Phase II trial of niraparib for BRCA-mutated biliary tract, pancreatic and other gastrointestinal cancers: NIR-B.

Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, via the mechanism of synthetic lethality. The aim of this phase II NIR-B trial is to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer or other gastrointestinal cancers with germline or somatic BRCA1/2 mutations revealed by genetic testing. The primary end point is an investigator-assessed objective response rate in each cohort.Clinical Trial Registration: jRCT2011200023 (ClinicalTrials.gov).

A clinical study to confirm the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with the BRCA genetic mutation: the NIR-B trial.BRCA gene is involved in repairing DNA injury and plays an important role in cancer growth. Cells with a mutation in the BRCA gene cannot repair DNA using a method called homologous recombination repair. Niraparib is part of a class of drugs called 'PARP inhibitors' that inhibit enzymes called 'PARP' involved in repairing DNA injury, and has shown efficacy against cancers with BRCA gene mutations. BRCA gene mutations are infrequent but have been found in a variety of cancers. The NIR-B trial is a clinical trial to evaluate the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with BRCA gene mutations.

Zinc Deficiency as a General Feature of Cancer: a Review of the Literature.

Trace elements are minerals that are present in very low concentrations in the human body and yet are crucial for a wide range of physiological functions. Zinc, the second most abundant trace element, is obtained primarily from the diet. After being taken up in the intestine, zinc is distributed to various target organs, where it plays key roles in processes such as immunity, protein folding, apoptosis, and antioxidant activity. Given the important role of zinc in a wide range of enzymatic reactions and physiological processes, zinc deficiency has been identified in a variety of diseases, notably cancer. In recent years, multiple meta-analyses and reviews looking at zinc levels in individual cancer types have been published, as have a plethora of primary studies demonstrating a link between low zinc levels and specific types of cancer. In this review, we summarize recent evidence implicating low zinc concentrations in serum or tissues as a characteristic in a wide range of cancers. We also discuss preliminary findings indicating that zinc level measurement could ultimately become a useful clinical tool for cancer diagnosis and predicting outcomes in patients with cancer. Finally, we suggest future directions for further elucidating the role of zinc deficiency in cancer development and progression.

Liver metastasis composed of pure squamous cell carcinoma component from pancreatic pure ductal adenocarcinoma: a case report.

BACKGROUND: Liver metastasis of pure squamous cell carcinoma (SCC) from pancreatic ductal adenocarcinoma has not been previously reported. CASE PRESENTATION: A 66-year-old man underwent a computed tomography scan 3 years after surgery for pancreatic head cancer, and the scan revealed a mass lesion in the right lobe of the liver. A liver tumor biopsy was performed, and SCC was diagnosed. Whole sections of the pancreatic head cancer were re-evaluated, but no areas of SCC-like differentiation were identified. Although the pathology differed between the pancreas and liver, metastasis of adenosquamous carcinoma was considered. Three courses of gemcitabine plus nab-paclitaxel were administered to treat the liver metastasis of pancreatic cancer, but no response was attained. Therefore, primary SCC of the liver was considered and hepatic resection was performed. The tumor had invaded the diaphragm, and S5/6 partial hepatic resection with right diaphragm resection was performed. Pathological examination showed pure SCC of the liver, which differed from the pancreatic cancer. KRAS mutations were evaluated in the pancreatic and liver tumor specimens, and Q61R mutation was identified in both specimens. This pure SCC of the liver was diagnosed as metastasis from pancreatic cancer not by histology but by genetic analysis. CONCLUSIONS: This is the first reported case of pure SCC liver metastasis from pancreatic cancer without a squamous cell component in the primary tumor. Evaluation of KRAS mutations in both specimens was useful for diagnosis.

Cofilin activation in pancreatic acinar cells plays a pivotal convergent role for mediating CCK-stimulated enzyme secretion and growth.

Introduction: The actin regulatory protein, cofilin plays a key signaling role in many cells for numerous cellular responses including in proliferation, development, motility, migration, secretion and growth. In the pancreas it is important in islet insulin secretion, growth of pancreatic cancer cells and in pancreatitis. However, there are no studies on its role or activation in pancreatic acinar cells. Methods: To address this question, we studied the ability of CCK to activate cofilin in pancreatic acinar cells, AR42J cells and CCK1-R transfected Panc-1 cells, the signaling cascades involved and its effect on enzyme secretion and MAPK activation, a key mediator of pancreatic growth. Results: CCK (0.3 and 100 nM), TPA, carbachol, Bombesin, secretin and VIP decreased phospho-cofilin (i.e., activate cofilin) and both phospho-kinetic and inhibitor studies of cofilin, LIM kinase (LIMK) and Slingshot Protein Phosphatase (SSH1) demonstrated these conventional activators of cofilin were not involved. Serine phosphatases inhibitors (calyculin A and okadaic acid), however inhibited CCK/TPA-cofilin activation. Studies of various CCK-activated signaling cascades showed activation of PKC/PKD, Src, PAK4, JNK, ROCK mediated cofilin activation, but not PI3K, p38, or MEK. Furthermore, using both siRNA and cofilin inhibitors, cofilin activation was shown to be essential for CCK-mediated enzyme secretion and MAPK activation. Conclusion: These results support the conclusion that cofilin activation plays a pivotal convergent role for various cell signaling cascades in CCK mediated growth/enzyme secretion in pancreatic acini.

Serum zinc levels in cancer patients are low and difficult to elevate when complicated by liver cirrhosis: A retrospective study.

In this study, we analyzed blood zinc concentration in patients with various cancer types and the degree of improvement in relation to the underlying disease following treatment with zinc preparations. Serum zinc levels of 530 cancer patients whose blood zinc levels were measured at our hospital from 2016 to 2021 were retrospectively examined in accordance with the primary disease. Changes in zinc levels were analyzed in 155 patients whose zinc levels had been measured on 2 or more occasions in accordance with whether they had received zinc preparations. In addition, the concentration course of zinc before and after zinc formulation administration in 73 patients was examined in accordance with the presence or absence of liver cirrhosis complications. Mean serum zinc levels were below normal in all carcinomas measured, and zinc levels were significantly lower in cirrhosis-hepatocarcinoma cases than in other primary disease cases. Furthermore, serum zinc levels in patients who did not receive zinc preparations decreased significantly over time. In patients who received zinc preparations, the elevated levels of zinc after treatment were significantly lower in patients with cirrhosis than in those without cirrhosis. There was a weak inverse correlation between pre-dose zinc concentration and increased zinc concentration in patients with cirrhosis. In the analysis of covariance, the presence of liver cirrhosis was predominantly correlated with elevated zinc per dose. In summary, serum zinc levels in cancer patients are low and especially low in cancer patients with liver cirrhosis compared with those without cirrhosis after the administration of zinc preparations.

Treatment Effect and Safety of Nanoliposomal Irinotecan with Fluorouracil and Folinic Acid after Gemcitabine-Based Therapy in Patients with Advanced Pancreatic Cancer: A Multicenter, Prospective Observational Study.

Although the combination of nanoliposomal irinotecan plus fluorouracil/folinic acid (nal-IRI/FF) exhibited survival benefits in gemcitabine-refractory patients with advanced pancreatic cancer (APC) in the phase III NAPOLI-1 trial, there is limited data on the efficacy and safety of this regimen in real-world settings in Japan. This multicenter, prospective observational study enrolled patients with APC who received nal-IRI/FF after a gemcitabine-based regimen from July 2020 to June 2021. We collected and analyzed clinical data and conducted survival and multivariate analyses. Thirty-one (78%) of the 40 patients had metastases. Nal-IRI/FF was the second-line therapy in 36 patients (90%). The median duration was 3.2 months. The disease control rate was 57%. The median progression-free survival and overall survival (OS) were 4.5 months (95% confidence interval [CI]: 2.8−5.5) and 7.4 months (95% CI: 5.1−10.6), respectively. Common ≥grade 3 toxicities included neutropenia (28%) and fatigue (23%). Fatigue led to treatment discontinuation in 6 out of 10 patients. Multivariate analysis showed that a neutrophil-to-lymphocyte ratio > 4 was a significant risk factor for a short OS (hazard ratio (HR) = 3.08, 95% CI: 1.21−7.85, p = 0.02). In conclusion, nal-IRI/FF is an appropriate treatment option for APC following gemcitabine-containing regimens.

Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies.

Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed.

Loss of adipose tissue or skeletal muscle during first-line gemcitabine/nab-paclitaxel therapy is associated with worse survival after second-line therapy of advanced pancreatic cancer.

AIM: Progression of cachexia indicated by decreased body weight and composition is associated with poor survival of advanced pancreatic cancer (APC). There are limited data concerning the prognostic effect of cachexia on second-line chemotherapy (L2). We aimed to assess the impact of cachexia progression during first-line therapy (L1) on survival after L2. METHODS: We reviewed patients with gemcitabine/nab-paclitaxel (GEM/nabPTX)-refractory APC who underwent L2 with modified FOLFIRINOX or S-1 between 2015 and 2019 in our institution. We determined clinicopathological data including body composition parameters: subcutaneous fat area (SFA), visceral fat area (VFA), and skeletal muscle index (SMI). Correlations of changes in these parameters, as well as their effect on overall survival after L2 (OS2), were examined. RESULTS: Median rates of change in SMI, SFA, and VFA were 0.19%, -4.17%, and -18.39%, respectively, in 59 patients during L1. Although there was moderate correlation in rate of change between SFA and VFA, there was no correlation between SMI and other parameters. We defined loss of SFA, VFA, and SMI as decreases greater than 8.5%, 34.1%, and 8.7%, respectively. Median OS2 of patients with loss in any of these parameters was significantly shorter than in patients without loss (3.83 vs. 8.73 months). Multivariate analysis revealed that loss in any parameters, performance status, and C-reactive protein/albumin ratio were independent negative prognostic factors. CONCLUSION: Loss of adipose tissue or skeletal muscle during L1 had a considerable impact on OS2 in APC refractory to GEM/nabPTX.

Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy.

G-protein-coupled receptors (GPCRs) are increasingly being considered as possible therapeutic targets in cancers. Activation of GPCR on tumors can have prominent growth effects, and GPCRs are frequently over-/ectopically expressed on tumors and thus can be used for targeted therapy. CNS/neural tumors are receiving increasing attention using this approach. Gliomas are the most frequent primary malignant brain/CNS tumor with glioblastoma having a 10-year survival <1%; neuroblastomas are the most common extracranial solid tumor in children with long-term survival<40%, and medulloblastomas are less common, but one subgroup has a 5-year survival <60%. Thus, there is an increased need for more effective treatments of these tumors. The Bombesin-receptor family (BnRs) is one of the GPCRs that are most frequently over/ectopically expressed by common tumors and is receiving particular attention as a possible therapeutic target in several tumors, particularly in prostate, breast, and lung cancer. We review in this paper evidence suggesting why a similar approach in some CNS/neural tumors (gliomas, neuroblastomas, medulloblastomas) should also be considered.

Improved indocyanine green retention after short-term lenvatinib withdrawal in three patients with hepatocellular carcinoma.

Use of lenvatinib, which has a high response rate in advanced hepatocellular carcinoma, sometimes results in tumor shrinkage and resectability of previously unresectable liver cancers. In Asia, including Japan, liver reserve, one of the determinants of resectability, is mainly determined by the indocyanine green (ICG) retention rate. Three patients with advanced liver cancer treated at our institution had very poor ICG retention rates during treatment with lenvatinib. Lenvatinib may reduce blood flow in both cancerous and non-cancerous regions by inhibiting vascular endothelial growth factor. Therefore, accurate determination of liver function likely requires withdrawal of this treatment several days before ICG retention testing.

Multiple Endocrine Neoplasia Type 1 and the Pancreas: Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement.

The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies.

The G Protein-Coupled Receptor PAC1 Regulates Transactivation of the Receptor Tyrosine Kinase HER3.

Peptide G protein-coupled receptors (GPCRs) for pituitary adenylate cyclase activating polypeptide (PACAP) regulate the growth of non-small cell lung cancer (NSCLC) cells. PACAP binds with high affinity to PAC1, which causes transactivation of receptor tyrosine kinases (RTK) for the EGFR and HER2 but its effect on HER3 is unknown. Using 3 NSCLC cell lines (NCI-H358, NCI-H441, and Calu-3), proteins for EGFR, HER2, HER3, and PAC1 were detected. The increase in EGFR tyrosine phosphorylation caused by PACAP was blocked by the EGFR tyrosine kinase inhibitor (TKI) gefitinib, or PACAP(6-38), a PAC1 antagonist. The increase in HER2 tyrosine phosphorylation caused by PACAP was inhibited by trastuzumab, a monoclonal antibody (mAb) for HER2, or PACAP(6-38). The increase in HER3 tyrosine phosphorylation caused by PACAP was inhibited by HER3 mAb3481 or PACAP(6-38). Immunoprecipitation experiments indicated the PACAP addition to Calu-3 cells resulted in the formation of EGFR/HER3 and HER2/HER3 heterodimers. Addition of the HER3 agonist neuregulin (NRG)-1 increased HER3 tyrosine phosphorylation in non-small-cell lung cancer (NSCLC) cells. PACAP or NRG-1 increased the proliferation of NSCLC cells, whereas PACAP(6-38), gefitinib, trastuzumab, or mAb3481 inhibited proliferation. The results indicate that PAC1 regulates the proliferation of NSCLC cells as a result of transactivation of the EGFR, HER2, and HER3.

Natural history and clinical outcomes of pancreatic neuroendocrine neoplasms based on the WHO 2017 classification; a single-center experience of 30 years.

BACKGROUND/OBJECTIVES: This single-center study aimed to evaluate treatment outcomes and long-term prognosis of patients with pancreatic neuroendocrine neoplasms (PanNENs) based on the World Health Organization (WHO) 2017 classification. METHODS: We enrolled 245 patients with PanNENs treated at Kyushu University Hospital between January 1987 and March 2018. PanNENs were categorized according to the WHO 2017 classification or further subdivisions of Ki-67 index. Clinicopathological features, median survival time (MST), and prognostic factors were retrospectively analyzed. RESULTS: The number of PanNENs, especially non-functioning PanNENs, has increased over the last decade. The mean MST of all patients was 202 months; which was longest in patients with NET G1 (n = 145, MST = 261 months) relative to NET G2 (n = 72, 132 months), NET G3 (n = 3, 34 months) and NEC G3 (n = 17, 9 months). Prognosis in patients with surgery as the first-line treatment was significantly better than in those with drug therapy. However, 26% of patients who underwent curative resection developed recurrence after a median time of 28.7 months. In unresectable PanNENs (n = 97), the MST and 5-year survival rate were 78 months and 55.8%, respectively. Poor differentiation, Ki-67 index of >10% and presence of liver metastasis were significant unfavorable predictors. Response to first-line therapy (stable disease/partial response) and three or more treatment regimens were significant favorable predictors for unresectable PanNENs according to multivariate analyses (p < 0.01). CONCLUSIONS: We demonstrated the utility of the WHO 2017 classification for PanNENs in the real clinical setting. For better prognosis in PanNENs, the use of three or more regimens should be considered.

Group II p21-activated kinase, PAK4, is needed for activation of focal adhesion kinases, MAPK, GSK3, and ß-catenin in rat pancreatic acinar cells.

PAK4 is the only member of the Group II p21-activated kinases (PAKs) present in rat pancreatic acinar cells and is activated by gastrointestinal hormones/neurotransmitters stimulating PLC/cAMP and by various pancreatic growth factors. However, little is known of the role of PAK4 activation in cellular signaling cascades in pancreatic acinar cells. In the present study, we examined the role of PAK4's participation in five different cholecystokinin-8 (CCK-8)-stimulated signaling pathways (PI3K/Akt, MAPK, focal adhesion kinase, GSK3, and ß-catenin), which mediate many of its physiological acinar-cell effects, as well as effects in pathophysiological conditions. To define PAK4's role, the effect of two different PAK4 inhibitors, PF-3758309 and LCH-7749944, was examined under experimental conditions that only inhibited PAK4 activation and not activation of the other pancreatic PAK, Group I PAK2. The inhibitors' effects on activation of these five signaling cascades by both physiological and pathophysiological concentrations of CCK, as well as by 12-O-tetradecanoylphobol-13-acetate (TPA), a PKC-activator, were examined. CCK/TPA activation of focal adhesion kinases(PYK2/p125FAK) and the accompanying adapter proteins (paxillin/p130CAS), Mek1/2, and p44/42, but not c-Raf or other MAPKs (JNK/p38), were mediated by PAK4. Activation of PI3K/Akt/p70s6K was independent of PAK4, whereas GSK3 and ß-catenin stimulation was PAK4-dependent. These results, coupled with recent studies showing PAK4 is important in pancreatic fluid/electrolyte/enzyme secretion and acinar cell growth, show that PAK4 plays an important role in different cellular signaling cascades, which have been shown to mediate numerous physiological and pathophysiological processes in pancreatic acinar cells.NEW & NOTEWORTHY In pancreatic acinar cells, cholecystokinin (CCK) or 12-O-tetradecanoylphobol-13-acetate (TPA) activation of focal adhesion kinases (p125FAK,PYK2) and its accompanying adapter proteins, p130CAS/paxillin; Mek1/2, p44/42, GSK3, and ß-catenin are mediated by PAK4. PI3K/Akt/p70s6K, c-Raf, JNK, or p38 pathways are independent of PAK4 activation.

Risk factors for de novo hepatitis B during solid cancer treatment.

BACKGROUND: Reactivation of hepatitis B virus (HBV) during anticancer treatment is a critical issue. When treating patients with solid tumors, it is unclear whether specific cancer types or treatments affect HBV reactivation in hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (HBcAb)-positive patients, so-called de novo hepatitis B patients. The risk of de novo hepatitis B may vary based on different background factors. AIM: To determine the frequency and risk factors for de novo hepatitis B during solid tumor treatment. METHODS: This retrospective cohort study comprised 1040 patients without HBsAgs and with HBcAbs and/or hepatitis B surface antibodies (HBsAbs). The patients were treated for solid cancer from 2008 to 2018 at the National Kyushu Cancer Center and underwent HBV DNA measurements. Patient characteristics and disease and treatment information were investigated. HBV DNA measurements were performed using TaqMan polymerase chain reaction (PCR). To identify the risk factors associated with HBV DNA expression, the age, sex, original disease, pathology, treatment method, presence or absence of hepatitis C virus (HCV), and HBsAb and/or HBcAb titers of all subjects were investigated. In patients with HBV DNA, the time of appearance, presence of HBsAgs and HBsAbs at the time of appearance, and course of the subsequent fluctuations in virus levels were also investigated. RESULTS: Among the 1040 patients, 938 were HBcAb positive, and 102 were HBcAb negative and HBsAb positive. HBV DNA expression was observed before the onset of treatment in nine patients (0.9%) and after treatment in 35 patients (3.7%), all of whom were HBcAb positive. The HBV reactivation group showed significantly higher median HBcAb values [9.00 (8.12-9.89) vs 7.22 (7.02-7.43), P = 0.0001] and significantly lower HBsAb values (14 vs 46, P = 0.0342) than the group without reactivation. Notably, the reactivated group showed a significantly higher proportion of cancers in organs related to digestion and absorption (79.0% vs 58.7%, P = 0.0051). A high HBcAb titer and cancers in organs involved in digestion and absorption were identified as independent factors for HBV reactivation (multivariate analysis, P = 0.0002 and P = 0.0095). The group without HBsAbs tended to have a shorter time to reactivation (day 43 vs day 193), and the frequency of reactivation within 6 mo was significantly higher in this group (P = 0.0459) than in the other group. CONCLUSION: A high HBcAb titer and cancers in organs involved in digestion and absorption are independent factors that contribute to HBV reactivation during solid tumor treatment.

Neuropeptide bombesin receptor activation stimulates growth of lung cancer cells through HER3 with a MAPK-dependent mechanism.

Despite recent advances in treatment of non-small cell lung cancer (NSCLC), prognosis still remains poor and new therapeutic approaches are needed. Studies demonstrate the importance of the EGFR/HER-receptor family in NSCLC growth, as well as that of other tumors. Recently, HER3 is receiving increased attention because of its role in drug resistance and aggressive growth. Activation of overexpressed G-protein-coupled receptors (GPCR) can also initiate growth by transactivating EGFR/HER-family members. GPCR transactivation of EGFR has been extensively studied, but little is known of its ability to transactivate other EGFR/HER-members, especially HER3. To address this, we studied the ability of bombesin receptor (BnR) activation to transactivate all EGFR/HER-family members and their principal downstream signaling cascades, the PI3K/Akt- and MAPK/ERK-pathways, in human NSCLC cell-lines. In all three cell-lines studied, which possessed EGFR, HER2 and HER3, Bn rapidly transactivated EGFR, HER2 and HER3, as well as Akt and ERK. Immunoprecipitation studies revealed Bn-induced formation of both HER3/EGFR- and HER3/HER2-heterodimers. Specific EGFR/HER3 antibodies or siRNA-knockdown of EGFR and HER3, demonstrated Bn-stimulated activation of EGFR/HER members is initially through HER3, not EGFR. In addition, specific inhibition of HER3, HER2 or MAPK, abolished Bn-stimulated cell-growth, while neither EGFR nor Akt inhibition had an effect. These results show HER3 transactivation mediates all growth effects of BnR activation through MAPK. These results raise the possibility that targeting HER3 alone or with GPCR activation and its signal cascades, may be a novel therapeutic approach in NSCLC. This is especially relevant with the recent development of HER3-blocking antibodies.

Prognostic and predictive factors on overall survival and surgical outcomes in pancreatic neuroendocrine tumors: recent advances and controversies.

Introduction: Recent advances in diagnostic modalities and therapeutic agents have raised the importance of prognostic factors in predicting overall survival, as well as predictive factors for surgical outcomes, in tailoring therapeutic strategies of patients with pancreatic neuroendocrine neoplasms (panNENs).Areas covered: Numerous recent studies of panNEN patients report the prognostic values of a number of clinically related factors (clinical, laboratory, imaging, treatment-related factors), pathological factors (histological, classification, grading) and molecular factors on long-term survival. In addition, an increasing number of studies showed the usefulness of various factors, specifically biomarkers and molecular makers, in predicting recurrence and mortality related to surgical treatment. Recent findings (from the last 3 years) in each of these areas, as well as recent controversies, are reviewed.Expert commentary: The clinical importance of prognostic and predictive factors for panNENs is markedly increased for both overall outcome and post resection, as a result of recent advances in all aspects of the diagnosis, management and treatment of panNENs. Despite the proven prognostic utility of routinely used tumor grading/classification and staging systems, further studies are required to establish these novel prognostic factors to support their routine clinical use.

Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome.

The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25-70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10-20 years). Zollinger-Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.

Neurotensin receptors regulate transactivation of the EGFR and HER2 in a reactive oxygen species-dependent manner.

Neurotensin is a 13 amino acid peptide which is present in many lung cancer cell lines. Neurotensin binds with high affinity to the neurotensin receptor 1, and functions as an autocrine growth factor in lung cancer cells. Neurotensin increases tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) and the neurotensin receptor 1 antagonist SR48692 blocks the transactivation of the EGFR. Here the effects of reactive oxygen species on the transactivation of the EGFR and HER2 were investigated. Using non-small cell lung cancer (NSCLC) cell lines, neurotensin receptor 1 mRNA and protein were present. Using NCI-H838 cells, neurotensin or neurotensin8-13 but not neurotensin1-8 increased EGFR, ERK and HER2 tyrosine phosphorylation which was blocked by SR48692. Neurotensin addition to NCI-H838 cells increased significantly reactive oxygen species which was inhibited by SR48692, Tiron (superoxide scavenger) and diphenylene iodonium (DPI inhibits the ability of NADPH oxidase and dual oxidase enzymes to produce reactive oxygen species). Tiron or DPI impaired the ability of neurotensin to increase EGFR, ERK and HER2 tyrosine phosphorylation. Neurotensin stimulated NSCLC cellular proliferation whereas the growth was inhibited by SR48692, DPI or lapatinib (lapatinib is tyrosine kinase inhibitor of the EGFR and HER2). Lapatinib inhibited the ability of the neurotensin receptor 1 to transactivate the EGFR and HER2. The results indicate that neurotensin receptor 1 regulates the transactivation of the EGFR and HER2 in a reactive oxygen species-dependent manner.

Development and Characterization of a Novel, High-Affinity, Specific, Radiolabeled Ligand for BRS-3 Receptors.

Bombesin (Bn) receptor subtype 3(BRS-3) is an orphan G-protein-coupled receptor of the Bn family, which does not bind any natural Bn peptide with high affinity. Receptor knockout studies show that the animals develop diabetes, obesity, altered temperature control, and other central nervous system (CNS)/endocrine/gastrointestinal changes. It is present in CNS, peripheral tissues, and tumors; however, its role in normal physiology/pathophysiology, as well as its receptor localization/pharmacology is largely unknown, in part due to the lack of a convenient, specific, direct radiolabeled ligand. This study was designed to address this problem and to develop and characterize a specific radiolabeled ligand for BRS-3. The peptide antagonist Bantag-1 had >10,000-fold selectivity for human BRS-3 (hBRS-3) over other mammalian Bn receptors (BnRs) [i.e., gastrin-releasing peptide receptor (GRPR) and neuromedin B receptor (NMBR)]. Using iodogen and basic conditions, it was radiolabeled to high specific activity (2200 Ci/mmol) and found to bind with high affinity/specificity to hBRS-3. Binding was saturable, rapid, and reversible. The ligand only interacted with known BRS-3 ligands, and not with other specific GRPR/NMBR ligands or ligands for unrelated receptors. The magnitude of 125I-Bantag-1 binding correlated with BRS-3 mRNA expression and the magnitude of activation of phospholipase C in lung cancer cells, as well as readily identifying BRS-3 in lung cancer cells and normal tissues, allowing the direct assessment of BRS-3 receptor pharmacology/numbers on cells containing BRS-3 with other BnRs, which is usually the case. This circumvents the need for subtraction assays, which are now frequently used to assess BRS-3 indirectly using radiolabeled pan-ligands, which interact with all BnRs.