Pancreatic Cancer-Secreted Proteins: Targeting Their Functions in Tumor Microenvironment.

Pancreatic Ductal Adenocarcinoma (PDAC) is a ravaging disease with a poor prognosis, requiring a more detailed understanding of its biology to foster the development of effective therapies. The unsatisfactory results of treatments targeting cell proliferation and its related mechanisms suggest a shift in focus towards the inflammatory tumor microenvironment (TME). Here, we discuss the role of cancer-secreted proteins in the complex TME tumor-stroma crosstalk, shedding lights on druggable molecular targets for the development of innovative, safer and more efficient therapeutic strategies.

Rare causes of acute non-variceal upper gastrointestinal bleeding: A comprehensive review.

Non-variceal upper gastrointestinal bleeding (NVUGIB) is a common gastroenterological emergency associated with significant morbidity and mortality. Gastroenterologists and other involved clinicians are generally assisted by international guidelines in its management. However, NVUGIB due to peptic ulcer disease only is mainly addressed by current guidelines, with upper gastrointestinal endoscopy being recommended as the gold standard modality for both diagnosis and treatment. Conversely, the management of rare and extraordinary rare causes of NVUGIB is not covered by current guidelines. Given they are frequently life-threatening conditions, all the involved clinicians, that is emergency physicians, diagnostic and interventional radiologists, surgeons, in addition obviously to gastroenterologists, should be aware of and familiar with their management. Indeed, they typically require a prompt diagnosis and treatment, engaging a dedicated, patient-tailored, multidisciplinary team approach. The aim of our review was to extensively summarize the current evidence with regard to the management of rare and extraordinary rare causes of NVUGIB.

Prospective minimally invasive pancreatic resections from the IGOMIPS registry: a snapshot of daily practice in Italy on 1191 between 2019 and 2022.

This retrospective analysis of the prospective IGOMIPS registry reports on 1191 minimally invasive pancreatic resections (MIPR) performed in Italy between 2019 and 2022, including 668 distal pancreatectomies (DP) (55.7%), 435 pancreatoduodenectomies (PD) (36.3%), 44 total pancreatectomies (3.7%), 36 tumor enucleations (3.0%), and 8 central pancreatectomies (0.7%). Spleen-preserving DP was performed in 109 patients (16.3%). Overall incidence of severe complications (Clavien-Dindo ≥ 3) was 17.6% with a 90-day mortality of 1.9%. This registry analysis provided some important information. First, robotic assistance was preferred for all MIPR but DP with splenectomy. Second, robotic assistance reduced conversion to open surgery and blood loss in comparison to laparoscopy. Robotic PD was also associated with lower incidence of severe postoperative complications and a trend toward lower mortality. Fourth, the annual cut-off of ≥ 20 MIPR and ≥ 20 MIPD improved selected outcome measures. Fifth, most MIPR were performed by a single surgeon. Sixth, only two-thirds of the centers performed spleen-preserving DP. Seventh, DP with splenectomy was associated with higher conversion rate when compared to spleen-preserving DP. Eighth, the use of pancreatojejunostomy was the prevalent reconstruction in PD. Ninth, final histology was similar for MIPR performed at high- and low-volume centers, but neoadjuvant chemotherapy was used more frequently at high-volume centers. Finally, this registry analysis raises important concerns about the reliability of R1 assessment underscoring the importance of standardized pathology of pancreatic specimens. In conclusion, MIPR can be safely implemented on a national scale. Further analyses are required to understand nuances of implementation of MIPR in Italy.

Stocky/Packed Pancreas: A Case of Focal Drug-Induced Acute Pancreatitis Mimicking Cancer.

Drug-induced acute pancreatitis (DIP) is a recognised but underreported entity in the literature. Immunotherapy drugs have been described as one possible emerging cause, although the pathogenic mechanism is still largely unclear. To date, only a few cases have been reported, even if in recent times there is an over-increasing awareness of this pathologic entity. The imaging-based diagnosis of DIP can be difficult to establish, representing a real challenge for a radiologist, especially when the inflammatory disease appears as a focal mass suspicious for a malignancy. Case report: We herein report the case of a 71-year-old man with a known history of partially responsive lung adenocarcinoma subtype with high programmed cell death ligand 1 (PD-L1) expression, who underwent positron emission tomography (PET)/computed tomography (CT) imaging follow-up after one year of immunotherapy. The exam revealed a stocky/packed lesion in the pancreatic body, with increased 18F-fluorodeoxyglucose (FDG) accumulation highly suggestive of pancreatic cancer, which finally was proven to be a DIP induced by immunotherapy. Conclusion: Distinguishing between focal DIP and pancreatic neoplasm is, therefore, crucial for timely therapeutic management and prognostic stratification. A deep knowledge of possible imaging pitfalls coupled with a comprehensive clinical and laboratory assessment is pivotal to avoid any delays in diagnosis.

The Italian National Registry for minimally invasive pancreatic surgery: an initiative of the Italian Group of Minimally Invasive Pancreas Surgery (IGoMIPS).

The value of minimally invasive pancreatic surgery (MIPS) is still uncertain, despite the growing number of publications, including reviews and meta-analyses, and the quick diffusion of these procedures worldwide. The Italian Group of Minimally Invasive Pancreas Surgery (IGoMIPS) was created under the auspices of three Scientific Societies: Associazione Italiana Studio Pancreas (AISP), Associazione Italiana Chirurgia Epato-Bilio-Pancreatica (AICEP, former IT-IHPBA), and Società Italiana di Chirurgia Endoscopica (SICE). The main aim of IGoMIPS is to develop and implement a national registry for MIPS. IGoMIPS was founded on February 22, 2019 in Pisa. The IGoMIPS registry became operational in September 2019, following approval by the Ethic Committees of founding Institutions, inscription into the Registry of Patient Registries (RoPR), and a wrap-up meeting held in Bologna during the Annual Congress of the Italian Surgical Society. During this meeting IGoMIPS members approved that the Italian Registry will provide data to the European Registry, while retaining the right to analyze and publish Italian data. An audience survey was also conducted to obtain information on perceived value and current implementation of MIPS in founding Institutions. MIPS is performed in 94.7% of IGoMIPS centers, including pancreaticoduodenectomy in 42.1%. Robotic assistance was employed in 52.6% of Institutions. The annual volume of MIPS was 6-10 cases in 38.9% of the centers, 11-20 cases in 16.7%, 21-30 cases in 22.2%, and > 30 cases in 22.2%. The registry was felt to be extremely important for both safety improvement and educational purposes by 94.5% of the centers.

First line nab-paclitaxel plus gemcitabine in elderly metastatic pancreatic patients: a good choice beyond age.

BACKGROUND: Nab-paclitaxel plus gemcitabine represents one of the standard regimens for first line treatment of metastatic pancreatic cancer (mPC). Few data are available on nab-paclitaxel plus gemcitabine in geriatric population. Our study aims to show whether this schedule can be feasible in the elderly as first-line treatment for mPC. METHODS: We retrospectively analyzed the data of 64 mPC patients (≥65 years old) treated according to the MPACT schedule. RESULTS: Median age was 69.5 years (range, 65-80 years); after a median of 5 cycles administered (range, 1-12), the most common adverse events (AEs) were grade 2 alopecia (46.9%), anemia (17.2%) and hypertransaminasemia (10.9%); all grades neutropenia occurred in 20.3% of pts. Global incidence of grade 3 and 4 toxicities were 26.5% and 0%, respectively, and no patients stopped treatment due to unacceptable toxicity. Stable disease (SD) was observed in 31.2% of patients, with a disease control rate (DCR) and overall response rate of 57.8% and 26.6%, respectively. After a median follow-up of 18 months, median progression free survival (PFS) was 8 months (95% CI: 6.3-9.6) and median OS was 12.0 months (95% CI: 8.4-15.6). The univariate analysis for overall survival (OS) showed that only ECOG performance status was an independent prognostic factor for survival. CONCLUSIONS: Nab-paclitaxel plus gemcitabine schedule is feasible and effective in the "daily clinical practice" geriatric population.

Nab-paclitaxel plus gemcitabine as first line therapy in metastatic pancreatic cancer patients relapsed after gemcitabine adjuvant treatment.

Nab-paclitaxel plus gemcitabine (Nab-Gem) represents one of the standard regimen for first-line treatment of metastatic pancreatic adenocarcinoma (mPDAC). However, few data are available in mPDAC relapsed after gemcitabine as adjuvant treatment. Our study aims to evaluate the efficacy and feasibility of Nab-Gem as first-line treatment for mPDAC patients previously treated with adjuvant treatment. We retrospectively analyzed the safety and efficacy data of 36 patients, who received first-line Nab-Gem after gemcitabine as adjuvant treatment. All patients received gemcitabine after radical surgery. Median disease-free survival was 12 months (95% CI 9.7-14.3); at relapse, all patients received Nab-Gem. We observed an objective response rate and disease control rate of 11.1% and 63.9%, respectively. With a median follow-up of 47 months, median progression-free survival was 5 months (95% CI 1.0-9.0), whereas median overall survival (OS) was 13 months (95% CI 5.5-20.5). Median OS was higher in patients with a relapse ≥ 7 months after the end of adjuvant treatment than in patients relapsed < 7 months (14 vs. 8 months, respectively, p: 0.52). Our results show that first-line Nab-Gem is feasible and effective in patients previously treated with gemcitabine as adjuvant treatment.

Occurrence of second primary malignancies in patients with neuroendocrine tumors of the digestive tract: A case report.

RATIONALE: There is an association between the presence of neuroendocrine neoplasms and incremented risk to develop second primary malignancies. This risk is estimated to be 17%. The most common secondary neoplasms were found in the Gastrointestinal and Genitourinary tracts. PATIENT CONCERNS: A 74-year-old Caucasian patient with melaena came to our observation in June 2015. The Esophago-gastro-duodenoscopy exam found a polypoid formation in the duodenal bulb. Histopathological examination showed a well-differentiated neuroendocrine neoplasm (G1). DIAGNOSIS: During the follow up for the neuroendocrine neoplasm, a CT scan was performed in August 2016 describing infiltration of the right renal sinus and the third proximal ureter segment with heterogeneous enhancement of vascular structure. An US-guided biopsy was conclusive for a Diffuse Large B Cell Lymphoma. In October 2016, a colonoscopy showed a neoplastic lesion at 20 cm from the anal orifice. The Histology exam was positive for an adenocarcinoma with a desmoplastic stroma infiltration. INTERVENTIONS: In November 2016, the patient underwent a left hemicolectomy: the pathologic staging described a G2 adenocarcinoma pT3N1b. In May 2018, the Octreotide scan was negative. In the same month, the patient started a treatment based on 6 cycles of Rituximab, Oxaliplatin, and Capecitabine due to the persistence of lymphomatous disease and hepatic metastases. In July 2018, other 3 cycles of the same treatment were scheduled. OUTCOMES: In January 2019, due to an increase in liver metastases' size, it was decided to start a new regimen for the colon cancer with FOLFIRI+Cetuximab. The patient is still in treatment with this regimen in April 2019. LESSONS: The risk of a second primary tumor is increased among patients older than 70. Therefore, it is necessary to follow them using total body CT scan and endoscopic techniques of gastrointestinal and genitourinary tracts, not only for the evaluation of the neuroendocrine tumor but also for the higher risk to develop other neoplastic diseases.

Preoperative diagnosis and surgical treatment for giant retroperitoneal liposarcoma: A case report.

INTRODUCTION: The purpose of this article is to present the diagnostic and surgical approach for a giant retroperitoneal sarcoma and to highlight the difficulty of a precise preoperative diagnosis and the extention of surgical resection. PRESENTATION OF CASE: A 63-year-old female patient was admitted at our department with light diffuse abdominal pain, fever and gradual increase of abdominal girth. A CT scan showed a giant fatty tumor occupying left hemiabdomen and indirect findings of renal damage, probably sustained by ureter stretching and urine stasis. At surgical exploration, no cleavage plane was discovered between the mass and the surrounding organs. The severe pielonephritis and the apparent intraoperatively involvement of surrounding tumour structures lead to an aggressive surgery. An "en-bloc" resection of tumor mass, left colon, spleen, pancreatic tail, left annex, left kidney and adrenal gland was performed. Histology revealed a well differentiated liposarcoma with large areas of high grade of dedifferentiation. DISCUSSION: Liposarcoma is an histologic subtype of soft tissue sarcoma and the most common type of sarcoma arising in retroperitoneum. It is difficult to make an accurate preoperative diagnosis through a percutaneous biopsy. Although it is required to obtain negative resection margins, literature shows that surgical radicality is not a primary endpoint if noble structures are strictly close. In some cases surgery must be more aggressive because of the apparent organ involvement or damage. CONCLUSION: This is a rare case of a giant liposarcoma involging many organs. Surgery should be tailored according to intraoperative findings and organ damage.

Dissecting the roles of thymoquinone on the prevention and the treatment of hepatocellular carcinoma: an overview on the current state of knowledge.

Thymoquinone (TQ) is the principal active monomer isolated from the seed of the medicinal plant Nigella sativa. This compound has antitumor effects against various types of cancer including hepatocellular carcinoma (HCC), mainly due to its anti-inflammatory and anti-oxidant properties. Several pre-clinical studies showed that TQ, through the modulation of different molecular pathways, is able to induce anti-apoptotic and anti-proliferative effects in HCC, without signs of toxicity. Moreover, it has been suggested that TQ has hepatoprotective effects by enhancing the tolerability and effectivity of neoadjuvant therapy prior to liver surgery, although the underlying mechanisms are not completely understood. Based on these findings, is assumable that TQ could represent a valuable therapeutic option for patients suffering from HCC. In this review, we summarize the potential roles of TQ in the prevention and treatment of HCC, by revising the preclinical studies and by highlighting the potential applications of TQ as a therapeutic choice for HCC treatment into clinical practices.

Epigallocatechin-3-gallate in the prevention and treatment of hepatocellular carcinoma: experimental findings and translational perspectives.

Hepatocellular carcinoma (HCC), a primary liver malignancy, is one of the deadliest cancers worldwide. Despite orthotopic liver transplantation and hepatic resection representing the principal lines of treatment for this pathology, only a minority of patients can be resected owing to cirrhosis or late diagnosis. Keeping in mind the end goal of conquering these challenges, new alternative approaches have been proposed. Accumulating evidence has demonstrated that epigallocatechin-3-gallate (EGCG), the principal catechin of green tea with multiple biological properties, is able to modulate different molecular mechanisms underlying HCC, mainly through its antioxidant activity. In this article, we revise these findings reported in the literature, in order to highlight the potential roles of EGCG in the treatment of HCC. The CAMARADES criteria were applied for quality assessment of animal studies, and a narrative synthesis performed. New bits of information available for translational perspectives into clinical practice are addressed.

The effectiveness of Hemopatch™ in preventing postoperative distal pancreatectomy fistulas.

OBJECTIVES: Postoperative fistula after distal pancreatectomy (DP) is still a significant complication, although many tools and tips have been utilized to try to reduce its elevated frequency. This paper focuses on the role of a sealing hemostatic device, Hemopatch™, to prevent postoperative pancreatic fistula (POPF) after DP. METHODS: Retrospectively we divided our sampling of 57 patients submitted to DP into two groups according to the availability of the device: 18 patients without Hemopatch™ and 39 patients using Hemopatch™. RESULTS: Significant difference was observed in leak occurrence (p < 0.05). No significant association was observed between the number of blood transfusions, the frequency of postoperative complications, associated splenectomy and POPF. CONCLUSION: This is a preliminary study and the first focused on the prevention of POPF after DP using Hemopatch™. Thanks to its double function of hemostasis and sealant, Hemopatch™ can be taken into consideration as an efficacy tool to prevent pancreatic POPF.

Pancreatic solitary and synchronous metastasis from breast cancer: a case report and systematic review of controversies in diagnosis and treatment.

BACKGROUND: Metastases from breast cancer cause the frequent involvement of lung, bone, liver, and brain, while the occurrence of metastases to the gastrointestinal tract is rare, and more frequently discovered after a primary diagnosis of breast cancer. Solitary pancreatic metastases from breast cancer, without widespread disease, are actually unusual, and only 19 cases have been previously described; truly exceptional is a solitary pancreatic metastasis becoming evident together with the primary breast cancer. CASE PRESENTATION: A 68-year-old woman reported general fatigue, lethargy, and jaundice. Abdominal ultrasound (US) and magnetic resonance imaging (MRI) showed an ampulloma of Vater's papilla; moreover, a neoplastic nodule in the left breast was diagnosed. She underwent surgery for both breast cancer and ampulloma of Vater's papilla. Pathological examination of pancreatic specimen, however, did not confirm primary carcinoma of the duodenal papilla, but showed a metastatic involvement of pancreas from lobular breast cancer. Immunohistochemistry has been essential to confirm the origin of the malignancy: hormone receptors and mammaglobin were expressed in both the primary breast tumor and the pancreatic metastasis. CONCLUSIONS: This is one of the few reported cases in literature of an isolated and synchronous pancreatic metastasis from breast cancer, where the definitive diagnosis was obtained only after surgery. We discuss the controversies in this diagnosis and the choice of correct treatment. The surgical resection of solitary metastases can be performed in the absence of disseminated disease.

A case of obscure gastrointestinal bleeding in a 18-year-old woman.

In this report, we discuss a case of an 18 year-old woman with obscure gastrointestinal bleeding (OGIB) revealed to be originated from a Meckel's diverticulum. OGIB is defined as persistent or recurrent bleeding from a difficult to identify source and accounts for approximately 5% of all cases of GI bleeding. Lesions in the small bowel most commonly cause it. OGIB represents one of the most challenging disorders faced by gastroenterologists due to its evasive nature and difficulty in identifying the exact source of the bleeding. Recent technological advances such as capsule endoscopy, balloon-assisted enteroscopy, spiral enteroscopy and CTE have significantly improved our ability to diagnose and manage these patients. We report this case to assess the importance of laparoscopy that nowadays is the only procedure that successfully detected the site of bleeding in up to 100% of cases. KEY WORDS: Enterorrhagia, Gastrointestinal bleeding, Meckel's diverticulum, Obscure gastrointestinal bleeding.

Therapy innovation for the treatment of pancreatic neuroendocrine tumors.

INTRODUCTION: Traditional therapeutic approaches for patients with advanced neuroendocrine tumors (NETs) have included treatment with somatostatin analogs, hepatic-directed therapies, interferon and cytotoxic chemotherapy. Current knowledge about biological behavior of pancreatic neuroendocrine tumors (pNETs) has increased in the last decade, and some studies have been conducted to translate in the clinical setting. Among several molecular agents investigated in patients with progressive pNETs, everolimus and sunitinib have been studied in large Phase III trials. Both have produced significant benefit, with improvement in progression-free survival. These results were published last year by NEJM and were updated at the ASCO Annual Meeting in June 2011. AREAS COVERED: This review focuses on the potential molecular targets in pancreatic NETs in the light of recent advances. Furthermore, it summarizes the available data for targeted agents from Phase II and III trials open to patients with this tumor. EXPERT OPINION: These new agents are likely to play an increasingly important role in the future management of advanced pNETs. Their use in earlier phases of the disease could improve clinical outcome, avoiding side effects of the more toxic chemotherapy. The challenge in medical treatment of pNET is to define the patients who can benefit from this innovative therapy; future research should be directed to find predictive markers for response to the targeted agent.

[Surgical management of schwannoma of biliary tract]. / Trattamento chirurgico di schwannoma della via biliare.

A borderline Schwann cell tumour with common bile duct compression and jaundice is extremely rare. This paper presents the first report in the Italian literature of a hepatojejunostomy for a symptomatic lesion midway between benign and malignant.

Hepaticojejunostomy in the treatment of iatrogenic biliary lesions following laparoscopic cholecystectomy. A retrospective study on 51 cases.

BACKGROUND/AIMS: Laparoscopic cholecystectomy is characterized by a higher incidence of iatrogenic biliary lesions. The Authors evaluate the role of hepaticojejunostomy in the treatment of iatrogenic biliary lesions following laparoscopic cholecystectomy in 51 patients observed in the Campania region, Italy from 1991 to 2003. METHODOLOGY: The Authors report the data of a retrospective multicentric study of 51 patients -39 women (76.47%), 12 men (13.53%)-reoperated on for major biliary lesions following laparoscopic cholecystectomy. Hepaticojejunostomy in 20 cases (39.21%) and T-Tube plasty in 20 cases (39.21%) were performed. RESULTS: The mean follow-up was 25.01 months. The mean hospital stay was 25.7 days. 1/51 patients (1.9%) died from intraoperative incontrollable hemorrhage while cumulative postoperative mortality was 9.8% (5/51 patients). Therapeutic success rate of hepaticojejunostomy was 70% with a T-Tube plasty success rate of 65%. 9/51 patients (17.64%) were reoperated while in 4/51 (7.84%) a biliary stent was positioned. In 1/51 patients (1.9%) a biliary cirrhosis and in 3/51 (5.7%) a bioumoral cholestasis was observed. CONCLUSIONS: Laparoscopic cholecystectomy causes a higher incidence of iatrogenic biliary lesions. Hepaticojejunostomy gives better long-term results and lower morbidity compared to T-Tube plasty. Management of septic complications in patients with iatrogenic biliary lesions represents the first therapeutic step.

[Surgical treatment of iatrogenic bile duct injuries following laparoscopic cholecystectomy: analysis of long-term results. Retrospective clinical study in 51 patients operated in the Campania region from 1991 to 2003]. / Trattamento chirurgico delle lesioni iatrogene della via biliare in seguito a colecistectomia videolaparoscopica: analisi dei risultati a distanza. Studio clinico retrospettivo in 51 pazienti operati nella regione Campania dal 1991 al 2003.

An higher incidence rate of iatrogenic bile duct injuries is reported in cholecystectomy performed with the laparoscopy than with the laparotomy approach. The aim of this study was to provide a multicentre report on surgical treatment and the outcome of biliary complications during and following laparoscopic cholecystectomy. A questionnaire was mailed to all surgeons with experience in laparoscopic cholecystectomy in the Campania region. Data were collected from January 1991 to December 2003. Each patient was requested to indicate age, gender, associated diseases, site and type of lesion, surgical experience, diagnosis, treatment and complications. Twenty-six surgeons answered the questionnaire. Fifty-one patients (36 F/15 M; mean age: 42.5 +/- 11.9, range 13-91 years) with bile duct injuries following laparoscopic cholecystectomy were reported. The most frequent lesions were main bile duct partial or total transection. The intraoperative mortality rate was 1/51 (1.9%) due to a complex biliary and vascular injury. The postoperative mortality rate of revision surgery was 5/50 (10%). T-tube positioning (n = 20) and Roux-en-Y hepato-jejunostomy (n = 20) were the procedures most frequently performed. The complication rate in patients treated with the T-tube was significantly higher than in those treated with hepatico-jejunostomy. Surgical treatment of biliary injuries following laparoscopic cholecystectomy was characterized by unusually high mortality and morbidity for a non-neoplastic disease. Roux-en-Y hepato-jejunostomy remains the procedure of choice for these injuries.

[Conservative treatment of the digestive fistulas: personal experience]. / Trattamento conservativo delle fistole digestive: nostra esperienza.

OBJECTIVE: The authors, thanks to experience obtained in an Unit for the treatment of digestive fistulas, discuss the possibility of a conservative treatment for the anastomotic fistulas. MATERIAL AND METHODS: From 2000 to 2003 were treated thirty-five patients with post-anastomotic gastroenteric fistulas marked according to their localization, way end output (51.5% high, 42.8% moderate and 5.7% low). The treatment is based on an aspiration system, sometimes integrated with an irrigation system. A semi-permeable barrier was created over the fistula by vacuum packing a synthetic, hydrophobic, polymer covered with a self-adherent surgical sheet. This system create a vacuum chamber equipped with a subathmospheric pressures between 262.2 and 337.5 mmHg (350-450 mmbar), integrated with a continuous irrigation using antibiotic solutions or 3% lactic acid. RESULTS: The AA. obtained the resolution in 30 patients (85.7%), 3 patients needs the surgery (8.6%), 2 died, one for sepsis and the other one for malnutrition. The mean time for the closure was 45 days (from 20 to 90). A part of digestive external fistulas goes to spontaneous resolution so comes the idea that the creation of particular condition is the basis of their closure.