Mustafa Suker

FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis

BACKGROUND 35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population. METHODS We systematically searched Embase, MEDLINE (OvidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar from July 1, 1994, to July 2, 2015, for studies of treatment-naive patients of any age who received FOLFIRINOX as first-line treatment of locally advanced pancreatic cancer. Our primary outcome was overall survival. Secondary outcomes were progression-free survival; rates of grade 3 or 4 adverse events; and the proportion of patients who underwent radiotherapy or chemoradiotherapy, surgical resection after FOLFIRINOX, and R0 resection. We evaluated survival outcomes with the Kaplan-Meier method with patient-level data. Grade 3 or 4 adverse events, and the proportion of patients who underwent subsequent radiotherapy or chemoradiotherapy or resection, were pooled in a random-effects model. FINDINGS We included 13 studies comprising 689 patients, of whom 355 (52%) patients had locally advanced pancreatic cancer. 11 studies, comprising 315 patients with locally advanced disease, reported survival outcomes and were eligible for patient-level meta-analysis. Median overall survival from the start of FOLFIRINOX ranged from 10·0 months (95% CI 4·0-16·0) to 32·7 months (23·1-42·3) across studies with a pooled patient-level median overall survival of 24·2 months (95% CI 21·7-26·8). Median progression-free survival ranged from 3·0 months (95% CI not calculable) to 20·4 months (6·5-34·3) across studies with a patient-level median progression-free survival of 15·0 months (95% 13·8-16·2). In ten studies comprising 490 patients, 296 grade 3 or 4 adverse events were reported (60·4 events per 100 patients). No deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent radiotherapy or chemoradiotherapy ranged from 31% to 100% across studies. In eight studies, 154 (57%) of 271 patients received radiotherapy or chemoradiotherapy after FOLFIRINOX. The pooled proportion of patients who received any radiotherapy treatment was 63·5% (95% CI 43·3-81·6, I(2) 90%). The proportion of patients who underwent surgical resection for locally advanced pancreatic cancer ranged from 0% to 43%. The proportion of patients who had R0 resection of those who underwent resection ranged from 50% to 100% across studies. In 12 studies, 91 (28%) of 325 patients underwent resection after FOLFIRINOX. The pooled proportion of patients who had resection was 25·9% (95% CI 20·2-31·9, I(2) 24%). R0 resection was reported in 60 (74%) of 81 patients. The pooled proportion of patients who had R0 resection was 78·4% (95% CI 60·2-92·2, I(2) 64%). INTERPRETATION Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months-longer than that reported with gemcitabine (6-13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX. FUNDING None.

Potentiation of peptide receptor radionuclide therapy by the PARP inhibitor olaparib

Metastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with radiolabeled somatostatin analogues, resulting in strongly increased progression-free survival and quality of life. There is nevertheless still room for improvement, as very few patients can be cured at this stage of disease. We aimed to specifically sensitize replicating tumor cells without further damage to healthy tissues. Thereto we investigated the DNA damaging effects of PRRT with the purpose to enhance these effects through modulation of the DNA damage response. Although PRRT induces DNA double strand breaks (DSBs), a larger fraction of the induced lesions are single strand breaks (expected to be similar to those induced by external beam radiotherapy) that require poly-[ADP-ribose]-polymerase 1 (PARP-1) activity for repair. If these breaks cannot be repaired, they will cause replication fork arrest and DSB formation during replication. Therefore, we used the PARP-1 inhibitor Olaparib to increase the number of cytotoxic DSBs. Here we show that this new combination strategy synergistically sensitized somatostatin receptor expressing cells to PRRT. We observed increased cell death and reduced cellular proliferation compared to the PRRT alone. The enhanced cell death was caused by increased numbers of DSBs that are repaired with remarkably slow kinetics, leading to genome instability. Furthermore, we validated the increased DSB induction after PARP inhibitor addition in the clinically relevant model of living human NET slices. We expect that this combined regimen can thus augment current PRRT outcomes.

Low skeletal muscle mass is associated with increased hospital expenditure in patients undergoing cancer surgery of the alimentary tract

Background Low skeletal muscle mass is associated with poor postoperative outcomes in cancer patients. Furthermore, it is associated with increased healthcare costs in the United States. We investigated its effect on hospital expenditure in a Western-European healthcare system, with universal access. Methods Skeletal muscle mass (assessed on CT) and costs were obtained for patients who underwent curative-intent abdominal cancer surgery. Low skeletal muscle mass was defined based on pre-established cut-offs. The relationship between low skeletal muscle mass and hospital costs was assessed using linear regression analysis and Mann-Whitney U-tests. Results 452 patients were included (median age 65, 61.5% males). Patients underwent surgery for colorectal cancer (38.9%), colorectal liver metastases (27.4%), primary liver tumours (23.2%), and pancreatic/periampullary cancer (10.4%). In total, 45.6% had sarcopenia. Median costs were €2,183 higher in patients with low compared with patients with high skeletal muscle mass (€17,144 versus €14,961; P<0.001). Hospital costs incrementally increased with lower sex-specific skeletal muscle mass quartiles (P = 0.029). After adjustment for confounders, low skeletal muscle mass was associated with a cost increase of €4,061 (P = 0.015). Conclusion Low skeletal muscle mass was independently associated with increased hospital costs of about €4,000 per patient. Strategies to reduce skeletal muscle wasting could reduce hospital costs in an era of incremental healthcare costs and an increasingly ageing population.

The Dutch Pancreas Biobank Within the Parelsnoer Institute: A Nationwide Biobank of Pancreatic and Periampullary Diseases

Objectives Large biobanks with uniform collection of biomaterials and associated clinical data are essential for translational research. The Netherlands has traditionally been well organized in multicenter clinical research on pancreatic diseases, including the nationwide multidisciplinary Dutch Pancreatic Cancer Group and Dutch Pancreatitis Study Group. To enable high-quality translational research on pancreatic and periampullary diseases, these groups established the Dutch Pancreas Biobank. Methods The Dutch Pancreas Biobank is part of the Parelsnoer Institute and involves all 8 Dutch university medical centers and 5 nonacademic hospitals. Adult patients undergoing pancreatic surgery (all indications) are eligible for inclusion. Preoperative blood samples, tumor tissue from resected specimens, pancreatic cyst fluid, and follow-up blood samples are collected. Clinical parameters are collected in conjunction with the mandatory Dutch Pancreatic Cancer Audit. Results Between January 2015 and May 2017, 488 patients were included in the first 5 participating centers: 4 university medical centers and 1 nonacademic hospital. Over 2500 samples were collected: 1308 preoperative blood samples, 864 tissue samples, and 366 follow-up blood samples. Conclusions Prospective collection of biomaterials and associated clinical data has started in the Dutch Pancreas Biobank. Subsequent translational research will aim to improve treatment decisions based on disease characteristics.

FOLFIRINOX and radiotherapy for locally advanced pancreatic cancer: A cohort study: SUKER et al.

One‐third of the patients with pancreatic cancer present with locally advanced unresectable pancreatic cancer (LAPC). Our aim was to determine survival outcomes and toxicity after FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) followed by radiotherapy (RT) in biopsy‐proven patients with LAPC.

Pancreatic Resection After Neoadjuvant Treatment

Pancreatic cancer has a very poor prognosis, with the projection to be the second leading cancer-related death in 2020 [1]. Pancreatic cancer can be divided in three stages: resectable (15%), locally advanced (35%) and metastatic disease (50%) [2]. The diagnosis of resectable and locally advanced pancreatic cancer is determined by the tumor invasion of critical structures, in particular the portal vein, superior mesenteric vein, coeliac artery and superior mesenteric artery. This tumor invasion is usually assessed by contrast enhanced computed tomography (CT). There are several definitions for resectable and locally advanced disease, usually based on the tumor burden of the surrounding major vessels. This tumor burden can be defined as no invasion at all to the surrounding structures (resectable disease) and too much invasion in the surrounding structures to be deemed resectable (locally advanced disease). In between these two extremes there is a diagnostic gap where a tumor has some vessel involvement but is still resectable, this gap is called borderline resectable disease. The two most commonly used definitions for (borderline) resectable disease and locally advanced disease are that of National Comprehensive Cancer (NCCN) and the combined definition of Americas Hepato-Pancreato-Biliary Association (AHPBA), the Society of Surgical Oncology (SSO), and the Society for Surgery of the Alimentary Tract (SSAT) [3, 4]. Both the definitions of NCCN and AHPBA/SSO/SSAT for borderline resectable and locally advanced disease are summarized in Table 20.1. For decades, the primary treatment for borderline resectable pancreatic cancer was upfront surgery. However, neoadjuvant therapy is becoming more and more a valuable upfront therapy for borderline resectable disease. Although there is no clear level I evidence for this treatment [5]. The main purpose of neoadjuvant treatment are threefold: (1) improve probability of radical resection, (2) patient selection of patients with rapid disease progression that will undergo unnecessary surgery, (3) early treatment of occult metastasis and finally more patients receiving systemic treatment since a significant portion of patient do not come to adjuvant therapy after surgical resection due to morbidity [6]. In contrary, locally advanced pancreatic cancer is conventionally treated with induction chemotherapy and sometimes followed by local therapy such as (chemo)radiotherapy or local ablation. Surgery is not recommended as an upfront treatment in locally advanced unresectable pancreatic cancer and is only reserved for patients with disease response and after tumor downstaging with chemotherapy and or (chemo)radiotherapy [7]. In this chapter, an overview will be given of studies that examined the effect of neoadjuvant treatment on surgical outcomes in borderline resectable and locally advanced unresectable pancreatic cancer. Lastly, an illustrative case report will be presented of a patient with locally advanced unresectable pancreatic cancer.

A Rare Tumor in the Common Bile Duct: A Case Report

Abstract Background: Lymphoepithelial-like carcinoma (LEC) is rarely found in organs outside the nasopharyngeal area. This is the first case report of Epstein–Barr virus (EBV)-associated LEC of the extrahepatic tract. As it is very difficult to distinguish between LEC and adenocarcinoma in the clinical presentation, this article can give more insight into how the pathological analysis can help with the diagnosis. Case presentation: A 37-year-old Caucasian male with a history of Crohns disease and primary sclerosing cholangitis presented with cholestasis. A computed tomography scan revealed a tumor in the pancreatic head without invasion into the surrounding organs. The patient underwent an uncomplicated pylorus-preserving pancreaticoduodenectomy, with pathology revealing an epithelial carcinoma of the common bile duct with metastases in 4 of the 18 resected lymph nodes. In situ hybridization demonstrated extensive EBV positivity in the tumor cells, and in serum, positive IgG anti-EBV was found. The diagnosis of EBV-associated LEC was hereby confirmed. The postoperative course was uneventful and 18 months after surgery there is no recurrence. Conclusion: In the case of an epithelial tumor in the periampullary region, one should consider EBV-associated LEC as this tumor may have a lot of similarity with the adenocarcinoma but has lower rates of recurrence after surgery and better overall survival.

Pancreatic Duct Obstruction in a Middle-Aged Woman: A Case Report

Abstract Background: Granular cell tumors (GCTs) are rare benign neoplasms of Schwann cells. These tumors have been described in almost every human organ. Although GCT has been described in the pancreas previously, we present a case report about GCTs in multiple organs at a simultaneous time. Case Presentation: A 51-year-old Caucasian female known with epilepsy and COPD presented with recurrent abdominal pain. Previously, endoscopic mucosal resection in the esophagus and lumpectomy of the right breast were performed for what proved to be GCTs. Computed tomography showed a hypodense unclearly demarcated tumor of the pancreas tail–body with the impression of infiltrative growth and pancreatic duct dilation. The patient underwent an uncomplicated distal pancreatectomy with the pathological examination showing a fibrotic area of 6 mm consisting of diffusely spread nests of large cells embedded in a collagenous stroma of the pancreatic tail. The tumor nuclei were not atypical and the cytoplasm was granular and eosinophilic. The cell clusters stained positive for S-100 and CD68 in the cell cytoplasm. The diagnosis, GCT of the pancreas, was made and the postoperative course was uneventful for our patient, and a year after surgery, there have been no new tumorous lesions detected. Conclusion: We present a rare case of multiple GCTs affecting the breast, esophagus, and pancreas. Although GCT of the pancreas is a rare disease, the diagnosis should be considered if there is GCT in the medical history of the patient.

Critical Illness is Top Sport

Extreme exercise has been used to study how normal physiology responds to states that resemble critical illness, such as hypoxemia and hypovolemia. Studies of the Extreme Everest Research Group have shown that the body can tolerate hypoxemia by using adaptation mechanisms. One of these mechanisms was found in lowlanders who climbed Mount Everest, mirroring the hypoxemia in critical illness. There was an increase in nitric oxide (NO) in the blood in response to the hypoxic environment. These enhanced NO levels were associated with changes in microcirculatory blood flow, which may affect local tissue oxygen delivery (DO2) [1]. Indeed extreme exercise can protect the body by adapting to cope with the hypoxic environment. This is seen in skeletal muscle function, with high altitude hypoxia inducing skeletal muscle atrophy despite unchanged exercise metabolites [2]. Another adaptation is seen in gluco-insular regulation, in which, despite an increase in insulin resistance in sustained hypoxia, glucose levels remain stable [3]. From these considerations, it can be concluded that lessons can be learned, which may be relevant to critically ill patients who need to cope with tissue hypoxia. Indeed, fitness and exercise might even hold potential lessons on how to ‘train’ patients to cope with surgery and critical illness. This chapter explores this idea and speculates on how such insight might benefit patients in need of surgery and at risk for critical illness.

Are a Double Duct Sign or Endoscopic Biopsies Reliable Predictors of Malignancy in Periampullary Lesions

Aim: To determine the predictive value of a double duct sign (DDS) and endoscopic biopsies to differentiate invasive carcinoma from premalignant lesions. Methods: Two hundred and forty one patients (mean age 65.8; male 55.6%) diagnosed with a periampullary lesion from January 1987 through March 2013 were reviewed retrospectively with regard to background characteristics, histology of endoscopic biopsy, diameter of both common bile duct (CBD) and main pancreatic duct (PD), bilirubin levels and final diagnosis. Results: DDS predicted malignancy with 73% specificity and 72% sensitivity. Endoscopic biopsies predicted malignancy with 96% specificity, 71% sensitivity and a negative predictive value (NPV) of 51%. Multivariable logistic regression analysis showed that DDS is a significant predictor for the presence of malignancy with an odds ratio of 6.37 adjusted to age, gender and endoscopic biopsy. Conclusion: Although DDS is indicative of malignancy in periampullary lesions, its clinical use is limited, given the low sensitivity and specificity. The diagnostic value of endoscopic biopsies is also poor due to a low sensitivity and NPV. If a double duct sign is present, physicians must be aware of an increased possibility of a malignant underlying cause, even if the histopathological examination of the biopsies did not show invasive malignancy.