A Comprehensive Approach to the Management of Benign and Malignant Ampullary Lesions: Management in Hereditary and Sporadic Settings.

PURPOSE OF REVIEW: The purpose of this review was to examine the historical roots of endoscopic management of ampullary lesions and explore emerging data on improved techniques, technologies, and outcomes. Of specific interest was answering whether there exists a reasonable body of data to support one resection technique or strategy above others. RECENT FINDINGS: Review of recent literature suggests the continued use of endoscopic ampullectomy is a safe and effective means of curative treatment of ampullary adenomas. Complications are relatively infrequent and complete endoscopic resection is possible in a majority of cases, with proper patient and lesion selection. Greater than 2 decades of experience with endoscopic ampullectomy have shown this to be a viable, well-tolerated, and highly effective means of treating ampullary adenomas. While few concrete guidelines exist to advise endoscopists on the ideal technique for resection, experience, patient selection, and prior planning can greatly influence the technical and clinical success of endoscopic ampullectomy.

The MAZ transcription factor is a downstream target of the oncoprotein Cyr61/CCN1 and promotes pancreatic cancer cell invasion via CRAF-ERK signaling.

Myc-associated zinc-finger protein (MAZ) is a transcription factor with dual roles in transcription initiation and termination. Deregulation of MAZ expression is associated with the progression of pancreatic ductal adenocarcinoma (PDAC). However, the mechanism of action of MAZ in PDAC progression is largely unknown. Here, we present evidence that MAZ mRNA expression and protein levels are increased in human PDAC cell lines, tissue samples, a subcutaneous tumor xenograft in a nude mouse model, and spontaneous cancer in the genetically engineered PDAC mouse model. We also found that MAZ is predominantly expressed in pancreatic cancer stem cells. Functional analysis indicated that MAZ depletion in PDAC cells inhibits invasive phenotypes such as the epithelial-to-mesenchymal transition, migration, invasion, and the sphere-forming ability of PDAC cells. Mechanistically, we detected no direct effects of MAZ on the expression of K-Ras mutants, but MAZ increased the activity of CRAF-ERK signaling, a downstream signaling target of K-Ras. The MAZ-induced activation of CRAF-ERK signaling was mediated via p21-activated protein kinase (PAK) and protein kinase B (AKT/PKB) signaling cascades and promoted PDAC cell invasiveness. Moreover, we found that the matricellular oncoprotein cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) regulates MAZ expression via Notch-1-sonic hedgehog signaling in PDAC cells. We propose that Cyr61/CCN1-induced expression of MAZ promotes invasive phenotypes of PDAC cells not through direct K-Ras activation but instead through the activation of CRAF-ERK signaling. Collectively, these results highlight key molecular players in PDAC invasiveness and may help inform therapeutic strategies to improve clinical management and outcomes of PDAC.

A decade's experience of managing suspected pancreatic adenocarcinoma at a tertiary cancer center.

Background: We present our experience and established management strategy for endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) in diagnosing suspected pancreatic neoplasms at a tertiary referral cancer hospital. Method: Relevant data were extracted from our database for patients who underwent EUS-FNA for suspected pancreatic neoplasms at our institution between 2007 and 2016. Results: Among the 309 patients, the median age was 67 years and 56% were men. The most common presenting symptoms were abdominal pain (37%) and jaundice (29%). Concordance between radiographic diagnosis and final pathology was 89%. The mean lesion size was 34.9 mm on computed tomography and 31.5 mm on EUS. There were 197 patients (64%) with localized disease, of whom 115 (58%) had resectable lesions, 61 (31%) had borderline resectable, and 21 (11%) had unresectable lesions (mean CA 19-9 levels 1705 U/mL, 2490 U/mL, and 479 U/mL, respectively). A median of 3 FNA passes were performed to establish a pathologic diagnosis. Two patients (1%) had postprocedural adverse events. Median overall survival was 47 months in those who underwent surgery after EUS and 12 months in those who did not (P<0.001). Conclusions: A multidisciplinary approach is employed for management of suspected pancreatic neoplasm at our tertiary cancer center. A combination of cross-sectional imaging and EUS-FNA serves as a highly effective duo in establishing a tissue diagnosis and staging with a low adverse event rate. Counterintuitively, CA 19-9 is not necessarily higher with resectable lesions than with unresectable lesions, indicating the limitation of CA 19-9 as a pancreatic tumor marker.

Cysteine-rich 61-connective tissue growth factor-nephroblastoma-overexpressed 5 (CCN5)/Wnt-1-induced signaling protein-2 (WISP-2) regulates microRNA-10b via hypoxia-inducible factor-1α-TWIST signaling networks in human breast cancer cells.

MicroRNAs (miRNAs) are naturally occurring single-stranded RNA molecules that post-transcriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in regulating processes commonly altered during tumorigenesis and metastatic growth. These include cell proliferation, differentiation, apoptosis, migration, and invasion. Among the several miRNAs, miRNA-10b (miR-10b) expression is increased in metastatic breast cancer cells and positively regulates cell migration and invasion through the suppression of the homeobox D10 (HOXD10) tumor suppressor signaling pathway. In breast metastatic cells, miR-10b expression is enhanced by a transcription factor TWIST1. We find that miR-10b expression in breast cancer cells can be suppressed by CCN5, and this CCN5 effect is mediated through the inhibition of TWIST1 expression. Moreover, CCN5-induced inhibition of TWIST1 expression is mediated through the translational inhibition/modification of hypoxia-inducible factor-1α via impeding JNK signaling pathway. Collectively, these studies suggest a novel regulatory pathway exists through which CCN5 exerts its anti-invasive function. On the basis of these findings, it is plausible that reactivation of CCN5 in miR-10b-positive invasive/metastatic breast cancers alone or in combination with current therapeutic regimens could provide a unique, alternative strategy to existing breast cancer therapy.

Engineering Tissue-Informed Biomaterials to Advance Pulmonary Regenerative Medicine.

Biomaterials intentionally designed to support the expansion, differentiation, and three-dimensional (3D) culture of induced-pluripotent stem cells (iPSCs) may pave the way to cell-based therapies for chronic respiratory diseases. These conditions are endured by millions of people worldwide and represent a significant cause of morbidity and mortality. Currently, there are no effective treatments for the majority of advanced lung diseases and lung transplantation remains the only hope for many chronically ill patients. Key opinion leaders speculate that the novel coronavirus, COVID-19, may lead to long-term lung damage, further exacerbating the need for regenerative therapies. New strategies for regenerative cell-based therapies harness the differentiation capability of human iPSCs for studying pulmonary disease pathogenesis and treatment. Excitingly, biomaterials are a cell culture platform that can be precisely designed to direct stem cell differentiation. Here, we present a closer look at the state-of-the-art of iPSC differentiation for pulmonary engineering, offer evidence supporting the power of biomaterials to improve stem cell differentiation, and discuss our perspective on the potential for tissue-informed biomaterials to transform pulmonary regenerative medicine.

Safety of gastrointestinal endoscopy in patients with acute coronary syndrome and concomitant gastrointestinal bleeding.

BACKGROUND: Gastrointestinal bleeding (GIB) is a major concern in patients hospitalized with acute coronary syndrome (ACS) due to the common use of both antiplatelet medications and anticoagulants. Studies evaluating the safety of gastrointestinal endoscopy (GIE) in ACS patients with GIB are limited by their relatively small size, and the focus has generally been on upper GIB and esophago-gastroduod-enoscopy (EGD) only. AIM: To evaluate the safety profile and the hospitalization outcomes of undergoing GIE in patients with ACS and concomitant GIB using the national database for hospitalized patients in the United States. METHODS: The Nationwide Inpatient Sample database was queried to identify patients hospitalized with ACS and GIB during the same admission between 2005 and 2014. The International Classification of Diseases Code, 9th Revision Clinical Modification was utilized for patient identification. Patients were further classified into two groups based on undergoing endoscopic procedures (EGD, small intestinal endoscopy, colonoscopy, or flexible sigmoidoscopy). Both groups were compared regarding demographic information, outcomes, and comorbi-dities. Multivariate analysis was conducted to identify factors associated with mortality and prolonged length of stay. Chi-square test was used to compare categorical variables, while Student's t-test was used to compare continuous variables. All analyses were performed using SAS 9.4 (Cary, NC, United States). RESULTS: A total of 35612318 patients with ACS were identified between January 2005 and December 2014. 269483 (0.75%) of the patients diagnosed with ACS developed concomitant GIB during the same admission. At least one endoscopic procedure was performed in 68% of the patients admitted with both ACS and GIB. Patients who underwent GIE during the index hospitalization with ACS and GIB had lower mortality (3.8%) compared to the group not undergoing endoscopy (8.6 %, P < 0.001). A shorter length of stay (LOS) was observed in patients who underwent GIE (mean 6.59 ± 7.81 d) compared to the group not undergoing endoscopy (mean 7.84 ± 9.73 d, P < 0.001). Multivariate analysis showed that performing GIE was associated with lower mortality (odds ratio: 0.58, P < 0.001) and shorter LOS (-0.36 factor, P < 0.001). CONCLUSION: Performing GIE during the index hospitalization of patients with ACS and GIB was correlated with a better mortality rate and a shorter LOS. Approximately two-thirds of patients with both ACS and GIB undergo GIE during the same hospitalization.

Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model.

Crocetin, a carotenoid compound derived from saffron, has long been used as a traditional ancient medicine against different human diseases including cancer. The aim of the series of experiments was to systematically determine whether crocetin significantly affects pancreatic cancer growth both in vitro and/or in vivo. For the in vitro studies, first, MIA-PaCa-2 cells were treated with crocetin and in these sets of experiments, a proliferation assay using H(3)-thymidine incorporation and flow cytometric analysis suggested that crocetin inhibited proliferation. Next, cell cycle proteins were investigated. Cdc-2, Cdc-25C, Cyclin-B1, and epidermal growth factor receptor were altered significantly by crocetin. To further confirm the findings of inhibition of proliferation, H(3)-thymidine incorporation in BxPC-3, Capan-1, and ASPC-1 pancreatic cancer cells was also significantly inhibited by crocetin treatment. For the in vivo studies, MIA-PaCa-2 as highly aggressive cells than other pancreatic cancer cells used in this study were injected into the right hind leg of the athymic nude mice and crocetin was given orally after the development of a palpable tumor. The in vivo results showed significant regression in tumor growth with inhibition of proliferation as determined by proliferating cell nuclear antigen and epidermal growth factor receptor expression in the crocetin-treated animals compared with the controls. Both the in vitro pancreatic cancer cells and in vivo athymic nude mice tumor, apoptosis was significantly stimulated as indicated by Bax/Bcl-2 ratio. This study indicates that crocetin has a significant antitumorigenic effect in both in vitro and in vivo on pancreatic cancer.

Cancer patients treated with the Banerji protocols utilising homoeopathic medicine: a Best Case Series Program of the National Cancer Institute USA.

Although many studies have been conducted on the role of alternative medicine in the treatment of cancer, only a few reports have been published regarding the total regression of malignant tumors. At the PBH Research Foundation (PBHRF), two of the authors have used homoeopathic therapy to treat many patients with various malignant tumors. The objective of the present study was to have their treatment procedures evaluated and validated by the United States (US) National Cancer Institute (NCI) Best Case Series (BCS) Program. Lung and oesophageal carcinoma patients were treated with homoeopathic remedies at the PBHRF according to Banerji's protocol until there was complete regression of the tumors. Case records including pathology and radiology reports for 14 patients were submitted for review by the US NCI BCS Program. Four of these cases had an independent confirmation of the diagnosis and radiographic response and were accepted as sufficient information for the NCI to initiate further investigation. These four cases are presented in detail in this report along with follow-up and outcome information. This study describes the process and outcome of a selected case series review through the NCI BCS Program. The results of the review were deemed to be sufficient to warrant NCI-initiated prospective research follow-up in the form of an observational study.

Loss of WISP-2/CCN5 signaling in human pancreatic cancer: a potential mechanism for epithelial-mesenchymal-transition.

The objective of this study was to explore the pathophysiological relevance of WISP-2/CCN5 in progression of human pancreatic adenocarcinoma (PAC). We found WISP-2/CCN5 mRNA and protein expression was faint and sporadic in PAC and detected in only 8.7-20% of the samples with varying grades as compared to adjacent normal and chronic pancreatitis samples where expression was very high in the ducts and acini. Colocalization studies in tissue-microarray slides revealed WISP-2/CCN5 mRNA loss was associated with p53 overexpression in PAC. Like tissue samples, p53 mutant-PAC cell lines show loss of WISP-2/CCN5. Moreover, functional analysis studies demonstrate exposure of pancreatic cancer cells to WISP-2/CCN5 recombinant protein enhances mesenchymal-epithelial-transition (MET). Collectively, we suggest WISP-2/CCN5 silencing may be a critical event during differentiation and progression of PAC and mutant p53 is possibly an important player in pursuing this episode.

Human pancreatic cancer progression: an anarchy among CCN-siblings.

Decades of basic and translational studies have identified the mechanisms by which pancreatic cancer cells use molecular pathways to hijack the normal homeostasis of the pancreas, promoting pancreatic cancer initiation, progression, and metastasis, as well as drug resistance. These molecular pathways were explored to develop targeted therapies to prevent or cure this fatal disease. Regrettably, the studies found that majority of the molecular events that dictate carcinogenic growth in the pancreas are non-actionable (potential non-responder groups of targeted therapy). In this review we discuss exciting discoveries on CCN-siblings that reveal how CCN-family members contribute to the different aspects of the development of pancreatic cancer with special emphasis on therapy.

Epidermal growth factor receptor: is a novel therapeutic target for pancreatic cancer?

Expression of epidermal growth factor receptors (EGFR) is exaggerated in pancreatic adenocarcinoma and activation of EGFR appears to have an important role in the growth and differentiation of this and in other tumors. Therefore, blockade or inactivation of EGFR by monoclonal antibodies or by tyrosine kinase inhibitors has significant potential as an effective anti-cancer therapy. One of the very recent significant developments in the field of molecular biology involves the use of antisense of EGFR or EGFR gene silencing in pancreatic cancer cells as a potential targeted therapy for patients with pancreatic adenocarcinoma.

Stimulation of MCF-7 tumor progression in athymic nude mice by 17beta-estradiol induces WISP-2/CCN5 expression in xenografts: a novel signaling molecule in hormonal carcinogenesis.

There was 100% solid tumor formation following inoculation of MCF-7 cells. However, MCF-7 tumor progression was significantly greater in the mice exposed to 17beta-estradiol (17beta-E2) compared to unexposed mice. WISP-2/CCN5 mRNA expression was correspondingly increased in 17beta-E2 exposed MCF-7 tumors compared to unexposed xenografts. Moreover, estrogen exposure followed by anti-estrogen tamoxifen treatment drastically inhibited the tumor growth and WISP-2 expression in nude mice. Therefore, the study suggests that higher WISP-2/CCN5 expression by estrogen may be associated with the estrogen-induced growth of MCF-7 tumors in vivo. Finally, overexpression of WISP-2/CCN5 may be considered as a prognostic marker of estrogen-sensitive tumor growth.

Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole.

BACKGROUND: Studies that report prevention of ulcer recurrence among long-term users of nonsteroidal anti-inflammatory drugs (NSAIDs) that do not stratify for Helicobacter pylori status may not be generalizable to the large population of individuals without H pylori. METHODS: This was a prospective, double-blind, multicenter, active- and placebo-controlled study among 537 patients without H pylori who were long-term users of NSAIDs and who had a history of endoscopically documented gastric ulcer. Patients were randomized to receive placebo, 200 microg of misoprostol 4 times a day, or 15 or 30 mg of lansoprazole once daily for 12 weeks. Ulcer status was determined by endoscopy at 4, 8, and 12 weeks. RESULTS: Patients receiving lansoprazole (15 or 30 mg) remained free from gastric ulcer longer than those who received placebo (P<.001) but for a shorter time than those who received misoprostol. By week 12, the percentages of gastric ulcer-free patients were as follows: placebo, 51% (95% confidence interval [CI], 41.1%-61.3%); misoprostol, 93% (95% CI, 87.2%-97.9%); 15-mg lansoprazole, 80% (95% CI, 72.5%-87.3%); and 30-mg lansoprazole, 82% (95% CI, 75.0%-89.6%). A significantly higher proportion of patients in the misoprostol group reported treatment-related adverse events and early withdrawal from the study. When the impact of withdrawals on ulcer development was considered (as failures), therapy was successful for 69% for each of the active treatment groups and 35% for the placebo group. CONCLUSIONS: Proton pump inhibitors such as lansoprazole are superior to placebo for the prevention of NSAID-induced gastric ulcers but not superior to misoprostol, 800 microg/d. When the poor compliance and potential adverse effects associated with misoprostol are considered, proton pump inhibitors and full-dose misoprostol are clinically equivalent.

Fistulae of the internal thoracic vessels: report of two cases.

Arteriovenous fistulae involving the internal thoracic vessels are extremely rare. The multiple causes, variable clinical presentation, and inconsistent delay of onset of clinical symptoms in addition to their rarity make their diagnosis difficult. However, the complications of untreated internal thoracic fistulae are potentially fatal, emphasizing the need to make a prompt and correct diagnosis. Once the diagnosis is made and the investigational workup complete, treatment consists of either surgical ligation and excision or percutaneous transcatheter embolization. We report two cases of patients with internal thoracic fistulae: one arising as a complication of a tube thoracostomy and the other following an anterior thoracotomy. The second case report describes a rupture of the internal thoracic fistulae, a complication not reported earlier.

Five-year colon surveillance after screening colonoscopy.

BACKGROUND & AIMS: Outcomes of colon surveillance after colorectal cancer screening with colonoscopy are uncertain. We conducted a prospective study to measure incidence of advanced neoplasia in patients within 5.5 years of screening colonoscopy. METHODS: Three thousand one hundred twenty-one asymptomatic subjects, age 50 to 75 years, had screening colonoscopy between 1994 and 1997 in the Department of Veterans Affairs. One thousand one hundred seventy-one subjects with neoplasia and 501 neoplasia-free controls were assigned to colonoscopic surveillance over 5 years. Cohorts were defined by baseline findings. Relative risks for advanced neoplasia within 5.5 years were calculated. Advanced neoplasia was defined as tubular adenoma greater than > or =10 mm, adenoma with villous histology, adenoma with high-grade dysplasia, or invasive cancer. RESULTS: Eight hundred ninety-five (76.4%) patients with neoplasia and 298 subjects (59.5%) without neoplasia at baseline had colonoscopy within 5.5 years; 2.4% of patients with no neoplasia had interval advanced neoplasia. The relative risk in patients with baseline neoplasia was 1.92 (95% CI: 0.83-4.42) with 1 or 2 tubular adenomas <10 mm, 5.01 (95% CI: 2.10-11.96) with 3 or more tubular adenomas <10 mm, 6.40 (95% CI: 2.74-14.94) with tubular adenoma > or =10 mm, 6.05 (95% CI: 2.48-14.71) for villous adenoma, and 6.87 (95% CI: 2.61-18.07) for adenoma with high-grade dysplasia. CONCLUSIONS: There is a strong association between results of baseline screening colonoscopy and rate of serious incident lesions during 5.5 years of surveillance. Patients with 1 or 2 tubular adenomas less than 10 mm represent a low-risk group compared with other patients with colon neoplasia.

WISP-2/CCN5 is involved as a novel signaling intermediate in phorbol ester-protein kinase Calpha-mediated breast tumor cell proliferation.

PMA and active phorbol esters stimulate the proliferation of various tumor cells, including ER-positive human breast tumor cell lines. However, the specific signaling pathways involved in the PMA-induced mitogenic effect on breast tumor cells have not been fully elucidated. In the present study, we explored the mechanisms associated with the mitogenic influence of PMA on breast tumor cells. Following an acute exposure (i.e., within 2 to 6 h) to PMA (50 nM), a mitogenic effect was observed on WISP-2/CCN5-positive breast tumor cell lines, including MCF-7, ZR-75-1 and SKBR-3 cells, and induction of WISP-2/CCN5 mRNA expression paralleled the observed mitogenic proliferation. This effect was undetected in WISP-2/CCN5 negative MDA-MB-231 breast tumor cells or human mammary epithelial cells with or without ER-alpha transfection. The mitogenic effect of PMA was perturbed by short hairpin RNA (shRNA)-mediated inhibition of WISP-2/CCN5 signaling in MCF-7 cells. Moreover, the upregulation of WISP-2/CCN5 by PMA is not ER dependent but is instead mediated through a complex PKCalpha-MAPK/ERK and SAPK/JNK signaling pathway, which leads to growth stimulation of MCF-7 breast tumor cells. These series of experiments provide the first evidence that WISP-2/CCN5 is a novel signaling molecule that critically participates in the mitogenic action of PMA on noninvasive, WISP-2/CCN5-positive breast tumor cells through PKCalpha-dependent, multiple molecular signal transduction pathways.

Differential expression of VEGF-A mRNA by 17beta-estradiol in breast tumor cells lacking classical ER-alpha may be mediated through a variant form of ER-alpha.

Beta-estradiol (17beta-E2) augments VEGF-A expression in various estrogen targeted organs and cells including breast tumor derived cell lines, via an ER-alpha mediated pathway. Ironically, 17beta-E2 is able to regulate some genes via ER-alpha independent pathways. In the present study, we sought to determine whether 17beta-E2 can modulate VEGF-A expression in absence of ER-alpha, and therefore, three different cell lines including ER-alpha+ MCF-7, and ER-alpha SKBR-3 and HMEC were used for this study. The present study demonstrates that 17beta-E2 also induces VEGF-A mRNA expression in ER-negative SKBR-3 breast tumor cells in a manner similar to that observed in ER-positive MCF-7 cells. Blocking the induced-expression by antiestrogen ICI 182,780 indicates the induction pathway is ER dependent. While ER-alpha mRNA is absent in both HMEC and SKBR-3 cells, the impact of estrogen was found only in SKBR-3 cells, suggesting the existence of an analogue to ER-alpha or overlapping signal in these cells. Consistent with this suggestion, the present studies demonstrate the existence of an ER-alpha(var2) protein in MCF-7 and in SKBR-3 cells. This variant is predominantly localized in the nuclei of SKBR-3 cells. Importantly, specific binding of 17beta-E2 by these cells suggest the ER-alpha(var2) may act as active receptor in SKBR-3 cells.

Effect of H. pylori status on gastric ulcer healing in patients continuing nonsteroidal anti-inflammatory therapy and receiving treatment with lansoprazole or ranitidine.

OBJECTIVES: The purpose of this research was to determine the impact of pretreatment Helicobacter pylori infection on gastric ulcer healing rates in patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and antisecretory medications. METHODS: This was a pooled, prospective analysis of two identical double blind, multicenter, parallel group studies. Six hundred ninety-two patients receiving NSAIDs and with endoscopy-documented gastric ulcers were enrolled from 90 North American sites in primary care and referral centers. Patients were randomized to receive ranitidine (150 mg b.i.d.) or lansoprazole (15 mg or 30 mg once daily) for 8 wk. Ulcer healing was assessed by endoscopy at 4 and 8 wk in an intent-to-treat population. H. pylori status was determined at baseline by histology. RESULTS: Across all three treatment groups, gastric ulcers were more likely to heal and heal faster if the individual was infected with H. pylori. Healing rates at 8 wk were statistically significantly greater among H. pylori positive patients (n = 181) than among negative patients (n = 497) (70% vs 61%, respectively; p < 0.05), especially among those with large ulcers (> 10 mm) and in younger patients (< 60 yr old). Simple healing rates (regardless of H. pylori status) were significantly better in the 15- and 30-mg lansoprazole groups than in the ranitidine group after 4 wk (46%, 54%, and 32%, respectively; p < or = 0.01) and 8 wk (66%, 74%, and 50%, respectively; p < 0.001). CONCLUSIONS: In patients receiving NSAIDs, gastric ulcer healing with an antisecretory agent is significantly enhanced in the presence of H. pylori infection.