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Background: The advent of liquid biopsies presents a novel, minimally invasive methodology for the detection of disease biomarkers, offering a significant advantage over traditional biopsy techniques. Particularly, the analysis of cell-free RNA (cfRNA) has garnered interest due to its dynamic expression profiles and the capability to study various RNA species, including messenger RNA (mRNA) and long non-coding RNA (lncRNA). These attributes position cfRNA as a versatile biomarker with broad potential applications in clinical research and diagnostics., Scope of Review: This review delves into the utility of cfRNA biomarkers as prognostic tools for obesity-related comorbidities, such as diabetes, dyslipidemia, and non-alcoholic fatty liver disease., Major Conclusions: We evaluate the efficacy of cfRNA in forecasting metabolic outcomes associated with obesity and in identifying patients likely to experience favorable clinical outcomes following bariatric surgery. Additionally, this review synthesizes evidence from studies examining circulating cfRNA across different physiological and pathological states, with a focus on its role in diabetes, including disease progression monitoring and treatment efficacy assessment. Through this exploration, we underscore the emerging relevance of cfRNA signatures in the context of obesity and its comorbidities, setting the stage for future investigative efforts in this rapidly advancing domain., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

A woman in her 40s underwent evaluation for abdominal pain, jaundice and acholic stools and was diagnosed with metastatic pancreatic head adenocarcinoma. She was enrolled in a clinical trial investigating the benefits of ibrutinib with nab-paclitaxel and gemcitabine, and subsequently received modified FOLFIRINOX. Over the course of 6 years on chemotherapy, she experienced complete regression of the pancreatic and liver lesions, as well as normalisation of her tumour markers. She has been off chemotherapy for 6 months with no evidence of disease and normal tumour markers. Despite advances in chemotherapy and surgical options, metastatic pancreatic adenocarcinoma continues to carry a grim prognosis. This case report demonstrates a rare case of a long-term survivor of unresectable metastatic pancreatic adenocarcinoma treated with chemotherapy alone., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Early detection of cancer can significantly improve patient outcomes; however, sensitive and highly specific biomarkers for cancer detection are currently missing. Nullomers are the shortest sequences that are absent from the human genome but can emerge due to somatic mutations in cancer. We examine over 10,000 whole exome sequencing matched tumor-normal samples to characterize nullomer emergence across exonic regions of the genome. We also identify nullomer emerging mutational hotspots within tumor genes. Finally, we provide evidence for the identification of nullomers in cell-free RNA from peripheral blood samples, enabling detection of multiple tumor types. We show multiple tumor classification models with an AUC greater than 0.9, including a hepatocellular carcinoma classifier with an AUC greater than 0.99., (© 2024. The Author(s).)

Early diagnosis of cancer can significantly improve survival of cancer patients; however sensitive and highly specific biomarkers for cancer detection are currently lacking for most cancer types. Nullpeptides are short peptides that are absent from the human proteome. Here, we examined the emergence of nullpeptides during cancer development. We analyzed 3,600,964 somatic mutations across 10,064 whole exome sequencing tumor samples spanning 32 cancer types. We analyze RNA-seq data from primary tumor samples to identify the subset of nullpeptides that emerge in highly expresed genes. We show that nullpeptides, and particularly the subset that is highly recurrent across cancer patients, can be identified in tumor biopsy samples. We find that cancer genes show an excess of nullpeptides and detect nullpeptide hotspots in specific loci of oncogenes and tumor suppressors. We also observe that recurrent nullpeptides are more likely to be found in neoantigens, which have been shown to be effective targets for immunotherapy, suggesting that they can be used to prioritize candidates. Our findings provide evidence for the utility of nullpeptides as cancer detection and therapeutic biomarkers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: End-stage ankle osteoarthritis is a condition that can be treated with ankle arthrodesis (AA) or total ankle arthroplasty (TAA). The goal of this study is to estimate the 2016-2017 United States' utilization of TAA and AA in specific ambulatory settings and delineate patient and hospital factors associated with the selection of TAA vs AA for treatment of ankle osteoarthritis., Methods: TAA and AA procedures performed for ankle osteoarthritis were identified in the 2016-2017 Nationwide Ambulatory Surgery Sample (NASS) Database. Notably, the NASS database only examines instances of ambulatory surgery encounters at hospital-owned facilities. As such, instances of TAA and AA performed at privately owned or freestanding ambulatory surgical centers or those performed inpatient are excluded from this analysis. Cases were weighted using nationally representative discharge weights. Univariate analyses and a combined multiple logistic regression model were used to compare demographic, hospital-related, and socioeconomic factors associated with TAA vs AA., Results: In total, 6577 cases were identified, which represents 9072 cases after weighting. Of these, TAA was performed for 2233 (24.6%). Based on the logistic regression model, several factors were associated with increased utilization of TAA vs AA. With regard to patient factors, older patients were more likely to undergo TAA, as well as females. Conversely, patients with a higher comorbidity burden were less likely to receive TAA over AA.With regard to socioeconomic factors, urban teaching and urban nonteaching hospitals were significantly more likely to use TAA compared to rural hospitals. Similarly, privately insured patients and those with a median household income of $71 000 or more were also more likely to receive TAA over AA. Private hospitals ("not-for-profit" and "investor-owned") were significantly more likely to offer TAA over AA., Conclusion: Using a large nationally representative cohort, the current data revealed that during 2016-2017, 24.6% of operatively treated cases of end-stage ankle osteoarthritis in the ambulatory setting are treated with TAA. Associations between socioeconomic and hospital-level factors with TAA utilization suggest that nonclinical factors may influence surgical treatment choice for ankle osteoarthritis., Level of Evidence: Level III, retrospective cohort study., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. ICMJE forms for all authors are available online., (© The Author(s) 2023.)

Colorectal cancer is one of the most common malignant diseases in the United States and worldwide, and it remains among the top three causes of cancer-related death. A new understanding of molecular characteristics has changed the profile of colorectal cancer and its treatment. Even controlling for known mutational differences, tumor side of origin has emerged as an independent prognostic factor, and one that impacts response to therapy. Left- and right-sided colon cancers differ in a number of key ways, including histology, mutational profile, carcinogenesis pathways, and microbiomes. Moreover, the frequency of certain molecular features gradually changes from the ascending colon to rectum. These, as well as features yet to be identified, are likely responsible for the ongoing role of tumor sidedness and colorectal subsites in treatment response and prognosis. Along with tumor molecular profiling, blood-based biopsy enables the identification of targetable mutations and predictive biomarkers of treatment response. With the application of known tumor characteristics including sidedness and subsites as well as the utilization of blood-based biopsy, along with the development of biomarkers and targeted therapies, the field of colorectal cancer continues to evolve towards the personalized management of a heterogeneous cancer.

Background: Behavioral addiction to smartphones is a common phenomenon in the present digital age, wherein indulgence in these devices is compulsive and impacts physical, social, and psychological health of the population. The smartphones effect on a dental student's life is detrimental to their academics, health, and efficiency in providing clinical patient care. To assess use and addiction of smartphones among dental students under six major domains and to compare this based on their gender, ethnicity, and year of study., Materials and Methods: A cross-sectional study using a validated questionnaire, Smartphone addiction scale was conducted among 349 undergraduate students ( N = 349) at a private dental school in Malaysia., Results: Overall results are presented as mean scores under six domains with total score as 142.40 (33.65). The total scores compared between two genders did not show statistical difference, however on comparing individual domains, females (25.25) had higher mean score for daily life disturbance ( P = 0.013) and males (30.17) for cyberspace-oriented relationship ( P = 0.001). Chinese students had higher scores with respect to withdrawal (32.45) and cyberspace-oriented relationship (29.48) as compared to other ethnicities. Year 4 students show higher scores than other years in daily life disturbance (27.44), tolerance (16.81), and overuse (16.51)., Conclusion: Our research presents the extent and pattern of smartphone of usage and addiction among the undergraduate students at a dental school in Malaysia. The indicators of addiction highlighted in the study are pivotal in spreading awareness regarding this overuse and addiction as well as planning further research in this area., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Education and Health Promotion.)

Background: Multiple international organizations have called for exercise to become standard practice in the setting of oncology care. The feasibility of integrating exercise within systemic chemotherapy has not been investigated., Methods: Patients slated to receive infusion therapy between April 2017 and October 2018 were screened for possible inclusion. The study goal was to establish the acceptability and feasibility of embedding an exercise professional into the chemotherapy infusion suite as a method of making exercise a standard part of cancer care. The exercise prescriptions provided to patients were individualized according to results of brief baseline functional testing., Results: In all, 544 patients were screened, and their respective treating oncologists deemed 83% of them to be medically eligible to participate. After further eligibility screening, 226 patients were approached. Nearly 71% of these patients (n = 160) accepted the invitation to participate in the Exercise in All Chemotherapy trial. Feasibility was established because 71%, 55%, 69%, and 63% of the aerobic, resistance, balance, and flexibility exercises prescribed to patients were completed. Qualitative data also supported the acceptability and feasibility of the intervention from the perspective of patients and clinicians. The per-patient cost of the intervention was $190.68 to $382.40., Conclusions: Embedding an exercise professional into the chemotherapy infusion suite is an acceptable and feasible approach to making exercise standard practice. Moreover, the cost of the intervention is lower than the cost of other common community programs. Future studies should test whether colocating an exercise professional with infusion therapy could reach more patients in comparison with not colocating., Lay Summary: Few studies have tested the implementation of exercise for patients with cancer by embedding an exercise professional directly into the chemotherapy infusion suite. The Exercise in All Chemotherapy trial shows that this approach is both acceptable and feasible from the perspective of clinicians and patients., (© 2020 American Cancer Society.)

Colon adenocarcinoma is one of the most common malignancies, and it is highly lethal. Chemotherapy plays an important role in the treatment of colon cancer at various stages of the disease. The gut microbiome has emerged as a key player in colon cancer development and progression, and it can also alter the therapeutic agent's efficacy and toxicities. Antibiotics can directly and/or indirectly affect the balance of the gut microbiome and, therefore, the clinical outcomes. In this article, we provided an overview of the composition of the gut microbiome under homeostasis and the mechanistic links between gut microbiota and colon cancer. The relationship between the use of oral antibiotics and colon cancer, as well as the impact of the gut microbiome on the efficacy and toxicities of chemotherapy in colon cancer, are discussed. Potential interventions to modulate microbiota and improve chemotherapy outcomes are discussed. Further studies are indicated to address these key gaps in the field and provide a scientific basis for the design of novel microbiota-based approaches for prevention/use as adjuvant therapeutics for patients with colon cancer.

Opioid use among metastatic breast cancer (MBC) patients has not been well-studied. This study examined the trends and patterns of opioid use among working-age, privately insured patients diagnosed with MBC. Using MarketScan data, we identified female patients diagnosed with MBC in 2006-2015. We determined the proportion of patients who filled a prescription for an opioid and calculated days' supply and daily morphine milligram equivalents (MMEs) from 1 year prior to diagnosis till 1 year after. We assessed the trend in opioid use over the 10-year study period and examined opioid usage patterns after the diagnosis of MBC. Among 24,752 patients included, 11,579 (46.8%) had an opioid prescription within 1 year before diagnosis of MBC, and 20,416 (81.4%) had an opioid prescription within 1 year after diagnosis. The proportion of patients with opioid prescriptions after diagnosis was relatively stable from 2006 to 2015. However, both the median daily MME and median days' supply decreased over time with most of the decline from the subgroup of patients with prior prescription opioid use. Most patients received an opioid prescription in the first month after diagnosis (57.3%), dropping to approximately 20% from 3 to 12 months after diagnosis. Also, the median days' supply increased substantially during the year after diagnosis for patients who received opioids (from 7 to 19). Most women with MBC require opioid analgesia within the first month after diagnosis. Judicious, long-term management of pain after diagnosis of MBC will continue to be necessary for many patients.

Pancreatic carcinoma (PC) is highly metastatic, and it tends to be detected at advanced stages. Identifying and developing biomarkers for early detection of PC is crucial for a potentially curative treatment. Extracellular vesicles (EVs) are bilayer lipid membrane-structured nanovesicles found in various human bodily fluids, and they play important roles in tumor biogenesis and metastasis. Cancer-derived EVs are enriched with DNA, RNA, protein, and lipid, and they have emerged as attractive diagnostic biomarkers for early detection of PC. In this article, we provided an overview of the cell biology of EVs and their isolation and analysis, and their roles in cancer pathogenesis and progression. Multiplatform analyses of plasma-based exosomes for genomic DNA, micro RNA, mRNA, circular RNA, and protein for diagnosis of PC were critically reviewed. Numerous lines of evidence demonstrate that liquid biopsy with analysis of EV-based biomarkers has variable performance for diagnosis of PC. Future investigation is indicated to optimize the methodology for isolating and analyzing EVs and to identify the combination of EV-based biomarkers and other clinical datasets, with the goal of improving the predictive value, sensitivity, and specificity of screening tests for early detection and diagnosis of PC.

Trifluridine/tipiracil or TAS-102 (Taiho Oncology, Lonsurf ® , Princeton, NJ, USA) is a combination tablet of trifluridine, a thymidine-based nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor, in a 1:0.5 molar ratio. This drug was first approved for use in metastatic colorectal cancer patients. Recently, the U S Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have granted approval of trifluridine/tipiracil for treatment of metastatic gastric and gastroesophageal junction adenocarcinoma in patients following at least two lines of chemotherapy including fluoropyrimidine and platinum chemotherapy agents, as well as taxanes or irinotecan. This approval was granted after the findings from first a Phase II trial (EPOC1201) investigating trifluridine/tipiracil, and later a global Phase III trial (TAGS trial) that compared trifluridine/tipiracil vs placebo with best supportive care. Both trials primarily utilized trifluridine/tipiracil at a dose of 35 mg/m 2 twice daily. In the EPOC1201 trial, the primary end point of disease control rate was greater than 50% after eight weeks of therapy. The most common grade three or four adverse event was neutropenia; additional toxicities included leukopenia, anemia, and anorexia. In the TAGS trial, overall survival in patients treated with trifluridine/tipiracil (5.7 months) was significantly improved as compared to the placebo-controlled group (3.6 months). Treatment with trifluridine/tipiracil not only did not impair quality of life but also tended to reduce the risk of deterioration of quality of life. The results of these studies along with the subsequent FDA and EMA approval have generated an important breakthrough in regard to treatment options for patients with refractory metastatic gastric or gastroesophageal junction adenocarcinoma., Competing Interests: Dr Nelson S Yee reports nonfinancial support from Astra Seneca, Daichii Sankyo, Novartis, Caris Life Sciences, Eli Lilly, Regeneron, Abbvie, and Genentech; grants from Eli Lilly, Ipsen, Onxeo, Boston Biomedical, EMD Serono, Pharmacyclics, Merck, outside the submitted work. Taiho provided grant support for the symposium “Multi-disciplinary Patient Care in Gastrointestinal Oncology” organized by Penn State College of Medicine. The authors report no other conflicts of interest in this work., (© 2020 Wheelden and Yee.)

Objectives: To assess relationships between preoperative and postoperative dating of second-trimester surgical abortion., Study Design: We used a deidentified institutional database to extract demographic, dating and pathology data for surgical abortions performed at 14 to 23-6/7 weeks' gestational age (GA) from 9/2015 to 5/2017. We excluded women with multiple gestations, fetal anomalies and missing fetal biometric measurements. We assigned preoperative GA by ultrasonography for unknown last menstrual period (LMP) or when discrepancy between sonographic and LMP dating exceeded 7 days (<15-6/7 weeks), 10 days (16 to 21-6/7 weeks) or 14 days (22 to 23-6/7 weeks). We determined postoperative GA using fetal foot length pathology standards published by Streeter in 1920 and Drey et al. in 2005. We performed regression analysis to estimate the relationship between pre- and postoperative estimates of GA and to assess demographic effects on these estimates, and χ 2 tests to assess whether fetal foot lengths were concordant with, larger than or smaller than the expected range for the preoperative GA., Results: The 469 patients analyzed had a median preoperative GA of 19-4/7 weeks (range 14-0/7 to 23-6/7 weeks). Preoperative dating highly correlated with postoperative dating using both pathology standards (r 2 =0.95, p<.001), without any clinically relevant effect by body mass index (Streeter and Drey, p=.79), parity (Streeter p=.89; Drey p=.71), race (Streeter p=.06; Drey p=.07) or GA. Fetal foot lengths were larger than expected in 134 (28.6%) women using Streeter and 17 (3.6%) women using Drey standards (p<.001)., Conclusions: Preoperative dating and postoperative dating for second-trimester surgical abortion highly correlate. Use of Streeter standards results in more women with a postoperative GA greater than expected compared to Drey standards., Implications: Increasing legal gestational age restrictions have placed additional burden on clinicians providing safe abortions, but guidelines on gestational age determination are lacking. Contemporary pathology standards consistent with modern practice and universally accepted by abortion providers and gynecologic pathologists are critical to our goal of safe and legal abortion provision., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Nanoscale extracellular vesicles (nEVs) have recently demonstrated potential value in cancer diagnostics and treatment monitoring, but translation has been limited by technical challenges in nEV isolation. Thus, we have developed a one-step nEV isolation platform that utilizes nEV size-matched silica nanostructures and a surface-conjugated lipid nanoprobe with an integrated microfluidic mixer. The reported platform has 28.8% capture efficiency from pancreatic cancer plasma and can sufficiently enrich nEVs for simpler positive identification of point mutations, particularly KRAS, in nEV DNA from the plasma of pancreatic cancer patients.

Background: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed., Methods: We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m 2 doxorubicin-loaded nanoparticles (30 mg/m 2 group), 20 mg/m 2 doxorubicin-loaded nanoparticles (20 mg/m 2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693., Findings: Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m 2 group; 130 to the 20 mg/m 2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 [95% CI 0·78-1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group., Interpretation: Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed., Funding: Onxeo., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Palliative chemotherapy is the mainstay of treatment of advanced gastric carcinoma (GC). Monoclonal antibodies including trastuzumab, ramucirumab, and pembrolizumab have been shown to provide additional benefits. However, the clinical outcomes are often unpredictable and they can vary widely among patients. Currently, no biomarker is available for predicting treatment response in the individual patient except human epidermal growth factor receptor 2 (HER2) amplification and programmed death-ligand 1 (PD-L1) expression for effectiveness of trastuzumab and pembrolizumab, respectively. Multi-platform molecular analysis of cancer, including GC, may help identify predictive biomarkers to guide selection of therapeutic agents. Molecular classification of GC by The Cancer Genome Atlas Research Network and the Asian Cancer Research Group is expected to identify therapeutic targets and predictive biomarkers. Complementary to molecular characterization of GC is molecular profiling by expression analysis and genomic sequencing of tumor DNA. Initial analysis of patients with gastroesophageal carcinoma demonstrates that the ratio of progression-free survival (PFS) on molecular profile (MP)-based treatment to PFS on treatment prior to molecular profiling exceeds 1.3, suggesting the potential value of MP in guiding selection of individualized therapy. Future strategies aiming to integrate molecular classification and profiling of tumors with therapeutic agents for achieving the goal of personalized treatment of GC are indicated., Competing Interests: The authors declare no conflict of interest.

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed ion channel with intrinsic kinase activity. Molecular and electrophysiological analyses of the structure and activity of TRPM7 have revealed functional coupling of its channel and kinase activity. Studies have indicated the important roles of TRPM7 channel-kinase in fundamental cellular processes, physiological responses, and embryonic development. Accumulating evidence has shown that TRPM7 is aberrantly expressed and/or activated in human diseases including cancer. TRPM7 plays a variety of functional roles in cancer cells including survival, cell cycle progression, proliferation, growth, migration, invasion, and epithelial-mesenchymal transition (EMT). Data from a study using mouse xenograft of human cancer show that TRPM7 is required for tumor growth and metastasis. The aberrant expression of TRPM7 and its genetic mutations/polymorphisms have been identified in various types of carcinoma. Chemical modulators of TRPM7 channel produced inhibition of proliferation, growth, migration, invasion, invadosome formation, and markers of EMT in cancer cells. Taken together, these studies suggest the potential value of exploiting TRPM7 channel-kinase as a molecular biomarker and therapeutic target in human malignancies.

Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis, with unbiased analysis of gene-expression studies identifying significant up-regulation of AGTR1, the gene encoding AT1R in ER+ve/HER2-ve tumors correlating with poor prognosis. However, there is no evidence, so far, of the functional contribution of AT1R to breast tumorigenesis. We explored the potential therapeutic benefit of ARB in a carcinogen-induced mouse model of breast cancer and clarified the mechanisms associated with its success.Mammary tumors were induced with 7,12-dimethylbenz[α]antracene (DMBA) and medroxyprogesterone acetate (MPA) in female wild type mice and the effects of the ARB, Losartan treatment assessed in a preventative setting (n = 15 per group). Tumor histopathology was characterised by immunohistochemistry, real-time qPCR to detect gene expression signatures, and tumor cytokine levels measured with quantitative bioplex assays. AT1R was detected with radiolabelled ligand binding assays in fresh frozen tumor samples.We showed that therapeutic inhibition of AT1R, with Losartan, resulted in a significant reduction in tumor burden; and no mammary tumor incidence in 20% of animals. We observed a significant reduction in tumor progression from DCIS to invasive cancer with Losartan treatment. This was associated with reduced tumor cell proliferation and a significant reduction in IL-6, pSTAT3 and TNFα levels. Analysis of tumor immune cell infiltrates, however, demonstrated no significant differences in the recruitment of lymphocytes or tumour-associated macrophages in Losartan or vehicle-treated mammary tumors.Analysis of AT1R expression with radiolabelled ligand binding assays in human breast cancer biopsies showed high AT1R levels in 30% of invasive ductal carcinomas analysed. Furthermore, analysis of the TCGA database identified that high AT1R expression to be associated with luminal breast cancer subtype.Our in vivo data and analysis of human invasive ductal carcinoma samples identify the AT1R is a potential therapeutic target in breast cancer, with the availability of a range of well-tolerated inhibitors currently used in clinics. We describe a novel signalling pathway critical in breast tumorigenesis, that may provide new therapeutic avenues to complement current treatments.

Purpose: To provide evidence-based recommendations to oncologists and others for treatment of patients with locally advanced, unresectable pancreatic cancer., Methods: American Society of Clinical Oncology convened an Expert Panel of medical oncology, radiation oncology, surgical oncology, gastroenterology, palliative care, and advocacy experts and conducted a systematic review of the literature from January 2002 to June 2015. Outcomes included overall survival, disease-free survival, progression-free survival, and adverse events., Results: Twenty-six randomized controlled trials met the systematic review criteria., Recommendations: A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed. Baseline performance status and comorbidity profile should be evaluated. The goals of care, patient preferences, psychological status, support systems, and symptoms should guide decisions for treatments. A palliative care referral should occur at first visit. Initial systemic chemotherapy (6 months) with a combination regimen is recommended for most patients (for some patients radiation therapy may be offered up front) with Eastern Cooperative Oncology Group performance status 0 or 1 and a favorable comorbidity profile. There is no clear evidence to support one regimen over another. The gemcitabine-based combinations and treatments recommended in the metastatic setting (eg, fluorouracil, leucovorin, irinotecan, and oxaliplatin and gemcitabine plus nanoparticle albumin-bound paclitaxel) have not been evaluated in randomized controlled trials involving locally advanced, unresectable pancreatic cancer. If there is local disease progression after induction chemotherapy, without metastasis, then radiation therapy or stereotactic body radiotherapy may be offered also with an Eastern Cooperative Oncology Group performance status ≤ 2 and an adequate comorbidity profile. If there is stable disease after 6 months of induction chemotherapy but unacceptable toxicities, radiation therapy may be offered as an alternative. Patients with disease progression should be offered treatment per the ASCO Metastatic Pancreatic Cancer Treatment Guideline. Follow-up visits every 3 to 4 months are recommended. Additional information is available at www.asco.org/guidelines/LAPC and www.asco.org/guidelines/MetPC and www.asco.org/guidelineswiki., (© 2016 by American Society of Clinical Oncology.)

The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.

This article provides a review and discussion of the transient receptor potential melastatin-subfamily member 8 (TRPM8) ion channel as a potential biomarker and target in cancer. TRPM8 is a Ca(2+)-permeable channel that plays a major physiological role in cellular sensation and transduction of cold temperature. TRPM8 is aberrantly expressed in a variety of solid tumors including pancreatic cancer. In pancreatic adenocarcinoma cell lines and tissues, TRPM8 is overexpressed as compared to normal pancreatic ductal epithelia. Analysis of anti-TRPM8 immunoreactivity in pancreatic adenocarcinoma indicates positive correlation of TRPM8 expression with tumor size and stages. The biological roles of TRPM8 in pancreatic cancer cells have been revealed from studies using RNA interference-mediated silencing of TRPM8. The experimental data show that TRPM8 channels are required for sustaining proliferation and cell cycle progression, preventing replicative senescence, and promoting cell invasion. Evidence to date implicates a contributory role of TRPM8 channels in the pathogenesis of pancreatic neoplasms and other tumors. Research focus on the mechanisms that underlie TRPM8-mediated roles in tumor growth and metastasis may help establish a novel link of physicochemical changes with pancreatic carcinogenesis. Translational and clinical investigation to exploit TRPM8 as a molecular biomarker and therapeutic target is expected to make a positive impact on precision medicine in pancreatic cancer and other malignant diseases., (© 2016 Elsevier Inc. All rights reserved.)

Pancreatic adenocarcinoma is highly lethal, and until prevention of this disease is possible, various treatments including the recently developed immunotherapy to improve patients' survival and quality of life are desperately needed. The objectives of this article are to examine the role of tumor-associated immunosuppression in pancreatic cancer development, dissect the cellular and molecular basis of the immunotherapeutic approaches, and discuss the current status and emerging strategies of immunotherapy in this malignant disease. Animal models and experimental evidence have shown that pancreatic tumor-associated stroma produces an immunosuppressive microenvironment, which promotes development and progression of pancreatic tumor. This results from dynamic interactions among pancreatic cancer cells and the immune effector cells through the actions of multiple cytokines and binding of immunomodulatory molecules. Various immunotherapeutic approaches have been developed in attempt to stimulate immune response by cytokine- or tumor-associated antigen-based vaccines, adoptive transfer of immunotoxins or antigen-primed immune cells, or antibodies directed against immune regulators. Results of these clinical studies show that these treatments are generally well tolerated without major serious complications, and demonstrate potential efficacy of immune-based therapies in pancreatic cancer. Strategies to improve the efficacy of immunotherapy may be accomplished by combining it with the conventionally used chemotherapy or targeted agents. Combinatorial approach using molecular profiling and bioinformatics may help identify predictive biomarkers of treatment response as well as identifying potential targets for personalized cancer vaccines. Hopefully, this article will stimulate further research interests and collaborative efforts to optimize therapy for patients with this devastating disease.

Background and Objectives: Effective therapies for hepatocellular carcinoma (HCC) are limited. Molecular profiling of HCC was performed to identify novel therapeutic targets., Methods: 350 HCC samples were evaluated using a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ), including gene sequencing, amplification, and protein expression., Results: EGFR, TOPO1, PD-1, TOP2A, SPARC, and c-Met were overexpressed in 25-83% of samples. Decreased expression of RRM1,TS, PTEN, and MGMT occurred in 31-82% of samples. TP53 was mutated in 30%, CTNNB1 in 20%, and BRCA2 in 18%; other gene mutation rates were <5%. TP53-mutated tumors showed significantly higher TOPO2A (90% vs. 38%, P < 0.0001) and TS (56% vs. 29%, P = 0.0139) expression. CTNNB1-mutated tumors had significantly higher AR (56% vs. 21%, P = 0.0017), SPARC (61% vs. 29%, P = 0.0135), PDL1 (29% vs. 0%, P = 0.0256) expression, and BRCA2 mutations (50% vs. 6%, P = 0.0458). Metastases exhibited significantly higher infiltration by PD-1+ lymphocytes (79% vs. 50%, P = 0.047) and TS (31% vs. 14%, P < 0.0003) than primary HCC., Conclusions: Multiplatform profiling reveals molecular heterogeneity in HCC and identifies potential therapies including tyrosine kinase, PI3 kinase, or PARP inhibitors for molecular subtypes. Chemotherapy may benefit some tumors. CTNNB1-mutated tumors may respond to multi-target inhibition. These limited and preliminary data require clinical validation., (© 2015 Wiley Periodicals, Inc.)

Hepatocellular carcinoma (HCC) is a highly lethal disease, therefore effective and tolerable treatment is urgently needed. In this article, we provide an updated review of the genetic abnormalities and mechanisms that drive carcinogenesis of HCC, and discuss the targeted therapeutics that are being investigated in HCC. Hepatocellular carcinogenesis typically begins with chronic inflammation of hepatocytes that progressively transform into invasive carcinoma. These events are associated with molecular abnormalities and chromosomal alterations. Multiple analyses of HCC have revealed aberrant expression or activity of growth factors and receptors, and the associated signaling pathways. These molecular alterations are implicated in the development and progression of HCC, and they have been exploited as targets for therapy. Targeted agents that inhibit receptor tyrosine kinases and their downstream signal mediators, angiogenesis, and immunomodulators have been developed and clinically investigated. Among these targeted agents, the multi-kinase inhibitor sorafenib has become the standard treatment for advanced HCC, though its therapeutic benefit is limited. Continued research is essential for improving treatment response and minimizing toxicity for patients with HCC. Future investigation will need to focus on utilizing patterns of gene expression to classify HCC into groups that display similar prognosis and treatment sensitivity, and combining targeted therapeutics with conventional chemotherapy that produce enhanced anti-tumor effect. By integration of tumor profiling and targeted therapeutics in HCC, we hope to advance towards the goal of precision treatment for patients with this malignant disease.

For biliary tract carcinoma (BTC), complete surgical resection of tumor is only feasible in a minority of patients, and the treatment options for patients with unresectable or metastatic disease are limited. Advances in cancer immunology have led to identification of tumor-infiltrating immune cells as indicators of prognosis and response to treatment in BTC. This has also facilitated development of immunotherapy that focuses on enhancing the immune system against biliary tumors. This includes peptide- and dendritic cell-based vaccines that stimulate in-vivo immune responses against tumor-specific antigens. Adoptive immunotherapy, which entails the ex-vivo expansion of tumor-infiltrating immune cells for subsequent reintroduction, and cytokine-based therapies have been developed in BTC. Clinical studies indicate that this type of therapy is generally well tolerated. Combination therapy with dendritic cell-based vaccines and adoptive immunotherapy has shown particularly good potential. Emerging strategies through discovery of novel antigen targets and by reversal of tumor-associated immunosuppression are expected to improve the efficacy of immunotherapy in BTC. Collaborative efforts by integration of targeted immunotherapeutics with molecular profiling of biliary tumor will hopefully make a positive impact on advancing towards the goal of developing precision treatment of patients with this highly lethal disease.

The goal of this article is to provide a critical review of the transient receptor potential melastatin-subfamily member 8 (TRPM8) in cancers, with an emphasis on its roles in cellular proliferation, survival, and invasion. The TRPM8 ion channels regulate Ca²⁺ homeostasis and function as a cellular sensor and transducer of cold temperature. Accumulating evidence has demonstrated that TRPM8 is aberrantly expressed in a variety of malignant solid tumors. Clinicopathological analysis has shown that over-expression of TRPM8 correlates with tumor progression. Experimental data have revealed important roles of TRPM8 channels in cancer cells proliferation, survival, and invasion, which appear to be dependent on the cancer type. Recent reports have begun to reveal the signaling mechanisms that mediate the biological roles of TRPM8 in tumor growth and metastasis. Determining the mechanistic roles of TRPM8 in cancer is expected to elucidate the impact of thermal and chemical stimuli on the formation and progression of neoplasms. Translational research and clinical investigation of TRPM8 in malignant diseases will help exploit these ion channels as molecular biomarkers and therapeutic targets for developing precision cancer medicine.

Traumatic brain injury (TBI) is induced by mechanical forces which initiate a cascade of secondary injury processes, including inflammation. Therapies which resolve the inflammatory response may promote neural repair without exacerbating the primary injury. Specific derivatives of omega-3 fatty acids loosely grouped as specialized pro-resolving lipid mediators (SPMs) and termed resolvins promote the active resolution of inflammation. In the current study, we investigate the effect of two resolvin molecules, RvE1 and AT-RvD1, on post-traumatic sleep and functional outcome following diffuse TBI through modulation of the inflammatory response. Adult, male C57BL/6 mice were injured using a midline fluid percussion injury (mFPI) model (6-10min righting reflex time for brain-injured mice). Experimental groups included mFPI administered RvE1 (100ng daily), AT-RvD1 (100ng daily), or vehicle (sterile saline) and counterbalanced with uninjured sham mice. Resolvins or saline were administered daily for seven consecutive days beginning 3days prior to TBI to evaluate proof-of-principle to improve outcome. Immediately following diffuse TBI, post-traumatic sleep was recorded for 24h post-injury. For days 1-7 post-injury, motor outcome was assessed by rotarod. Cognitive function was measured at 6days post-injury using novel object recognition (NOR). At 7days post-injury, microglial activation was quantified using immunohistochemistry for Iba-1. In the diffuse brain-injured mouse, AT-RvD1 treatment, but not RvE1, mitigated motor and cognitive deficits. RvE1 treatment significantly increased post-traumatic sleep in brain-injured mice compared to all other groups. RvE1 treated mice displayed a higher proportion of ramified microglia and lower proportion of activated rod microglia in the cortex compared to saline or AT-RvD1 treated brain-injured mice. Thus, RvE1 treatment modulated post-traumatic sleep and the inflammatory response to TBI, albeit independently of improvement in motor and cognitive outcome as seen in AT-RvD1-treated mice. This suggests AT-RvD1 may impart functional benefit through mechanisms other than resolution of inflammation alone., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Our previous studies in zebrafish development have led to identification of the novel roles of the transient receptor potential melastatin-subfamily member 7 (TRPM7) ion channels in human pancreatic cancer. However, the biological significance of TRPM7 channels in pancreatic neoplasms was mostly unexplored. In this study, we determined the expression levels of TRPM7 in pancreatic tissue microarrays and correlated these measurements in pancreatic adenocarcinoma with the clinicopathological features. We also investigated the role of TRPM7 channels in pancreatic cancer cell invasion using the Matrigel(TM)-coated transwell assay. In normal pancreas, TRPM7 is expressed at a discernable level in the ductal cells and centroacinar cells and at a relatively high level in the islet endocrine cells. In chronic pancreatitis, pre-malignant tissues, and malignant neoplasms, there is variable expression of TRPM7. In the majority of pancreatic adenocarcinoma specimens examined, TRPM7 is expressed at either moderate-level or high-level. Anti-TRPM7 immunoreactivity in pancreatic adenocarcinoma significantly correlates with the size and stages of tumors. In human pancreatic adenocarcinoma cells in which TRPM7 is highly expressed, short hairpin RNA-mediated suppression of TRPM7 impairs cell invasion. The results demonstrate that TRPM7 channels are over-expressed in a proportion of the pre-malignant lesions and malignant tumors of the pancreas, and they are necessary for invasion by pancreatic cancer cells. We propose that TRPM7 channels play important roles in development and progression of pancreatic neoplasm, and they may be explored as clinical biomarkers and targets for its prevention and treatment., (© 2015. Published by The Company of Biologists Ltd.)

Metastatic colorectal cancer (mCRC) carries a poor prognosis with an overall 5-year survival of 13.1%. Therapies guided by tumor profiling have suggested benefit in advanced cancer. We used a multiplatform molecular profiling (MP) approach to identify key molecular changes that may provide therapeutic options not typically considered in mCRC. We evaluated 6892 mCRC referred to Caris Life Sciences by MP including sequencing (Sanger/NGS), immunohistochemistry (IHC) and in-situ hybridization (ISH). mCRC metastases to liver, brain, ovary or lung (n = 1507) showed differential expression of markers including high protein expression of TOPO1 (52%) and/or low RRM1 (57%), TS (71%) and MGMT (39%), suggesting possible benefit from irinotecan, gemcitabine, 5FU/capecitabine and temozolomide, respectively. Lung metastases harbored a higher Her2 protein expression than the primary colon tumors (4% vs. 1.8%, p = 0.028). Brain and lung metastases had higher KRAS mutations than other sites (65% vs 59% vs 47%, respectively, p = 0.07, <0.01), suggesting poor response to anti-EGFR therapies. BRAF-mutated CRC (n = 455) showed coincident high protein expression of RRM1 (56%), TS (53%) and low PDGFR (22%) as compared with BRAF wild-type tumors. KRAS-mutated mCRC had higher protein expression of c-MET (47% vs. 36%) and lower MGMT (56% vs. 63%), suggesting consideration of c-MET inhibitors and temozolomide. KRAS-mutated CRC had high TUBB3 (42% vs. 33%) and low Her2 by IHC (0.5%) and HER2 by FISH (3%, p <0.05). CRC primaries had a lower incidence of PIK3CA and BRAF mutations in rectal cancer versus colon cancer (10% and 3.3%, respectively). MP of 6892 CRCs identified significant differences between primary and metastatic sites and among BRAF/KRAS sub-types. Our findings are hypothesis generating and need to be examined in prospective studies. Specific therapies may be considered for different actionable targets in mCRC as revealed by MP.

The purpose of this article is to provide a critical review of the current systemic treatment and the emerging targeted therapeutic strategies in pancreatic adenocarcinoma. Cytotoxic chemotherapeutic drugs have been used for palliative treatment of pancreatic adenocarcinoma, as well as for neoadjuvant therapy to facilitate surgical resection, and as adjuvant therapy to prevent tumor recurrence. The recent findings of early metastasis of cancer cells in pancreatic adenocarcinoma provide support for systemic therapy even in the case of small and localized tumors. However, the clinical benefits of systemic chemotherapy are generally limited and it is typically associated with a multitude of toxicities. Cancer-specific therapies with improved efficacy and safety are urgently needed. Tremendous advances have been made in understanding the biology and genetic regulation of normal and neoplastic development of the pancreas. These have led to identification of molecular targets in pancreatic cancer cells, the tumor microenvironment, and the cancer stem cells. Tumor-specific modalities are emergent by exploitation of the aberrant signaling pathways and molecular alterations in pancreatic cancer with the goals of improving treatment response. Integrative approaches that combine various targeting strategies with molecular bioinformatics will hopefully lead to the development of personalized therapies that may produce a positive impact on the quality of life and survival for patients with this deadly disease.

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed cation-permeable ion channel with intrinsic kinase activity that plays important roles in various physiological functions. Biochemical and electrophysiological studies, in combination with molecular analyses of TRPM7, have generated insights into its functions as a cellular sensor and transducer of physicochemical stimuli. Accumulating evidence indicates that TRPM7 channel-kinase is essential for cellular processes, such as proliferation, survival, differentiation, growth, and migration. Experimental studies in model organisms, such as zebrafish, mouse, and frog, have begun to elucidate the pleiotropic roles of TRPM7 during embryonic development from gastrulation to organogenesis. Aberrant expression and/or activity of the TRPM7 channel-kinase have been implicated in human diseases including a variety of cancer. Studying the functional roles of TRPM7 and the underlying mechanisms in normal cells and developmental processes is expected to help understand how TRPM7 channel-kinase contributes to pathogenesis, such as malignant neoplasia. On the other hand, studies of TRPM7 in diseases, particularly cancer, will help shed new light in the normal functions of TRPM7 under physiological conditions. In this article, we will provide an updated review of the structural features and biological functions of TRPM7, present a summary of current knowledge of its roles in development and cancer, and discuss the potential of TRPM7 as a clinical biomarker and therapeutic target in malignant diseases.

The transient receptor potential melastatin-subfamily member 8 (TRPM8) channels control Ca2+ homeostasis. Recent studies indicate that TRPM8 channels are aberrantly expressed and required for cellular proliferation in pancreatic adenocarcinoma. However, the functional significance of TRPM8 in pancreatic tissues is mostly unknown. The objectives of this study are to examine the expression of TRPM8 in various histopathological types of pancreatic tissues, determine its clinical significance in pancreatic adenocarcinoma, and investigate its functional role in cancer cells invasion. We present evidence that, in normal pancreatic tissues, anti-TRPM8 immunoreactivity is detected in the centroacinar cells and the islet endocrine cells. In pre-malignant pancreatic tissues and malignant neoplasms, TRPM8 is aberrantly expressed to variable extents. In the majority of pancreatic adenocarcinoma, TRPM8 is expressed at moderate or high levels, and anti-TRPM8 immunoreactivity positively correlates with the primary tumor size and stage. In the pancreatic adenocarcinoma cell lines that express relatively high levels of TRPM8, short hairpin RNA-mediated interference of TRPM8 expression impaired their ability of invasion. These data suggest that aberrantly expressed TRPM8 channels play contributory roles in pancreatic tumor growth and metastasis, and support exploration of TRPM8 as a biomarker and target of pancreatic adenocarcinoma.

A new series of N-sec/tert-butyl 2-arylbenzimidazole derivatives was synthesised in 85-96% yields within 2-3.5 min by condensing ethyl 3-amino-4-butylamino benzoate with various substituted metabisulfite adducts of benzaldehyde under focused microwave irradiation. The benzimidazole analogues were characterised using (1)H NMR, (13)C NMR, high resolution MS and melting points. Evaluation of antiproliferative activity of the benzimidazole analogues against MCF-7 and MDA-MB-231 revealed several compounds with unexpected selective inhibitions of MDA-MB-231 in micromolar range. All analogues were found inactive towards MCF-7. The most potent inhibition against MDA-MB-231 human breast cancer cell line came from the unsubstituted 2-phenylbenzimidazole 10a.

Background: This study aimed to determine knowledge of medication use, to investigate the treatment-seeking pattern and to identify factors affecting the use of public health clinics among the study population., Methods: A survey was conducted in Mantin Town of Malaysia using a structured questionnaire based on a literature review. Households were recruited through a three-stage sampling technique., Results: Of 183 respondents (mean age 44.6 [±16.9] years; 115 [62.8%] women), 157 (85.8%) did not know about the term 'generic name' and 159 (86.9%) were not sure about the difference in price between a generic medicine and a branded medicine. The majority sought healthcare from the public health clinics (102/183; 55.7%). In the multivariate analysis, higher education level of respondents (p = 0.028), good quality of services in public health clinics (p = 0.001) and short distances between their residences and the public health clinics (p<0.001) were the significant variables for predicting the use of a public health clinic., Conclusion: This study highlights that health education on the use of generic drugs needs to be scaled up. These findings are important to the health policy makers who may need to consider addressing factors such as quality of care and physical distance to the clinic in the design and implementation of health facilities and the selection of the catchment areas.

Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer.

Background: Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models. A phase I clinical trial was performed to establish safety and tolerability of pharmacological ascorbate combined with gemcitabine in patients with biopsy-proven stage IV pancreatic adenocarcinoma., Design: Nine subjects received twice-weekly intravenous ascorbate (15-125 g) employing Simon's accelerated titration design to achieve a targeted post-infusion plasma level of ≥350 mg/dL (≥20 mM). Subjects received concurrent gemcitabine. Disease burden, weight, performance status, hematologic and metabolic laboratories, time to progression and overall survival were monitored., Results: Mean plasma ascorbate trough levels were significantly higher than baseline (1.46 ± 0.02 vs. 0.78 ± 0.09 mg/dL, i.e., 83 vs. 44 μM, p < 0.001). Adverse events attributable to the drug combination were rare and included diarrhea (n = 4) and dry mouth (n = 6). Dose-limiting criteria were not met for this study. Mean survival of subjects completing at least two cycles (8 weeks) of therapy was 13 ± 2 months., Conclusions: Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy. Further studies powered to determine efficacy should be conducted.

The purpose of this article is to provide a critical review of the molecular alterations in pancreatic cancer that are clinically investigated as therapeutic targets and their potential impact on clinical outcomes. Adenocarcinoma of exocrine pancreas is generally associated with poor prognosis and the conventional therapies are marginally effective. Advances in understanding the genetic regulation of normal and neoplastic development of pancreas have led to development and clinical evaluation of new therapeutic strategies that target the signaling pathways and molecular alterations in pancreatic cancer. Applications have begun to utilize the genetic targets as biomarkers for prediction of therapeutic responses and selection of treatment options. The goal of accomplishing personalized tumor-specific therapy with tolerable side effects for patients with pancreatic cancer is hopefully within reach in the foreseeable future.