen in ACC. CONCLUSIONS: ACC had characteristic cytological features that could be observed on LBC preparations, such as high cellularity, necrotic/apoptotic background, nuclear tangles, acinar arrangement of cells, and macronucleoli. These findings also help distinguish ACC from PanNEN and SPN on LBC. It is important to be familiar with these features, as an accurate diagnosis on endoscopic ultrasound-guided fine needle aspiration cytology would have impact on the management of the patient.

Artificial Intelligence-based Segmentation of Residual Pancreatic Cancer in Resection Specimens Following Neoadjuvant Treatment (ISGPP-2): International Improvement and Validation Study.

Neoadjuvant therapy (NAT) has become routine in patients with borderline resectable pancreatic cancer. Pathologists examine pancreatic cancer resection specimens to evaluate the effect of NAT. However, an automated scoring system to objectively quantify residual pancreatic cancer (RPC) is currently lacking. Herein, we developed and validated the first automated segmentation model using artificial intelligence techniques to objectively quantify RPC. Digitized histopathological tissue slides were included from resected pancreatic cancer specimens from 14 centers in 7 countries in Europe, North America, Australia, and Asia. Four different scanner types were used: Philips (56%), Hamamatsu (27%), 3DHistech (10%), and Leica (7%). Regions of interest were annotated and classified as cancer, non-neoplastic pancreatic ducts, and others. A U-Net model was trained to detect RPC. Validation consisted of by-scanner internal-external cross-validation. Overall, 528 unique hematoxylin and eosin (H & E) slides from 528 patients were included. In the individual Philips, Hamamatsu, 3DHistech, and Leica scanner cross-validations, mean F1 scores of 0.81 (95% CI, 0.77-0.84), 0.80 (0.78-0.83), 0.76 (0.65-0.78), and 0.71 (0.65-0.78) were achieved, respectively. In the meta-analysis of the cross-validations, the mean F1 score was 0.78 (0.71-0.84). A final model was trained on the entire data set. This ISGPP model is the first segmentation model using artificial intelligence techniques to objectively quantify RPC following NAT. The internally-externally cross-validated model in this study demonstrated robust performance in detecting RPC in specimens. The ISGPP model, now made publically available, enables automated RPC segmentation and forms the basis for objective NAT response evaluation in pancreatic cancer.

TIPRL Regulates Stemness and Survival in Lung Cancer Stem Cells through CaMKK2-CaMK4-CREB Feedback Loop Activation.

Frequent recurrence and metastasis caused by cancer stem cells (CSCs) are major challenges in lung cancer treatment. Therefore, identifying and characterizing specific CSC targets are crucial for the success of prospective targeted therapies. In this study, it is found that upregulated TOR Signaling Pathway Regulator-Like (TIPRL) in lung CSCs causes sustained activation of the calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) signaling pathway by binding to CaMKK2, thereby maintaining stemness and survival. CaMKK2-mediated activation of CaM kinase 4 (CaMK4) leads to phosphorylation of cAMP response element-binding protein (CREB) at Ser129 and Ser133, which is necessary for its maximum activation and the downstream constitutive expression of its target genes (Bcl2 and HMG20A). TIPRL depletion sensitizes lung CSCs to afatinib-induced cell death and reduces distal metastasis of lung cancer in vivo. It is determined that CREB activates the transcription of TIPRL in lung CSCs. The positive feedback loop consisting of CREB and TIPRL induces the sustained activation of the CaMKK2-CaMK4-CREB axis as a driving force and upregulates the expression of stemness- and survival-related genes, promoting tumorigenesis in patients with lung cancer. Thus, TIPRL and the CaMKK2 signaling axis may be promising targets for overcoming drug resistance and reducing metastasis in lung cancer.

Computed tomography-based vascular burden index as a predictor of vascular resection and pathological vascular invasion in pancreatic cancer with neo-adjuvant chemotherapy.

BACKGROUND: Determination of vessel resection in patients with pancreatectomy after neo-adjuvant chemotherapy remains controversial. The recently introduced computed tomography-based vascular burden index presents a potential solution to this challenge. This study aimed to evaluate the model performance for the prediction of vascular resection and pathological invasion. METHODS: Patients who underwent surgery after neo-adjuvant chemotherapy were included. Two independent reviewers measured the vascular tumour burden index around the adjacent artery (AVBI), and vein (VVBI). The area under the curve was compared to assess the predictive capacity of vascular burden index values and their changes for vascular resection and pathological vascular invasion. RESULTS: Among 252 patients, 179 and 73 had borderline resectable and locally advanced pancreatic cancer, respectively. Concurrent vessel resection and pathological vascular invasion were observed in 121 (48.0 %) and 42 (16.6 %) patients, respectively. In all patients, the VVBI (area under the curve: 0.872) and AVBI (0.911) after neo-adjuvant therapy significantly predicted vessel resection. In patients with vascular resection, the VVBI after neo-adjuvant chemotherapy (0.752) and delta value of the AVBI (0.706) demonstrated better performance for predicting pathological invasion of the resected vein. The regression of the AVBI and VVBI was an independent prognostic factor for survival (hazard ratio: 0.54, 95 % confidence interval: 0.34-0.85; P = 0.009) CONCLUSIONS: Regressed VVBI on serial computed tomography scans is useful for predicting vein resection and pathological venous invasion before surgery. The delta value of the AVBI may therefore be helpful for predicting pathological arterial invasion after neo-adjuvant chemotherapy.

Comprehensive Characterization of Intraductal Oncocytic Papillary Neoplasm of the Pancreas: A Systematic and Critical Review.

Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a recently recognized pancreatic tumor. Here, we aimed to determine its most essential features with the systematic review tool. PubMed, Scopus, and Embase were searched for studies reporting data on pancreatic IOPN. The clinicopathologic, immunohistochemical, and molecular data were extracted and summarized. Then, a comparative analysis of the molecular alterations of IOPN with those of pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm from reference cohorts (including The Cancer Genome Atlas) was conducted. The key findings from 414 IOPNs were as follows: 1) The male-to-female ratio was 1.5:1. Pancreatic head was the most common site (131/237; 55.3%), but a diffuse tumor extension involving more than one pancreatic segment was described in about 1 out of 5 cases (49/237; 20.6%). The mean size was 45.5 mm. An associated invasive carcinoma was present in 50% of cases (168/336). In those cases, most tumors were pT1 or pT2 and pN0 (>80%), and vascular invasion was uncommon (20.6%). Regarding survival, more than 90% of patients were alive after surgical resection. 2) Immunohistochemical and molecular features were as follows. The most commonly expressed mucins were MUC5AC (110/112; 98.2%) and MUC6 (78/84; 92.8%). Compared with pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, and GNAS were less altered in IOPN (P < .01). Moreover, fusions involving PRKACA or PRKACB gene were detected in all of the 68 cases examined, with PRKACB::ATP1B1 being the most common (27/68 cases; 39.7%). These genomic events emerged as an entity-defining molecular alteration of IOPN (P < .01). Thus, such fusions represent a promising biomarker for diagnostic purposes. Recent evidence also suggests their role in influencing the acquisition of oncocytic morphology. IOPN is a distinct pancreatic neoplasm with specific clinicopathologic and molecular features. Considering the clinical or prognostic implications, its recognition is essential for pathologists and, ultimately, patients' management.

Fourier space aberration correction for high resolution refractive index imaging using incoherent light.

An aberration correction method is introduced for 3D phase deconvolution microscopy. Our technique capitalizes on multiple illumination patterns to iteratively extract Fourier space aberrations, utilizing the overlapping information inherent in these patterns. By refining the point spread function based on the retrieved aberration data, we significantly improve the precision of refractive index deconvolution. We validate the effectiveness of our method on both synthetic and biological three-dimensional samples, achieving notable enhancements in resolution and measurement accuracy. The method's reliability in aberration retrieval is further confirmed through controlled experiments with intentionally induced spherical aberrations, underscoring its potential for wide-ranging applications in microscopy and biomedicine.

Extranodal extension influences prognosis in pancreatic body/tail cancer: A retrospective cohort study.

BACKGROUND/PURPOSE: Extranodal extension (ENE) is an established prognostic factor in various malignancies, affecting survival in pancreatic head cancer (PHC). However, its significance in pancreatic body/tail cancer (PBTC) remains unclear. Therefore, we aimed to investigate the impact of ENE on PTBC prognosis. METHODS: We analyzed data collected from electronic medical records of patients with PBTC who underwent distal pancreatectomy at a single center between January 2011 and December 2015. The patients were categorized based on ENE presence and prognostic implications were evaluated using Kaplan-Meier survival curves and Cox proportional hazards model. RESULTS: PBTC cases involving lymph node (LN) metastasis and ENE exhibited significantly lower disease-free (DFS) and overall survival (OS) rates compared to cases without LN metastasis or ENE (median DFS; N0, 23 months; LN+/ENE-, 10 months; LN+/ENE+, 5 months; p < .001). No statistically significant difference was observed in DFS and OS rates between patients with N1/N2 in the group without ENE and those with ENE+. Multivariate analysis confirmed ENE as a significant adverse prognostic factor. CONCLUSIONS: ENE significantly predicts poor prognosis in PBTC, particularly in cases with nodal metastasis. The current cancer staging system for PBTC should incorporate ENE status. Moreover, different staging systems should be considered for PHC and PBTC.

Extended depth-of-field wide-field fluorescence microscopy with a micro-mirror array lens system for versatile cellular examination.

We present a versatile extended depth-of-field (EDOF) wide-field fluorescence microscopy using a new, to the best of our knowledge, active device, micro-mirror array lens system (MALS) for calibration-free and orientation-insensitive EDOF imaging. The MALS changed the focal plane during image acquisition, and the system could be operated in any orientation. Two EDOF imaging modes of high-speed accumulation and low-speed surface sectioning were implemented. The performance was demonstrated in non-contact imaging of conjunctival goblet cells in live mice and depth-resolved cellular examination of ex-vivo human cancer specimens. MALS-based EDOF microscopy has potential for versatile cellular examination.

Radiologic tumor border can further stratify prognosis in patients with pancreatic neuroendocrine tumor.

BACKGROUND AND OBJECTIVES: Pancreatic neuroendocrine tumor (PanNET), although rare in incidence, is increasing in recent years. Several clinicopathologic and molecular factors have been suggested for patient stratification due to the extensive heterogeneity of PanNETs. We aimed to discover the prognostic role of assessing the tumor border of PanNETs with pre-operative computed tomography (CT) images and correlate them with other clinicopathologic factors. METHODS: The radiologic, macroscopic, and microscopic tumor border of 183 surgically resected PanNET cases was evaluated using preoperative CT images (well defined vs. poorly defined), gross images (expansile vs. infiltrative), and hematoxylin and eosin-stained slides (pushing vs. infiltrative). The clinicopathologic and prognostic significance of the tumor border status was compared with other clinicopathologic factors. RESULTS: A poorly defined radiologic tumor border was observed in 65 PanNET cases (35.5 %), and were more frequent in male patients (P = 0.031), and tumor with larger size, infiltrative macroscopic growth pattern, infiltrative microscopic tumor border, higher tumor grade, higher pT category, lymph node metastasis, lymphovascular and perineural invasions (all, P < 0.001). Patients with PanNET with a poorly defined radiologic tumor border had significantly worse overall survival (OS) and recurrence-free survival (RFS; both, P < 0.001). Multivariable analysis revealed that PanNET with a poorly defined radiologic border is an independent poor prognostic factor for both OS (P = 0.049) and RFS (P = 0.027). CONCLUSION: Pre-operative CT-based tumor border evaluation can provide additional information regarding survival and recurrence in patients with PanNET.

Long-term Outcomes of Ampullary Adenoma According to Resected Margin Status after Endoscopic Papillectomy.

Background/Aims: : Endoscopic papillectomy (EP) is increasingly used as an alternative to surgery for managing benign ampullary neoplasms. However, post-EP resection margins are often positive or indeterminate, and there is no consensus on the management of ampullary adenomas with positive or indeterminate margins after EP. This study was designed to compare the long-term outcomes between resected margin-negative (RMN) and resected margin-positive/indeterminate (RMPI) groups and to identify factors associated with clinical outcomes. Methods: : This retrospective analysis included patients with ampullary adenoma without evidence of adenocarcinoma who underwent EP between 2004 and 2016. The RMN and RMPI groups were compared for recurrence rates and recurrence-free duration during a mean follow-up duration of 71.7±39.8 months. Factors related to clinical outcomes were identified using multivariate analysis. Results: : Of the 129 patients who underwent EP, 82 were in the RMN group and 47 were in the RMPI group. The RMPI group exhibited a higher recurrence rate compared to the RMN group (14.6% vs 34.0%, p=0.019). However, the recurrence-free duration was not significantly different between the groups (34.7±32.6 months vs 36.2±27.4 months, p=0.900). Endoscopic treatment successfully managed recurrence in both groups (75% vs 75%). Submucosal injection was a significant risk factor for residual lesions (hazard ratio, 4.11; p=0.009) and recurrence (hazard ratio, 2.57; p=0.021). Conclusions: : Although ampullary adenomas with positive or indeterminate margins after EP showed a higher rate of recurrence at long-term follow-up, endoscopic treatment was effective with favorable long-term outcomes. Submucosal injection prior to resection was associated with increased risk of recurrence and residual lesions.

Comparison of the different versions of NCCN guidelines for predicting margin-negative resection of pancreatic cancer in patients undergoing upfront surgery.

OBJECTIVES: The purpose of this study was to compare the different versions of the National Comprehensive Cancer Network (NCCN) guidelines for defining resectability of pancreatic ductal adenocarcinoma (PDAC) in predicting margin-negative (R0) resection, and to assess inter-reader agreement. METHODS: This retrospective study included 283 patients (mean age, 65.1 years ± 9.4 [SD]; 155 men) who underwent upfront pancreatectomy for PDAC between 2017 and 2019. Two radiologists independently determined the resectability on preoperative CT according to the 2017, 2019, and 2020 NCCN guidelines. The sensitivity and specificity for R0 resection were analyzed using a multivariable logistic regression analysis with generalized estimating equations. Inter-reader agreement was assessed using kappa statistics. RESULTS: R0 resection was accomplished in 239 patients (84.5%). The sensitivity and specificity averaged across two readers were, respectively, 76.6% and 29.5% for the 2020 guidelines, 74.1% and 32.9% for the 2019 guidelines, and 72.6% and 34.1% for the 2017 guidelines. Compared with the 2020 guidelines, both 2019 and 2017 guidelines showed significantly lower sensitivity for R0 resection (p ≤ .009). Specificity was significantly higher with the 2017 guidelines (p = .043) than with the 2020 guidelines. Inter-reader agreements for determining the resectability of PDCA were strong (k ≥ 0.83) with all guidelines, being highest with the 2020 guidelines (k = 0.91). CONCLUSION: The 2020 NCCN guidelines showed significantly higher sensitivity for prediction of R0 resection than the 2017 and 2019 guidelines.

Oncocytic type has distinct immunohistochemical and recurrence-free survival than other histologic types of the intraductal papillary neoplasm of the bile duct.

Although intraductal oncocytic papillary neoplasm (IOPN) was considered distinct from the intraductal papillary neoplasm of the pancreas, the oncocytic histologic type remained as a subtype of intraductal papillary neoplasms of the bile duct (IPNBs) with gastric, intestinal, and pancreatobiliary types based on the fifth edition of the WHO classification. To test the characteristics of the oncocytic type of IPNBs, the histopathologic, immunohistochemical (Hep Par-1 and CD117), and clinical characteristics of 13 oncocytic type were compared with 114 others (15 gastric, 39 pancreatobiliary, and 60 intestinal) IPNB types. The oncocytic type, which occupied about 9% of IPNBs, was more frequent in females (p < 0.05) and larger (mean, 5.3 vs. 3.6 cm; p < 0.002) than other IPNB types. Immunohistochemically, the oncocytic type had more frequent combined Hep Par-1 and CD117 expression than other IPNB types (all p < 0.05). The recurrence-free survival rate for patients with the oncocytic type (5-year survival, 100%) was significantly higher (p = 0.015) than for those with other histologic types (59.9%). The oncocytic type had distinct histopathologic, immunohistochemical, and survival outcomes from other IPNBs. Therefore, it can be separated from other IPNB types and classified as one independent entity, similar to IOPN of the pancreas.

Prognostic performance of microscopic size measurements in small invasive carcinomas arising in intraductal papillary mucinous neoplasms of the pancreas.

AIMS: Small invasive carcinomas arising in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can present as multiple, small foci. In such cases, there is no clear optimal measurement method for determining the invasive size for tumour staging and prognostication. METHODS: In all, 117 small invasive IPMNs (size of largest invasive component ≤2 cm) from seven institutions (2000-2016) were reviewed, and all individual foci of invasive carcinoma were measured. T stages (AJCC 8th edition) based on the largest single focus size (LS), average size of all foci (AS), and total sum of all foci (TS) were examined in association with clinicopathologic parameters and patient outcomes. RESULTS: The cohort comprised IPMNs with invasive tubular-type (n = 82, 70%) and colloid-type (n = 35, 30%) carcinomas. The mean LS, AS, and TS were 0.86, 0.71, and 1.32 cm, respectively. Based on the LS, AS, and TS, respectively, 48, 65, and 39 cases were classified as pT1a; 22, 18, and 11 cases as pT1b; and 47, 34, and 50 cases as pT1c. Higher pT stages based on all measurements were significantly associated with small vessel, large vessel, and perineural invasion (P < 0.05). LS-, AS-, and TS-based pT stages were not significantly associated with recurrence-free survival (RFS) or overall survival (OS) by univariate or multivariate analyses. However, among tubular-type carcinomas, higher LS-, AS-, and TS-based pT stages trended with lower RFS (based on 1-, 3-, and 5-year survival rates). All microscopic measurement methods were most predictive of RFS and OS using a 1.5-cm cutoff, with LS significantly associated with both RFS and OS by univariate and multivariate analysis. CONCLUSIONS: For invasive tubular-type carcinomas arising in IPMN, microscopic size-based AJCC pT stages were not significant predictors of patient outcomes. However, for LS, a size threshold of 1.5 cm was optimal for stratifying both RFS and OS. The AJCC 8th ed. may not be applicable for stratifying small invasive IPMNs with colloid-type histology that generally portend a more favourable prognosis.

Practice guidelines for managing extrahepatic biliary tract cancers.

Backgrounds/Aims: Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021. Methods: Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop. Results: In November 2021, the finalized draft was presented for public scrutiny during a formal hearing. Conclusions: The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.

Open-top Bessel beam two-photon light sheet microscopy for three-dimensional pathology.

Nondestructive pathology based on three-dimensional (3D) optical microscopy holds promise as a complement to traditional destructive hematoxylin and eosin (H&E) stained slide-based pathology by providing cellular information in high throughput manner. However, conventional techniques provided superficial information only due to shallow imaging depths. Herein, we developed open-top two-photon light sheet microscopy (OT-TP-LSM) for intraoperative 3D pathology. An extended depth of field two-photon excitation light sheet was generated by scanning a nondiffractive Bessel beam, and selective planar imaging was conducted with cameras at 400 frames/s max during the lateral translation of tissue specimens. Intrinsic second harmonic generation was collected for additional extracellular matrix (ECM) visualization. OT-TP-LSM was tested in various human cancer specimens including skin, pancreas, and prostate. High imaging depths were achieved owing to long excitation wavelengths and long wavelength fluorophores. 3D visualization of both cells and ECM enhanced the ability of cancer detection. Furthermore, an unsupervised deep learning network was employed for the style transfer of OT-TP-LSM images to virtual H&E images. The virtual H&E images exhibited comparable histological characteristics to real ones. OT-TP-LSM may have the potential for histopathological examination in surgical and biopsy applications by rapidly providing 3D information.

Chemistry of Polythiols and Their Industrial Applications.

Thiols can react with readily available organic substrates under benign conditions, making them suitable for use in chemical, biological, physical, and materials and engineering research areas. In particular, the highly efficient thiol-based click reaction includes the reaction of radicals with electron-rich enes, Michael addition with electron-poor enes, carbonyl addition with isocyanate SN2 ring opening with epoxies, and SN2 nucleophilic substitution with halogens. This mini review provides insights into emerging venues for their industrial applications, especially for the applications of thiol-ene, thiol-isocyanate, and thiol-epoxy reactions, highlighting a brief chemistry of thiols as well as various approaches to polythiol synthesis.

Malignant potential of neuroendocrine microtumor of the pancreas harboring high-grade transformation: lesson learned from a patient with von Hippel-Lindau syndrome.

Pancreatic neuroendocrine microtumor (PNEMT) is a neuroendocrine tumor (NET) < 0.5 cm in diameter, and it is considered benign. We report a PNEMT with high-grade transformation (HGT). A man in his 60s with von Hippel-Lindau syndrome underwent surgical resection of a NET. A second sub-centimeter nodule with a nodule-in-nodule pattern was discovered. The 0.4 cm outer nodule contained clear columnar cells with round nuclei and indistinct nucleoli, while the 0.1 cm inner nodule had eosinophilic cells with an increased nuclear to cytoplasmic ratio, vesicular nuclei, and prominent nucleoli. Tumor cells in the outer and inner nodules were synaptophysin and chromogranin positive. Only the inner nodule was p53 positive, while the outer nodule was exclusively positive for carbonic anhydrase 9 and vimentin. The Ki-67 labeling indices for the outer and inner nodules were 2.1% (grade 1) and 44.3% (grade 3), respectively. This nodule was determined to be a PNEMT with HGT. Our findings suggest that a PNEMT may not always be benign and can undergo HGT.

Uncovering the clinicopathological features of early recurrence after surgical resection of pancreatic cancer.

To identify risk factors and biomarker for early recurrence in patients diagnosed with pancreatic cancer who undergo curative resection. Early recurrence after curative resection of pancreatic cancer is an obstacle to long-term survival. We retrospectively reviewed 162 patients diagnosed with pancreatic cancer who underwent curative resection. Early recurrence was defined as recurrence within 12 months of surgery. We selected S100A2 as a biomarker and investigated its expression using immunohistochemistry. Of the total, 79.6% (n = 129) of patients received adjuvant chemotherapy after surgery and 117 (72.2%) experienced recurrence, of which 73 (45.1%) experience early recurrence. In multivariate analysis, age < 60 years, presence of lymph node metastasis, and no adjuvant chemotherapy were significantly associated with early recurrence (all P < 0.05). The proportion of patients with high S100A2 expression (H-score > 5) was significantly lower in the early recurrence group (41.5% vs. 63.3%, P = 0.020). The cumulative incidence rate of early recurrence was higher in patients with an S100A2 H-score < 5 (41.5% vs. 63.3%, P = 0.012). The median overall survival of patients with higher S100A2 expression was longer than those with lower S100A2 expression (median 30.1 months vs. 24.2 months, P = 0.003). High-risk factors for early recurrence after surgery for pancreatic cancer include young age, lymph node metastasis, and no adjuvant therapy. Neoadjuvant treatment or intensive adjuvant therapy after surgery may improve the prognosis of patients with high-risk signatures. In patients who receive adjuvant therapy, high S100A2 expression is a good predictor.

Somatostatin receptor 2 (SSTR2) expression is associated with better clinical outcome and prognosis in rectal neuroendocrine tumors.

Somatostatin analogues have recently been used as therapeutic targets for metastatic or surgically unresectable gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), and associated somatostatin receptor (SSTR) expression has been well demonstrated in most GEP NETs, with the exception of rectal NETs. SSTR2 immunohistochemical expressions were evaluated in 350 surgically or endoscopically resected rectal NETs and compared to clinicopathologic factors. SSTR2 expression was observed in 234 (66.9%) rectal NET cases and associated tumors with smaller size (p = 0.001), low pT classification (p = 0.030), low AJCC tumor stage (p = 0.012), and absence of chromogranin expression (p = 0.009). Patients with rectal NET and SSTR2 expression had significantly better overall survival than those without SSTR2 expression both by univariable (p = 0.006) and multivariable (p = 0.014) analyses. In summary, approximately two-thirds of rectal NETs expressed SSTR2. SSTR2 expression was significantly associated with favorable behavior and good overall survival in patients with rectal NETs. Furthermore, SSTR2 expression can be used as prognostic factors. When metastatic disease occurs, SSTR2 expression can be used a possible target for somatostatin analogues.

Clinical outcomes of second-line therapy following disease progression on first-line modified FOLFIRINOX for borderline resectable and locally advanced pancreatic adenocarcinoma.

BACKGROUND: Modified FOLFIRINOX (mFOLFIRINOX) is one of the standard first-line therapies in borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). However, there is no globally accepted second-line therapy following progression on mFOLFIRINOX. METHODS: Patients with BRPC and LAPC (n = 647) treated with first-line mFOLFIRINOX between January 2017 and December 2020 were included in this retrospective analysis. The details of the treatment outcomes and patterns of subsequent therapy after mFOLFIRINOX were reviewed. RESULTS: With a median follow-up duration of 44.2 months (95% confidence interval [CI], 42.3-47.6), 322 patients exhibited disease progression on mFOLFIRINOX-locoregional progression only in 177 patients (55.0%) and distant metastasis in 145 patients (45.0%). The locoregional progression group demonstrated significantly longer post-progression survival (PPS) than that of the distant metastasis group (10.1 vs. 7.3 months, p = 0.002). In the locoregional progression group, survival outcomes did not differ between second-line chemoradiation/radiotherapy and systemic chemotherapy (progression-free survival with second-line therapy [PFS-2], 3.2 vs. 4.3 months; p = 0.649; PPS, 10.7 vs. 10.2 months; p = 0.791). In patients who received second-line systemic chemotherapy following progression on mFOLFIRINOX (n = 211), gemcitabine plus nab-paclitaxel was associated with better disease control rates (69.2% vs. 42.3%, p = 0.005) and PFS-2 (3.8 vs. 1.7 months, p = 0.035) than gemcitabine monotherapy. CONCLUSIONS: The current study showed the real-world practice pattern of subsequent therapy and clinical outcomes following progression on first-line mFOLFIRINOX in BRPC and LAPC. Further investigation is necessary to establish the optimal therapy after failure of mFOLFIRINOX.