A prospective clinical and biological database for pancreatic adenocarcinoma: the BACAP cohort.

BACKGROUND: The prognosis for pancreatic cancer remains poor despite diagnostic advances and treatments with new chemotherapeutic regimens. The five year survival rate remains below 3%. Consequently, there is an urgent need for new treatments to significantly improve the prognosis. In addition, there is a big gap in terms of the screening, early diagnosis and prevention of pancreatic cancer the incidence of which is increasing dramatically. METHODS: Design: the BACAP cohort is a prospective multicenter pancreatic cancer cohort (pancreatic ductal carcinoma) with clinical and multiple biological samples; Participating centers: 15 French academic and private hospitals; Study Population: any cytologically and/or histologically proven pancreatic carcinoma regardless of the stage (resectable, borderline, locally advanced or metastatic) or treatment (surgery, palliative chemotherapy, best supportive care). At least 1500 patients will be included. Clinical data collected include: disease presentation, epidemiological and social factors, baseline biology, radiology, endoscopic ultrasound, staging, pathology, treatments, follow-up (including biological and radiological), and survival. All these data are collected and stored through an e-observation system at a centralized data center. Biological samples and derived products (i.e. before any treatment): blood, saliva, endoscopic ultrasound-guided fine needle aspiration materials from the primary tumor, fine needle biopsy of metastases and surgically resected tissue. DNA and RNA are extracted from fine needle aspiration materials and are quantified and characterized for quality. Whole blood, plasma and serum are isolated from blood samples. Frozen tissues were specifically allocated to the cohort. All derived products and saliva are stored at - 80 °C. Main end-points: i) to centralize clinical data together with multiple biological samples that are harmonized in terms of sampling, the post sampling process and storage; ii) to identify new molecular markers for the diagnosis, prognosis and possibly the predictive response to pancreatic cancer surgery and or chemotherapy. DISCUSSION: The BACAP cohort is a unique prospective biological clinical database that provides the opportunity to identify correlations between the presence/expression of a broad panel of biomarkers (DNA, RNA, miRNA, proteins, etc.), epidemiological and social data, various clinical situations, various stages and the differentiation of the tumor, treatments and survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02818829 . Registration date: June 30, 2016.

Pancreaticoduodenal Artery Pseudoaneurysm Associated with Pancreatic Fibroinflammatory Mass and Duodenal Obstruction.

BACKGROUND When people in their 60s experiences abdominal pain, vomiting, and unexplained weight loss without a history of abdominal surgery, the usual diagnosis is obstruction caused by a neoplastic mass. Nevertheless, in exceptionally rare cases, these symptoms arise from complications linked to a visceral artery aneurysm. CASE REPORT We present a case of a 60-year-old man with immunodeficiency and Sneddon-Wilkinson disease (a rare subcorneal pustular dermatosis), who developed a pancreaticoduodenal aneurysm of uncertain origin, associated with pancreatic mass, retroperitoneal hematoma, and duodenal obstruction. The treatment approach included transcatheter arterial coil embolization with supportive measures such as parenteral nutrition, a nasogastric tube, octreotide administration, and antiemetics. Despite these interventions, persistence gastrointestinal symptoms prompted an endoscopic ultrasound fine-needle aspiration to rule out malignancy. The biopsy confirmed localized fibro-inflammation. Although he was initially considered for a gastro-jejunal bypass, conservative management effectively improved the pancreatic lesion and duodenal obstruction, leading to discontinuation of parenteral nutrition. The patient was able to resume a regular diet 4 weeks after embolization. CONCLUSIONS Pancreaticoduodenal artery aneurysm is a rare visceral aneurysm with multiple etiologies and potentially fatal consequences. We report an unusual case of a pancreaticoduodenal artery aneurysm associated with pancreatic mass and duodenal obstruction. This diagnosis warrants consideration when an immunodeficient patient presents symptoms of abdominal pain and vomiting. Early endovascular embolization, combined with conservative approaches, effectively alleviated the symptoms in our patient.

Targeting HER2 in metastatic gastroesophageal adenocarcinomas: What is new?

Gastric and esophageal adenocarcinomas represent a biologically heterogeneous disease. The identification, in early eighties, of human epidermal growth factor receptor 2 (HER2) overexpression, being present in 12 to 20% of the cases, marked a major milestone in the efforts of unraveling the molecular complexity of this disease. This led to the development of anti-HER2-therapies, trastuzumab being the first to demonstrate, in combination with cisplatin and 5FU/capecitabine chemotherapy, an improvement in response rate and survival in the first-line setting of patients with metastatic, HER2-positive gastroesophageal adenocarcinomas. Afterwards, during a decade, several studies have tried new strategies either to block HER2 pathway differently or to combine different anti-HER2, without efficacy. Everything changed with studies demonstrating additive effect between anti-HER2 and immune checkpoint inhibitors and leading to phase III clinical trials combining anti-HER2 and anti-PD-L1/PD1 therapies. Pembrolizumab, a PD-1 inhibitor, was recently granted by FDA an accelerated approval, in patients with HER2-positive gastro-oesophageal adenocarcinomas, in combination with trastuzumab and platinum-based chemotherapy following meaningful improvement in overall response rate over standard treatment. Progression-free and overall-survival results are still awaited to change our first-line standard treatment. Furthermore, new HER2 inhibitors have been developed, blocking HER2-mediated pathway signaling via different mechanisms from pan-HER inhibition to anti-HER2 antibody drug conjugates with promising results in pretreated patients. Trastuzumab-deruxtecan has in particular showed interesting results in pretreated patients. We present here a review of the recent data and perspectives in HER2-positive metastatic gastroesophageal adenocarcinomas.

A Promising Biomarker and Therapeutic Target in Patients with Advanced PDAC: The Stromal Protein ßig-h3.

With an overall survival rate of 2-9% at 5 years, pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related deaths in the industrialized world and is predicted to become the second by 2030. Owing to often late diagnosis and rare actionable molecular alterations, PDAC has not yet benefited from the recent therapeutic advances that immune checkpoint inhibitors (ICI) have provided in other cancer types, except in specific subgroups of patients presenting with tumors with high mutational burden (TMB) or microsatellite instability (MSI). The tumor microenvironment (TME) plays a substantial role in therapeutic resistance by facilitating immune evasion. An extracellular stromal protein, ßig-h3/TGFßi, is involved in the pathogenesis of PDAC by hampering T cell activation and promoting stiffness of the TME. The study BIGHPANC included 41 patients with metastatic PDAC, and analyzed ßig-h3 levels in serum and tumor samples to assess the ßig-h3 prognostic value. ßig-h3 serum levels are significantly associated with overall survival (HR 2.05, 95%CI 1.07-3.93; p = 0.0301). Our results suggest that ßig-h3 serum levels may be considered a prognostic biomarker in patients with metastatic PDAC.

Precision medicine for patients with gastro-oesophageal cancer: A subset analysis of the ProfiLER program.

BACKGROUND: Chemotherapy, anti-HER2 and PD-1 antibodies are standard treatments but only a minority of patients derive long-term benefit from these agents. METHODS: In this report we describe the mutational landscape and outcome of patients with gastroesophageal cancers enroled in the ProfiLER program. RESULTS: Adenocarcinoma (n = 86, 59%), signet-cell (n = 37, 25%) and squamous-cell (n = 21, 14%) were the dominant histology amongst 147 patients. Genomic analyses could be performed for 114 (78%) patients. The most common genomic alterations involved ERBB2 (15%), KRAS (12%), CCND1 (7%), FGFR1-3 (8%), EGFR (5%) and MET (3%), TP53 (51%) and CDKN2A/B (10%). ERBB2, MET and FGFR alterations were found exclusively in the adenocarcinoma and signet-cell subtypes, while CCND1 amplification, TP53 mutations and CDKN2A/B loss were found in both adenocarcinoma and squamous-cell subtypes. Nine patients (8%) received therapy matched to their genomic alteration, with 5 of them achieving disease control. In an exploratory analysis, patients with stage IV disease at diagnosis who had an actionable alteration had longer overall survival compared to those without. CONCLUSION: Genomic profiling for patients with advanced gastroesophageal cancers allows the identification of actionable alterations in large proportion of patients. Increased accessibility to molecularly matched therapy may improve survival in this disease.

A human mandible (BH-1) from the Pleistocene deposits of Mala Balanica cave (Sicevo Gorge, Nis, Serbia).

Neandertals and their immediate predecessors are commonly considered to be the only humans inhabiting Europe in the Middle and early Late Pleistocene. Most Middle Pleistocene western European specimens show evidence of a developing Neandertal morphology, supporting the notion that these traits evolved at the extreme West of the continent due, at least partially, to the isolation produced by glacial events. The recent discovery of a mandible, BH-1, from Mala Balanica (Serbia), with primitive character states comparable with Early Pleistocene mandibular specimens, is associated with a minimum radiometric date of 113 + 72 - 43 ka. Given the fragmented nature of the hemi-mandible and the fact that primitive character states preclude assignment to a species, the taxonomic status of the specimen is best described as an archaic Homo sp. The combination of primitive traits and a possible Late Pleistocene date suggests that a more primitive morphology, one that does not show Neandertal traits, could have persisted in the region. Different hominin morphologies could have survived and coexisted in the Balkans, the "hotspot of biodiversity." This first hominin specimen to come from a secure stratigraphic context in the Central Balkans indicates a potentially important role for the region in understanding human evolution in Europe that will only be resolved with more concentrated research efforts in the area.

Hyperprogressive Disease After Combined Anti-PD-L1 and Anti-CTLA-4 Immunotherapy for MSI-H/dMMR Gastric Cancer: A Case Report.

Immune checkpoint inhibitors (ICI) have been developed in gastric adenocarcinomas and approved in first-line metastatic setting (in combination with chemotherapy) as well as in pretreated patients. Microsatellite instability-high (MSI-H) tumors are predicted to derive high benefit from ICI but data in gastric locations are limited. Here, we describe the case of a 68-year old patient with stage IV MSI-H gastric adenocarcinoma, referred to our center to receive immunotherapy after failure of standard of care (surgery with perioperative platin-based chemotherapy and paclitaxel plus ramucirumab at disease progression). The patient received one injection of durvalumab and tremelimumab and was hospitalized eighteen days after because of occlusive syndrome. The CT scan showed hyperprogression of the lymph nodes and hepatic lesions, compressing the gastric stump. He died few days later. Molecular analyses did not explain this outcome. To our knowledge, this is one of the first reported cases of hyperprogressive disease after combined ICI for a patient with MSI-H tumor. We review the potential causes and discuss the emerging literature regarding predictive factors of hyperprogression in the particular subset of MSI-H patients. If some data were available in retrospective studies, validation of strong predictive factors is needed to avoid such dramatic evolutions.

A New Score to Predict the Resectability of Pancreatic Adenocarcinoma: The BACAP Score.

Surgery remains the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Therefore, a predictive score for resectability on diagnosis is needed. A total of 814 patients were included between 2014 and 2017 from 15 centers included in the BACAP (the national Anatomo-Clinical Database on Pancreatic Adenocarcinoma) prospective cohort. Three groups were defined: resectable (Res), locally advanced (LA), and metastatic (Met). Variables were analyzed and a predictive score was devised. Of the 814 patients included, 703 could be evaluated: 164 Res, 266 LA, and 273 Met. The median ages of the patients were 69, 71, and 69, respectively. The median survival times were 21, 15, and nine months, respectively. Six criteria were significantly associated with a lower probability of resectability in multivariate analysis: venous/arterial thrombosis (p = 0.017), performance status 1 (p = 0.032) or ≥ 2 (p = 0.010), pain (p = 0.003), weight loss ≥ 8% (p = 0.019), topography of the tumor (body/tail) (p = 0.005), and maximal tumor size 20-33 mm (p < 0.013) or >33 mm (p < 0.001). The BACAP score was devised using these criteria (http://jdlp.fr/resectability/) with an accuracy of 81.17% and an area under the receive operating characteristic (ROC) curve of 0.82 (95% confidence interval (CI): 0.78; 0.86). The presence of pejorative criteria or a BACAP score < 50% indicates that further investigations and even neoadjuvant treatment might be warranted. Trial registration: NCT02818829.

Primary malignant melanoma of the esophagus, treated with immunotherapy: a case report.

Primary malignant melanoma of the esophagus is rare, accounting for less than 0.1-0.2% of all esophageal malignancies. It is associated with a poor outcome due to late detection and high metastatic potential. Here, we report a case of esophageal cancer, which was initially diagnosed as an adenocarcinoma and finally was confirmed as a primary malignant melanoma. This 75-year-old Caucasian male had a history of dysphagia and recent lingering abdominal pain. First biopsy showed a poorly-differentiated adenocarcinoma. He was then treated with neoadjuvant radiochemotherapy. Biopsies were repeated because of an incomplete tumor response, evaluated by endoscopic and imaging studies. The final diagnosis was a malignant melanoma. The patient has been treated with immune-checkpoint inhibitor, nivolumab, an anti-PD1 antibody.

Use of gemcitabine as a second-line treatment following chemotherapy with folfirinox for metastatic pancreatic adenocarcinoma.

There is a lack of prospective data about second-line treatments for metastatic pancreatic ductal adenocarcinoma patients. This is partially due to recent changes in first-line chemotherapy treatments. Despite this dearth of information, 50.0% of the patients who experience failure with first-line folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (folfirinox) treatment are eligible for additional chemotherapy. In this setting, gemcitabine is widely used without any standard recommendations available. The present study evaluated 42 patients who received gemcitabine subsequent to a first-line treatment of folfirinox between January 2008 and December 2012 at the Centre Léon Bérard (Lyon, France). Clinical data, biological data and tumor characteristics were retrospectively analyzed to identify prognostic factors for successful treatment with gemcitabine. In total, 11 patients (26.2%) experienced control of their cancer with gemcitabine treatment. However, there was no predictive marker for their response to the drug. The median overall survival was 3.6 months from gemcitabine initiation [95% confidence interval (CI), 2.1-5.1]. The median length of gemcitabine treatment was 1.5 months (95% CI, 0.3-13.3). Among the 11 patients who were successfully treated with gemcitabine, 6 were resistant to first-line folfirinox treatment. Patients who were non responsive to folfirinox had a higher probability of success with gemcitabine compared with patients that responded to folfirinox (54.5 vs. 21.4%, respectively; P=0.061). The present study did not identify any clinical or biological marker with a predictive value for successful gemcitabine treatment. Furthermore, successful gemcitabine treatment was not correlated with patients' response to first-line folfirinox treatment. This suggests an absence of cross-resistance in the chemotherapy protocols and provides evidence for effective cancer treatment with the second-line gemcitabine therapy.

Cisplatin pharmacokinetics in nontumoral pig liver treated with intravenous or transarterial hepatic chemoembolization.

PURPOSE: To evaluate cisplatin (CDDP) pharmacokinetics after its intravenous (IV) or intrahepatic arterial administration (IHA) in healthy pigs with or without embolization by absorbable gelatine. MATERIAL AND METHODS: We analysed plasmatic and hepatic drug concentration in four groups of six mini-pigs each according to the modality of administration of CDDP (1 mg/kg): IV, IHA, IHA with partial embolization using absorbable gelatine (IHA-Pe), and IHA with complete embolization (IHA-Te). Unbounded plasmatic and hepatic platinum concentrations were measured. Concentration and pharmacokinetics parameters were compared using analysis of variance. RESULTS: For all groups, there was a rapid and biexponential decrease in free platinum concentration. Plasmatic terminal half-life (T(1/2)) was significantly decreased after embolization at 191, 178, 42, and 41 min after IV, IHA, IHA-Pe, and IHA-Te administration, respectively. Maximal plasmatic concentration and systemic exposure to CDDP (AUC(24)) values were significantly decreased after embolization (C(max) p = 0.0075; AUC(24) p = 0.0053). Hepatic CDDP concentration rapidly peaked and then decreased progressively. After 24 h, the residual concentration represented 45, 47, 60, and 63 % of C(max), respectively, after IV, IHA, IHA-Pe, and IHA-Te. Hepatic T(1/2) and AUC(∞) values were increased after embolization, but the differences were not statistically significant. CONCLUSION: This preliminary study confirms the feasibility of a pig model to study systemic and hepatic CDDP pharmacokinetics. Systemic exposure is lower after embolization, which could minimize systemic toxicity. Hepatic T(1/2) elimination and hepatic exposition values are increased with IHA compared with IV administration.