De novo expression of gastrokines in pancreatic precursor lesions impede the development of pancreatic cancer

Molecular events occurring in stepwise progression from pre-malignant lesions (pancreatic intraepithelial neoplasia; PanIN) to the development of pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Thus, characterization of early PanIN lesions may reveal markers that can help in diagnosing PDAC at an early stage and allow understanding the pathology of the disease. We performed the molecular and histological assessment of patient-derived PanINs, tumor tissues and pancreas from mouse models with PDAC (KC mice that harbor K-RAS mutation in pancreatic tissue), where we noted marked upregulation of gastrokine (GKN) proteins. To further understand the role of gastrokine proteins in PDAC development, GKN-deficient KC mice were developed by intercrossing gastrokine-deficient mice with KC mice. Panc-02 (pancreatic cancer cells of mouse origin) were genetically modified to express GKN1 for further in vitro and in vivo analysis. Our results show that gastrokine proteins were absent in healthy pancreas and invasive cancer, while its expression was prominent in low-grade PanINs. We could detect these proteins in pancreatic juice and serum of KC mice. Furthermore, accelerated PanIN and tumor development were noted in gastrokine deficient KC mice. Loss of gastrokine 1 protein delayed apoptosis during carcinogenesis leading to the development of desmoplastic stroma while loss of gastrokine 2 increased the proliferation rate in precursor lesions. In summary, we identified gastrokine proteins in early pancreatic precursor lesions, where gastrokine proteins delay pancreatic carcinogenesis

ASO Visual Abstract: FOLFIRINOX or Gemcitabine Based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-Institutional, Patient-Level Meta-Analysis and Systematic Review

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FOLFIRINOX or Gemcitabine-based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-institutional, Patient-Level, Meta-analysis and Systematic Review

BackgroundPancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC.MethodsWe performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based.ResultsA total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC.ConclusionsIn patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting

Serum procalcitonin improves diagnosis of infectious complications after CRS/HIPEC

Abstract Background Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improve the survival of selected patients with peritoneal metastasis. A major cause of treatment-related morbidity after CRS/HIPEC is infection and sepsis. HIPEC alters the diagnostic sensitivity and specificity of blood and serum markers and therefore has an impact on early diagnosis of postoperative complications. This study aimed to assess the sensitivity and specificity of blood and serum markers after CRS/HIPEC. Methods Patients from two centers, operated between 2009 and 2017, were enrolled in this study. Perioperative blood samples were analyzed for white blood cells (WBC), C-reactive protein (CRP), and procalcitonin (PCT); postoperative complications were graded according to Clavien-Dindo and infectious complications according to CDC criteria. Results Overall, n=248 patients were included with peritoneal metastasis from different primary tumors treated by CRS/HIPEC. Depending on the applied HIPEC protocol, patients presented a suppressed WBC response to infection. In addition, a secondary and unspecific CRP elevation in absence of an underlining infection, and pronounced after prolonged perfusion for more than 60 min. PCT was identified as a highly specific — although less sensitive — marker to diagnose infectious complications after CRS/HIPEC. Discussion/conclusion Sensitivity and specificity of WBC counts and CRP values to diagnose postoperative infection are limited in the context of HIPEC. PCT is helpful to specify suspected infection. Overall, diagnosis of postoperative complications remains a clinical diagnosis, requiring surgical expertise and experience

18FDG-PET-CT identifies histopathological non-responders after neoadjuvant chemotherapy in locally advanced gastric and cardia cancer: cohort study

BACKGROUND Pathologic response to neoadjuvant chemotherapy (neoCTX) is a prognostic factor in many cancer types, and early prediction would help to modify treatment. In patients with gastric and esophagogastric junction (AEG) cancer, the accuracy of FDG PET-CT to predict early pathologic response after neoadjuvant chemotherapy (neoCTX) is currently not known. METHODS From a consecutive cohort of 72 patients, 44 patients with resectable, locally-advanced gastric cancer or AEG Siewert type II and III received neoCTX after primary staging with endoscopic ultrasound, PET-CT and laparoscopy. Overall, 14 patients did not show FDG uptake, and the remaining 30 were restaged by PET-CT 14 days after the first cycle of neoCTX. Metabolic response was defined as decrease of tumor standardized uptake value (SUV) by ≥35%. Major pathologic regression was defined as less than 10% residual tumor cells. RESULTS Metabolic response after neoCTX was detected in 20/30 (66.7%), and non-response in 10/30 (33.3%) patients. Among metabolic responders, n = 10 (50%) showed major and n = 10 (50%) minor pathologic regression. In non-responders, n = 9 (90%) had minor and 1 (10%) a major pathologic regression. This resulted in a sensitivity of 90.9%, specificity 47.3%, positive predictive value 50%, negative predictive value 90% and accuracy of 63.3%. CONCLUSION Response PET-CT after the first cycle of neoCTX does not accurately predict overall pathologic response. However, PET-CT reliably detects non-responders, and identifies patients who should either immediately proceed to resection or receive a modified multimodality therapy. TRIAL REGISTRATION The trial was registered and approved by local ethics committee PB_2016-00769

Gastric Cancer with Positive Peritoneal Cytology: Survival Benefit after Induction Chemotherapy and Conversion to Negative Peritoneal Cytology

Background The optimal treatment in patients with gastric cancer and peritoneal disease remains controversial. Some guidelines indicate palliative treatment only, while others consider surgical treatment in case of positive lavage cytology (CY+) or limited peritoneal disease. Here, we analyzed the role of peritoneal disease in patients with gastric cancer, and the prognostic relevance of response to neoadjuvant therapy. Methods In this retrospective cohort analysis, we analyzed patients with adenocarcinoma of the stomach or esophago-gastric junction from a single center operated between 2011 and 2019. According to histology and lavage cytology, patients were classified into four risk groups: (A) no peritoneal disease, (B) CY+ who converted to negative lavage cytology (CY−) after neoadjuvant chemotherapy, (C) CY+ without conversion after chemotherapy, and (D) patients with visible peritoneal metastasis. Results Overall, n = 172 patients were included. At initial presentation, n = 125 (73%) had no peritoneal disease, and about a third of patients (n = 47, 27%) had microscopic or macroscopic peritoneal disease. Among them, n = 14 (8%) were CY+ without visible peritoneal metastasis, n = 9 converted to CY− after chemotherapy, and in n = 5 no conversion was observed. Median overall survival was not reached in patients who had initially no peritoneal disease and in patients who converted after chemotherapy, resulting in 3-year survival rates of 65% and 53%. In contrast, median overall survival was reduced to 13 months (95% CI 8.7–16.7) in patients without conversion and was 16 months (95% CI 12–20.5) in patients with peritoneal metastasis without difference between the two groups (p = .364). The conversion rate from CY+ to CY− was significantly higher after neoadjuvant treatment with FLOT (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel) compared to ECF (epirubicin, cisplatin, and 5-fluorouracil) (p = 0.027). Conclusion Conversion of CY+ to CY− after neoadjuvant chemotherapy with FLOT is a significant prognostic factor for a better overall survival. Surgical treatment in well-selected patients should therefore be considered. However, peritoneal recurrence remains frequent despite conversion, urging for a better local control

Systemic inflammatory response after Hyperthermic Intraperitoneal Hemotherapy (HIPEC): the perfusion protocol matters!

BACKGROUND:: CRS/HIPEC gained acceptance as a treatment for selected patients with peritoneal metastasis. However, the pathophysiology behind HIPEC is poorly understood, and a variety of regimens are currently in use. In this study, we describe for the first-time changes in the postoperative systemic inflammatory reaction, highly different among HIPEC treatment protocols. METHODS:: HIPEC was performed with three protocols, different with regard to perfusion times and drugs: (mitomycinC/doxorubicin, 90min), (cisplatin, 90min) (oxaliplatin, 30min). Serial blood samples were assessed for C-reactive protein (CRP), white blood cells (WBC), pancreatic stone protein (PSP) and bacterial component (16s rDNA). The study was approved by the local ethics committee and registered at clinicaltirals.gov (NCT02741167). RESULTS:Overall, 140 patients from two European centers were included. In patients without postoperative complications, a secondary peak of inflammatory parameters, CRP (p = 0.015) and PSP (p = 0.004) was observed after HIPEC for 90 min with mitomycinC/doxorubicin or cisplatin but not after 30 min oxaliplatin. In patients after 90 min HIPEC, postoperative serum bacterial 16srDNA level were 2.1 times higher (95% CI 0.646-3.032, p = 0.015) compared to 30 min oxaliplatin. DISCUSSION: In conclusion, we identified a secondary inflammatory reaction after 90 min HIPEC, either with mitomycinC/doxorubicin or cisplatin, not observed after short course HIPEC with oxaliplatin. This protocol dependent physiology of acute phase proteins should be known in the clinical management of patients after HIPEC