Molecular Characteristics and Immunogenomic Profiling of Cholangioblastic Variant of Intrahepatic Cholangiocarcinoma in a 68-year-old Patient.

BACKGROUND/AIM: Cholangioblastic variant of intrahepatic cholangiocarcinoma (CVICC) is an exceedingly rare primary biliary tract tumor and typically occurs in young patients with a median age of 24.5-year-old. It can mimic metastatic well-differentiated neuroendocrine tumors in the liver with its similar histologic and immunophenotypic features. CASE REPORT: We hereby report a CVICC in a 68-year-old female patient with distinctive biphasic cytologic features. The patient was diagnosed and treated as a metastatic well differentiated neuroendocrine tumor. The recurrent liver tumor was resected and the tumor cells were strongly positive for Inhibin A and cytokeratin 19 (CK19), focally and weakly positive for synaptophysin and chromogranin, and negative for Insulinoma associated protein 1 (INSM1). Ribonucleic acid (RNA) sequencing showed that the tumor bared a characteristic Nipped-B-like protein (NIPBL)-Nucleus accumbens-associated protein 1 (NACC1) gene fusion. CONCLUSION: To the best of our knowledge, this is the first documented case in an elder patient of this entity with NIPPL-NACC1 gene fusion. Acknowledgment of the biphasic cytology, screening with Inhibin A in suspicious cases, and coupled with a molecular study may facilitate accurate classification of this aggressive tumor and lead to proper clinical management.

Blood-Based Multi-Cancer Detection Using a Novel Variant Calling Assay (DEEPGENTM): Early Clinical Results.

This is an early clinical analysis of the DEEPGENTM platform for cancer detection. Newly diagnosed cancer patients and individuals with no known malignancy were included in a prospective open-label case-controlled study (NCT03517332). Plasma cfDNA that was extracted from peripheral blood was sequenced and data were processed using machine-learning algorithms to derive cancer prediction scores. A total of 260 cancer patients and 415 controls were included in the study. Overall, sensitivity for all cancers was 57% (95% CI: 52, 64) at 95% specificity, and 43% (95% CI: 37, 49) at 99% specificity. With 51% sensitivity and 95% specificity for all stage 1 cancers, the stage-specific sensitivities trended to improve with higher stages. Early results from this preliminary clinical, prospective evaluation of the DEEPGENTM liquid biopsy platform suggests the platform offers a clinically relevant ability to differentiate individuals with and without known cancer, even at early stages of cancer.

The Florida Pancreas Collaborative Next-Generation Biobank: Infrastructure to Reduce Disparities and Improve Survival for a Diverse Cohort of Patients with Pancreatic Cancer.

Background: Well-annotated, high-quality biorepositories provide a valuable platform to support translational research. However, most biorepositories have poor representation of minority groups, limiting the ability to address health disparities. Methods: We describe the establishment of the Florida Pancreas Collaborative (FPC), the first state-wide prospective cohort study and biorepository designed to address the higher burden of pancreatic cancer (PaCa) in African Americans (AA) compared to Non-Hispanic Whites (NHW) and Hispanic/Latinx (H/L). We provide an overview of stakeholders; study eligibility and design; recruitment strategies; standard operating procedures to collect, process, store, and transfer biospecimens, medical images, and data; our cloud-based data management platform; and progress regarding recruitment and biobanking. Results: The FPC consists of multidisciplinary teams from fifteen Florida medical institutions. From March 2019 through August 2020, 350 patients were assessed for eligibility, 323 met inclusion/exclusion criteria, and 305 (94%) enrolled, including 228 NHW, 30 AA, and 47 H/L, with 94%, 100%, and 94% participation rates, respectively. A high percentage of participants have donated blood (87%), pancreatic tumor tissue (41%), computed tomography scans (76%), and questionnaires (62%). Conclusions: This biorepository addresses a critical gap in PaCa research and has potential to advance translational studies intended to minimize disparities and reduce PaCa-related morbidity and mortality.

Feasibility of pancreatectomy following high-dose proton therapy for unresectable pancreatic cancer.

AIM: To review surgical outcomes for patients undergoing pancreatectomy after proton therapy with concomitant capecitabine for initially unresectable pancreatic adenocarcinoma. METHODS: From April 2010 to September 2013, 15 patients with initially unresectable pancreatic cancer were treated with proton therapy with concomitant capecitabine at 1000 mg orally twice daily. All patients received 59.40 Gy (RBE) to the gross disease and 1 patient received 50.40 Gy (RBE) to high-risk nodal targets. There were no treatment interruptions and no chemotherapy dose reductions. Six patients achieved a radiographic response sufficient to justify surgical exploration, of whom 1 was identified as having intraperitoneal dissemination at the time of surgery and the planned pancreatectomy was aborted. Five patients underwent resection. Procedures included: Laparoscopic standard pancreaticoduodenectomy (n = 3), open pyloris-sparing pancreaticoduodenectomy (n = 1), and open distal pancreatectomy with irreversible electroporation (IRE) of a pancreatic head mass (n = 1). RESULTS: The median patient age was 60 years (range, 51-67). The median duration of surgery was 419 min (range, 290-484), with a median estimated blood loss of 850 cm3 (range, 300-2000), median ICU stay of 1 d (range, 0-2), and median hospital stay of 10 d (range, 5-14). Three patients were re-admitted to a hospital within 30 d after discharge for wound infection (n = 1), delayed gastric emptying (n = 1), and ischemic gastritis (n = 1). Two patients underwent R0 resections and demonstrated minimal residual disease in the final pathology specimen. One patient, after negative pancreatic head biopsies, underwent IRE followed by distal pancreatectomy with no tumor seen in the specimen. Two patients underwent R2 resections. Only 1 patient demonstrated ultimate local progression at the primary site. Median survival for the 5 resected patients was 24 mo (range, 10-30). CONCLUSION: Pancreatic resection for patients with initially unresectable cancers is feasible after high-dose [59.4 Gy (RBE)] proton radiotherapy with a high rate of local control, acceptable surgical morbidity, and a median survival of 24 mo.

Expression of specificity protein transcription factors in pancreatic cancer and their association in prognosis and therapy.

Pancreatic cancer is an aggressive malignancy with poor prognosis. Pancreatic adenocarcinoma is one of the leading causes of cancer-related deaths in the United States. Due to the aggressive nature of this malignancy, there is a serious concern for identifying effective targets, and adopting novel strategies for therapy. Members of the Specificity Protein (Sp) family of transcription factors, Sp1, Sp3, and Sp4 regulate the expression of a number of genes associated with cancer cell proliferation, differentiation, and metastasis. Sp1 levels are upregulated in pancreatic cancer cell lines, and surgically resected human pancreatic adenocarcinoma. Sp1 overexpression in tumor tissues is associated with aggressive disease, poor prognosis and inversely correlated with survival. Sp1 is also known to affect angiogenesis by regulating the expression of vascular endothelial growth factor and its receptors. Results from clinical studies suggest Sp1 as new biomarker to identify aggressive pancreatic ductal adenocarcinoma. The pharmacological inhibition of Sp1 using agents such as celecoxib, mithramycin, curcumin, and tolfenamic acid has showed promising results in pre-clinical studies and demonstrated Sp transcription factors as potential targets for pancreatic cancer therapy. This review summarizes studies showing the association of Sp proteins with this malignancy, with a special emphasis on pre-clinical studies that tested strategies to target Sp transcription factors for inhibiting human pancreatic cancer cell proliferation and tumor growth in laboratory animals. The results showed remarkable efficacy and suggest that such approaches have the potential for high success in developing clinically relevant strategies for treating pancreatic cancer.

Neuropilin-2 mediated ß-catenin signaling and survival in human gastro-intestinal cancer cell lines.

NRP-2 is a high-affinity kinase-deficient receptor for ligands belonging to the class 3 semaphorin and vascular endothelial growth factor families. NRP-2 has been detected on the surface of several types of human cancer cells, but its expression and function in gastrointestinal (GI) cancer cells remains to be determined. We sought to determine the function of NRP-2 in mediating downstream signals regulating the growth and survival of human gastrointestinal cancer cells. In human gastric cancer specimens, NRP-2 expression was detected in tumor tissues but not in adjacent normal mucosa. In CNDT 2.5 cells, shRNA mediated knockdown NRP-2 expression led to decreased migration and invasion in vitro (p<0.01). Focused gene-array analysis demonstrated that loss of NRP-2 reduced the expression of a critical metastasis mediator gene, S100A4. Steady-state levels and function of ß-catenin, a known regulator of S100A4, were also decreased in the shNRP-2 clones. Furthermore, knockdown of NRP-2 sensitized CNDT 2.5 cells in vitro to 5FU toxicity. This effect was associated with activation of caspases 3 and 7, cleavage of PARP, and downregulation of Bcl-2. In vivo growth of CNDT 2.5 cells in the livers of nude mice was significantly decreased in the shNRP-2 group (p<0.05). Intraperitoneal administration of NRP-2 siRNA-DOPC decreased the tumor burden in mice (p = 0.01). Collectively, our results demonstrate that tumor cell-derived NRP-2 mediates critical survival signaling in gastrointestinal cancer cells.

Multidisciplinary management strategy for incidental cystic lesions of the pancreas.

BACKGROUND: At our institution, incidental pancreatic cysts are frequently identified in asymptomatic patients undergoing routine imaging for staging of nonpancreatic malignancies. Management of these patients is unclear because a small but significant number of incidental pancreatic cysts are malignant. STUDY DESIGN: Our institutional database was reviewed for patients with ICD-9 codes for pancreatic cysts from 1980 to 2005. Clinicopathologic factors, including CT and endoscopic ultrasound (EUS) characteristics and management strategies, were analyzed. RESULTS: Over 25 years, 942 patients were identified with pancreatic cysts. Excluding those with symptoms or pseudocysts, 350 patients remained with incidental pancreatic cysts. Mean overall survival was 41.4 months (mean follow-up 32.7 months). Forty-one patients underwent resection, of whom 38 (92.7%) had premalignant or malignant pathology. Univariate analysis of variables predicting pathologic premalignant or malignant diagnosis identified pancreatic neck or body location as significant factors. CONCLUSIONS: These data suggest that most incidental pancreatic cysts can be managed nonoperatively using a selective strategy based on detailed review of CT imaging and EUS findings.

Vascular endothelial growth factor targeted therapy in the perioperative setting: implications for patient care.

Vascular endothelial growth factor (VEGF) targeted therapy, either alone or in combination with chemotherapy, has become the standard of care in several solid tumours, including colorectal cancer, renal-cell carcinoma, breast cancer, non-small-cell lung cancer, and glioblastoma. VEGF is crucial in the process of angiogenesis and wound healing and, thus, its inhibition has the potential to affect wound healing in patients undergoing surgery. In this review, we summarise the data available on the use of VEGF-targeted therapies, and their effect on perioperative wound complications. Surgery in patients receiving VEGF-targeted therapies seems to be safe when an appropriate interval of time is allowed between surgical procedures and treatment. Recommendations regarding this interval are provided in a disease and agent site-specific manner. We also discuss complications arising from the use of VEGF-directed therapies that might require surgical intervention and the considerations important in their management. At this juncture, safety data on the use of VEGF-targeted therapies in the perioperative period are sparse, and investigators are urged to continue to study this issue prospectively in current and future clinical trials to establish firm guidelines.

Role of class 3 semaphorins and their receptors in tumor growth and angiogenesis.

Class 3 semaphorins (SEMA3) were first identified as glycoproteins that negatively mediate neuronal guidance by binding to neuropilin and repelling neurons away from the source of SEMA3. However, studies have shown that SEMA3s are also secreted by other cell types, including tumor cells, where they play an inhibitory role in tumor growth and angiogenesis (specifically SEMA3B and SEMA3F). SEMA3s primarily inhibit the cell motility and migration of tumor and endothelial cells by inducing collapse of the actin cytoskeleton via neuropilins and plexins. Besides binding to SEMA3s, neuropilin also binds the protumorigenic and proangiogenic ligand vascular endothelial growth factor (VEGF). Although some studies attribute the antitumorigenic and antiangiogenic properties of SEMA3s to competition between SEMA3s and VEGF for binding to neuropilin receptors, several others have shown that SEMA3s display growth-inhibitory activity independent of competition with VEGF. A better understanding of these molecular interactions and the role and signaling of SEMA3s in tumor biology will help determine whether SEMA3s represent potential therapeutic agents. Herein, we briefly review (a) the role of SEMA3s in mediating tumor growth, (b) the SEMA3 receptors neuropilins and plexins, and (c) the potential competition between SEMA3s and VEGF family members for neuropilin binding.

Targeting tumor angiogenesis.

Our understanding of the process of tumor angiogenesis has changed significantly since the late 1970s, when vascular endothelial growth factor (VEGF) was first identified as vascular permeability factor and later found to be the major mediator of physiologic and pathologic angiogenesis. Since then, several additional VEGF-related ligands, VEGF receptors (VEGFRs), and complementary/alternative pathways that regulate tumor angiogenesis have been identified. Over the last decade, several antiangiogenic agents have been developed with the aim to inhibit new blood vessel growth, and we have learned that VEGF inhibition does far more than simply block new blood vessel growth. Clinical studies have demonstrated an improvement of progression-free and overall survivals with anti-VEGF therapy (with or without chemotherapy) in patients with advanced-stage malignancies. Unfortunately, even when anti-VEGF therapy is effective, the benefit of therapy is short-lived, with the development of tumor growth. We now recognize the presence of numerous complementary and redundant pathways that regulate tumor vasculature. For example, VEGF/VEGFR and angiopoietin/Tie-2 axes are two redundant, complementary components regulating tumor angiogenesis and vascular maintenance. The current clinical challenge is to identify: (1) factors that predict efficacy, and (2) markers of tumor response to anti-VEGF therapy, which can be achieved only by developing a thorough understanding of the biology of the VEGF system and the role of complementary pathways that may mediate resistance to anti-VEGF therapy.

Attempted salvage resection for recurrent gastric or gastroesophageal cancer.

The purpose of this study was to determine the outcome of surgery for patients with recurrent gastric or gastroesophageal cancer. We queried records from 7,459 patients who presented with gastric or gastroesophageal cancer to our institution from 1973 through 2005 to identify those for whom resection of recurrent disease had been attempted. We assessed the associations between various clinicopathologic factors and resectability with logistic regression analysis and between clinicopathologic factors and overall survival (OS) with the Cox proportional hazards model. Sixty patients underwent attempted resection for recurrent cancer. In 31 cases (52%), recurrent disease proved unresectable at laparotomy. Factors associated with the ability to undergo re-resection included neoadjuvant treatment prior to initial resection [odds ratio (OR) 12.2, 95% confidence interval (CI) 1.9-75.6] and having an isolated local recurrence (OR 5.1, 95% CI 1.3-20.5). Of the 29 patients who underwent re-resection, 14 required adjacent organ resection, and 6 required interposition grafting. Three- and 5-year OS rates for all 60 patients were 21% and 12%, respectively; median follow-up time was 23 months. Median OS for patients undergoing resection was 25.8 months (95% CI 17.1-49.8) versus 6.0 months (95% CI 4.0-10.5) for unresectable patients (P < 0.001). Initial tumor location at the gastroesophageal junction was associated with diminished OS [hazard ratio (HR) 2.8, 95% CI 1.2-6.5] and ability to undergo resection of recurrence was associated with improved OS (HR 0.2, 95% CI 0.1-0.6). We conclude that surgical resection of select patients with recurrent gastric or gastroesophageal cancer can result in improved OS but often requires adjacent organ resection or interposition graft placement.