Proton pump inhibitors and all-cause mortality risk among cancer patients

BACKGROUND Proton pump inhibitors(PPIs)are widely used,including among cancer patients,to manage gastroesophageal reflux and other gastric acid-related disorders.Recent evidence suggests associations between long-term PPI use and higher risks for various adverse health outcomes,including greater mortality.AIM To investigate the association between PPI use and all-cause mortality among cancer patients by a comprehensive analysis after adjustment for various confounders and a robust methodological approach to minimize bias.METHODS This retrospective cohort study used data from the TriNetX research network,with electronic health records from multiple healthcare organizations.The study employed a new-user,active comparator design,which compared newly treated PPI users with non-users and newly treated histamine2 receptor antagonists(H2RA)users among adult cancer patients.Newly prescribed PPIs(esomeprazole,lansoprazole,omeprazole,pantoprazole,or rabeprazole)users were compared to non-users or newly prescribed H2RAs(cimetidine,famotidine,nizatidine,or ranitidine)users.The primary outcome was all-cause mortality.Each patient in the main group was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding effects.Multivariable Cox regression models were used to estimate hazard ratios(HRs)and 95% confidence interval(CI).RESULTS During the follow-up period(median 5.4±1.8 years for PPI users and 6.5±1.0 years for non-users),PPI users demonstrated a higher all-cause mortality rate than non-users after 1 year,2 years,and at the end of follow up(HRs:2.34-2.72).Compared with H2RA users,PPI users demonstrated a higher rate of all-cause mortality HR:1.51(95%CI:1.41-1.69).Similar results were observed across sensitivity analyses by excluding deaths from the first 9 months and 1-year post-exposure,confirming the robustness of these findings.In a sensitivity analysis,we analyzed all-cause mortality outcomes between former PPI users and individuals who have never used PPIs,providing insights into the long-term effects of past PPI use.In addition,at 1-year follow-up,the analysis revealed a significant difference in mortality rates between former PPI users and non-users(HR:1.84;95%CI:1.82-1.96).CONCLUSION PPI use among cancer patients was associated with a higher risk of all-cause mortality compared to non-users or H2RA users.These findings emphasize the need for cautious use of PPIs in cancer patients and suggest that alternative treatments should be considered when clinically feasible.However,further studies are needed to corroborate our findings,given the significant adverse outcomes in cancer patients.

Neoadjuvant treatment of esophageal cancer

The management of esophageal cancer has been evolving over the past 30 years. In the United States, multimodality treatment combining chemotherapy and radiotherapy (RT) prior to surgical resection has come to be accepted by many as the standard of care, although debate about its overall effect on survival still exists, and rightfully so. Despite recent improvements in detection and treatment, the overall survival of patients with esophageal cancer remains lower than most solid tumors, which highlights why further advances are so desperately needed. The aim of this article is to provide a complete review of the history of esophageal cancer treatment with the addition of chemotherapy, RT, and more recently, targeted agents to the surgical management of resectable disease.

Generation of iPS cells using defined factors linked via the self-cleaving 2A sequences in a single open reading frame

Generation of induced pluripotent stem （iPS） cells from somatic cells has been achieved successfully by simultaneous viral transduction of defined reprogramming transcription factors （TFs）. However, the process requires multiple viral vectors for gene delivery. As a result, generated iPS cells harbor numerous viral integration sites in their genomes. This can increase the probability of gene mutagenesis and genomic instability, and present significant barriers to both research and clinical application studies of iPS cells. In this paper, we present a simple lentivirus reprogramming system in which defined factors are fused in-frame into a single open reading frame （ORF） via self-cleaving 2A sequences. A GFP marker is placed downstream of the transgene to enable tracking of transgene expression. We demonstrate that this polycistronic expression system efficiently generates iPS cells. The generated iPS cells have normal karyotypes and are similar to mouse embryonic stem cells in morphology and gene expression. Moreover, they can differentiate into cell types of the three embryonic germ layers in both in vitro and in vivo assays. Remarkably, most of these iPS cells only harbor a single copy of viral vector. This system provides a valuable tool for generation of iPS cells, and our data suggest that the balance of expression of transduced reprogramming TFs in each cell is essential for the reprogramming process. More importantly, when delivered by non-integrating gene-delivery systems, this re-engineered single ORF will facilitate efficient generation of human iPS cells free of genetic modifications.

Immunological properties of embryonic and adult stem cells

The possibility of treating degenerative diseases by stem cell-based approaches is a promising therapeutical option.Among major concerns for the clinical application of stem cells,some derive from the possibility that stem cells may be rejected by the immune system as a consequence of histoincompatibility and that stem cells themselves may interfere with the normal functions of host immune response.Therefore,the immunogenicity and the immunomodulatory properties of stem cells must be carefully addressed.Although these properties are common features of different stem cell types,some peculiarities can be recognized and characterized for their proper clinical use.

Drug eluting biliary stents to decrease stent failure rates:Areview of the literature

Biliary stenting is clinically effective in relieving both malignant and non-malignant obstructions. However, there are high failure rates associated with tumor ingrowth and epithelial overgrowth as well as internally from biofilm development and subsequent clogging. Within the last decade, the use of prophylactic drug eluting stents as a means to reduce stent failure has been investigated. In this review we provide an overview of the current research on drug eluting biliary stents. While there is limited human trial data regarding the clinical benefit of drug eluting biliary stents in preventing stent obstruction, recent research suggests promise regarding their safety and potential efficacy.

Emerging data supporting stromal cell therapeutic potential in cancer:reprogramming stromal cells of the tumor microenvironment for anti-cancer effects

After more than a decade of controversy on the role of stromal cells in the tumor microenvironment,the emerging data shed light on pro-tumorigenic and potential anti-cancer factors,as well as on the roots of the discrepancies.We discuss the pro-tumorigenic effects of stromal cells,considering the effects of tumor drivers like hypoxia and tumor stiffness on these cells,as well as stromal cell-mediated adiposity and immunosuppression in the tumor microenvironment,and cancer initiating cells'cellular senescence and adaptive metabolism.We summarize the emerging data supporting stromal cell therapeutic potential in cancer,discuss the possibility to reprogram stromal cells of the tumor microenvironment for anti-cancer effects,and explore some causes of discrepancies on the roles of stromal cells in cancer in the available literature.

Features of hepatocellular carcinoma in Hispanics differ from African Americans and non-Hispanic Whites

AIM To compare features of hepatocellular carcinoma(HCC) in Hispanics to those of African Americans and Whites.METHODS Patients treated for HCC at an urban tertiary medical center from 2005 to 2011 were identified from a tumor registry. Data were collected retrospectively, including demographics, comorbidities, liver disease characteristics, tumor parameters, treatment, and survival(OS) outcomes. OS analyses were performed using Kaplan-Meier method.RESULTS One hundred and ninety-five patients with HCC were identified: 80.5% were male, and 22% were age 65 or older. Mean age at HCC diagnosis was 59.7 ± 9.8 years. Sixty-one point five percent of patients had Medicare or Medicaid; 4.1% were uninsured. Compared to African American(31.2%) and White(46.2%) patients, Hispanic patients(22.6%) were more likely to have diabetes(P = 0.0019), hyperlipidemia(P = 0.0001), nonalcoholic steatohepatitis(NASH)(P = 0.0021), end stage renal disease(P = 0.0057), and less likely to have hepatitis C virus(P < 0.0001) or a smoking history(P < 0.0001). Compared to African Americans, Hispanics were more likely to meet criteria for metabolic syndrome(P = 0.0491), had higher median MELD scores(P = 0.0159), ascites(P = 0.008), and encephalopathy(P = 0.0087). Hispanic patients with HCC had shorter OS than the other racial groups(P = 0.020), despite similarities in HCC parameters and treatment. CONCLUSION In conclusion, Hispanic patients with HCC have higher incidence of modifiable metabolic risk factors including NASH, and shorter OS than African American and White patients.

Role of Chlamydia in the Development of Ocular Adnexal Lymphoma

The aetiology of OAL is undefined, although much attention has been recently focused on determining whether OAL is caused by an autoimmune disorder, chronic antigenic stimulation or both. It is becoming evident that infectious agents underlying chronic eye infection, as Chlamydia, may play a role in ocular lymphomagenesis. The high prevalence of Chlamydophila psittaci in patients with OAL has suggested a potential oncogenic role for its tendency to cause chronic and persistent infections, although it has been documented an evident geographical variability and response to antibiotic treatment. For C. pneumoniae, the findings so far obtained are very limited not only for identification in OAL but also for the specific treatment with antibiotics. The recent molecular and cultural evidence of C. trachomatis in patients with OAL, seems to suggest that also this pathogen may contribute to pathogenesis of such lymphoma. The potential application of bacteria-eradicating therapy at local and systemic level may ultimately result in safer and more efficient therapeutic option for patients affected by these malignancies. Moreover, a close collaboration between experts in ophthalmology, infectious diseases and hematology will help, in the future, to effectively manage this disease. This review attempts to weigh the currently available evidence regarding the role that Chlamydia play in development of OAL and focuses on patients with OAL observed at our Institution.

Increased Risk of Acute Myeloid Leukemia in Patients with CYP1A1 Polymorphisms

Acute Myeloid Leukemia (AML) is a group of genetically diverse hematopoietic malignancies arising from cell progenitors developing in the myeloid pathway or from primitive stem cells. Genetic susceptibility of AML may account for an increased risk of AML due to partial metabolism of or biocativation of carcinogens. Chemical compounds are metabolized by a two-tiered phase detoxifying system. Polymorphisms in these pathways may lead to DNA damage and development of AML. We determined the frequencies of carcinogen metabolism gene polymorphisms (CYP1A1, del{GSTM1} and del{GSTT1}) in a case control-study based on polymorphism analysis. Fifty-eight consecutively AML patients (median age 62 years) and 174 sex and age-matched control group were assessed by a PCR-RFLP assay. There were 51 de novo and 7 secondary AML. CYP1A1*2A and CYP1A1*2C polymorphisms were more frequent in CG than AML p 0.001 and in contrast, CYP1A1*3 and CYP1A1*4 were more frequent in AML than CG p 0.001. There were no differences in del{GSTM1} neither del{GSTT1} between AML and CG (p = 0.999 and p = 0.539). Odds ratio for AML in patients harboring CYP1A1*3 was 2.36 (95% CI 1.2 - 4.5), 2.38 for CYP1A1*4 (95% CI 0.8 - 6.8). Adjusted OR was 2.63 for CYP1A1*3 (95% CI 1.4 - 5.1) and 2.66 for CYP1A1*4 (95% CI 0.9 - 7.8). In the multivariate analysis CYP1A1*3 polymorphism was a risk factor for AML with an OR for 3.99 (95%CI 1.9 - 8.6). To the best of our knowledge this is the first study to show that CYP1A1*3 heterozygous genotypes increase the risk of AML. Our data support that inherited absence of this carcinogen detoxification pathway may be an important determinant of AML.

Simultaneous Diagnosis of Myeloid Sarcoma of the Jaw and Mycobacterium tuberculosis Infection

Granulocytic or myeloid sarcoma (MS) is a rare neoplastic condition consisting of a tumor mass of myeloid blasts with or without maturation occurring at an anatomical site other than the bone marrow the association between tuberculosis and MS is extremely rare. A 21-year-old female patient presented cough, sore throat and a suppurative swollen gum for 10 days prior to hospital admission. Physical examination revealed moderate pallor and swollen inferior gum. CBC revealed Hb6.5 g/dL, hematocrit 18.4% MCV 97 fL MCH 34 pg, WBC 18.5 ′ 109/μL (1 My/3 Bt/69 Sg/1 Eo/0 Ba/20 Ly/6 Mo), Platelets 43 ′ 109/μL. The peripheral blood smear presented with 3% blast cells (type 1) and granulocytic dysplasia. Bone marrow biopsy showed 100% cellularity. 50% of cells were from granulocytic precursors, diagnosis of granulocytic sarcoma. The diagnosis of AML was established: granulocytic sarcoma with massive gum infiltration (immature granulocytic cells) and 10% of blasts in bone marrow. The patient received induction chemotherapy (3 + 7 daunorubicin 90 mg/m2), and gum tissue culture was positive for Mycobacterium tuberculosis. Simultaneously, a qRT- PCR test confirmed the same bacteria in the gum tissue. Patient treated with isoniazid, rifampicin, pyrazinamide and ethambutol ciprofloxacin and amikacin). Remission was achieved and the patient was submitted for consolidation/ intensification (HiDAC x3) schema and referred to allogeneic HSCT. After induction and full hematological recovery there was no further evidence or recurrence of fever and lytic lesions. Currently patient is under CR and ling follow up (48 months) did not show recurrence of either AML or tuberculosis.

WJSC 6^(th) Anniversary Special Issues(1):Hematopoietic stem cell transplantation Allogeneic hematopoietic cell transplant for acute myeloid leukemia:Current state in 2013 and future directions

Acute myeloid leukemia(AML)represents a heterogeneous group of high-grade myeloid neoplasms of the elderly with variable outcomes.Though remissioninduction is an important first step in the management of AML,additional treatment strategies are essential to ensure long-term disease-free survival.Recent pivotal advances in understanding the genetics and molecular biology of AML have allowed for a risk-adapted approach in its management based on relapse-risk.Allogeneic hematopoietic cell transplantation(allo-HCT)represents an effective therapeutic strategy in AML providing the possibility of cure with potent graft-versus-leukemia reactions,with a demonstrable survival advantage in younger patients with intermediate-or poor-risk cytogenetics.Herein we review the published data regarding the role of allo-HCT in adults with AML.We searched MEDLINE/PubMed and EMBASE/Ovid.In addition,we searched reference lists of relevant articles,conference proceedings and ongoing trial databases.We discuss the role of allo-HCT in AML patients stratified by cytogenetic-and molecular-risk in first complete remission,as well as allo-HCT as an option in relapsed/refractory AML.Besides the conventional sibling and unrelated donor allografts,we review the available data and recent advances for alternative donor sources such as haploidentical grafts and umbilical cord blood.We also discuss conditioning regimens,including reduced intensity conditioning which has broadened the applicability of allo-HCT.Finally we explore recent advances and future possibilities and directions of allo-HCT in AML.Practical therapeutic recommendations have been made where possible based on available data and expert opinion.

Stem cells in gastrointestinal cancers: The road less travelled

Cancer stem cells(CSC) are thought to be malignant cells that have the capacity to initiate and maintain tumor growth and survival. Studies have described CSC in various gastrointestinal neoplasms such as colon, pancreas and liver and gastroesophageal tumors. The mechanism by which CSC develop remains unclear. Several studies have explored the role of dysregulation of the Wnt/β-catenin, transformation growth factor-beta and hedhog pathways in generation of CSC. In this review, we discuss the various molecular abnormalities that may be related to formation of CSC in gastrointestinal malignancies, strategies to identify CSC and therapeutic strategies that are based on these concepts. Identification and targeting CSC is an intriguing area and may provide a new therapeutic option for patients with cancer including gastrointestinal malignancies. Although great progress has been made, many issues need to be addressed. Precise targeting of CSC will require precise isolation and characterization of those cells. This field is also evolving but further research is needed to identify markers that are specific for CSC.Although the application of this field has not entered the clinic yet, there continues to be significant optimism about its potential utility in overcoming cancer resistance and curing patients with cancer.

Update on acute myeloid leukemia stem cells:New discoveries and therapeutic opportunities

The existence of cancer stem cells has been wellestablished in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells(LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells(HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the selfrenewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.

Androgen receptor in bladder cancer:A promising therapeutic target

There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma,unfortunately,only a minority of patients respond to immunotherapy.Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma.The first targeted therapy targeting the fibroblast growth factor receptor(FGFR)was recently approved for bladder cancer,but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations.Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials.Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer.Exploitation of androgen receptor(AR)is a potential strategy for targeted drug development in bladder cancer.A significant proportion of urothelial carcinoma patients express AR irrespective of gender.AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms,including activation of human epidermal growth factor receptor-2(EGFR or HER-2)signaling and epithelial to mesenchymal transition(EMT).Furthermore,AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy.Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy.We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis,progression and its role as a novel therapeutic target and future directions.

Hepatic failure caused by plasma cell infiltration in multiple myeloma

Although plasma cell infiltration is not rare in autopsy of patients with multiple myeloma （MM）, it is very rarely detected in living patients. This is because MM rarely causes significant liver dysfunction that requires further evaluation. A 49-year-old man presented with acute renal failure and was diagnosed with kappa light chain MM stageⅡB. Thalidomide and dexamethasone were initiated. The patient developed a continuous increase in bilirubin that led to severe cholestasis. A liver biopsy revealed plasma cell infiltration. He then rapidly progressed to liver failure and died. Treatment options are limited in MM with significant liver dysfunction. Despite new drug therapies in MM, those patients with rapidly progressive liver failure appear to have a dismal outcome.

Intravascular large B-cell lymphoma presenting with altered mental status: A case report

BACKGROUND Intravascular large B-cell lymphoma(IVLBCL)is a rare and aggressive subtype of non-Hodgkin lymphoma with a varied presentation and no pathognomonic findings.Early diagnosis is critical to altering the disease course as early treatment with chemoimmunotherapy is required to prevent a rapidly fatal outcome.Strategies including improved awareness of this clinical entity through publication of cases with unique presentations are essential to prompt consideration of IVLBCL early in the disease workup.Here,we present a case of IVLBCL presenting with altered mental status and systemic organ dysfunction.CASE SUMMARY A 61-year-old male patient presented with flu-like symptoms and a high fever.He experienced rapid clinical deterioration with liver,kidney failure,and shock despite rapid antibiotic administration and supportive care.A broad infectious workup was negative.Intracranial imaging revealed nonspecific changes to the corpus callosum suspicious for vasculitis.Renal biopsy was non-diagnostic.After further progression of his symptoms,the family elected to withdraw care and the patient died shortly thereafter.Post-mortem analysis revealed clear multi-organ involvement by IVLBCL,prompting re-examination of the ante-mortem renal biopsy that also identified IVLBCL involvement.CONCLUSION IVLBCL is a rare disease.Communication with specialties and early biopsy is critical to establishing the diagnosis and initiating therapy.

Bleeding and clotting in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia(HHT) is arelatively common inherited vascular disorder that was first described in 1864, and is notable for epistaxis, telangiectasia, and arterial venous malformations. While genetic tests are available, the diagnosis remains clinical, and is based on the Curacao criteria. Patients with HHT are at increased risk for both bleeding and clotting events. Because of these competing complications, hematologists are often faced with difficult clinical decisions. While the majority of management decisions revolve around bleeding complications, it is not infrequent for these patients to require anticoagulation for thrombosis. Any anticoagulation recommendations must take into account the bleeding risks associated with HHT. Recent reviews have found that HHT patients can be safely anticoagulated, with the most frequent complication being worsened epistaxis. Large clinical trials have shown that factor Ⅱa and Ⅹa inhibitors have less intracranial bleeding than warfarin, and basic coagulation research has provided a possible mechanism. This article describes the anticoagulation dilemma posed when a 62-year-old female patient with a history of bleeding events associated with HHT was diagnosed with a pulmonary embolism. The subsequent discussion focuses on the approach to anticoagulation in the HHT patient, and addresses the role of the new oral anticoagulants.

New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers

Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy,including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin,Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo-resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed.

Hemorrhagic colitis induced by trientine in a 51-year-old patient with Wilson's disease waiting for liver transplantation:A case report

BACKGROUND Wilson's disease(WD)is a rare inherited disorder of copper metabolism.Treatment consists of chelating agents,but side effects are common.We describe a patient who developed colitis during trientine treatment leading to decompensation of liver cirrhosis.CASE SUMMARY A healthy 51-year-old woman was diagnosed with liver cirrhosis due to decompensation with ascites.Etiologic evaluation raised suspicion of hereditary hemochromatosis because of compound heterozygosity HFE p.C282Y/p.H63D,and phlebotomy was started.Re-evaluation showed low ceruloplasmin,increased urinary copper excretion and the presence of Kayser-Fleischer rings.WD was confirmed by genetic analysis.Because of decompensated cirrhosis,she was referred for liver transplant evaluation.Simultaneously,treatment with trientine was initiated.Liver function initially stabilized,and the patient was not accepted for a liver transplant.Shortly after this,she developed severe hemorrhagic colitis,most probably a side effect of trientine.During that episode,she decompensated with hepatic encephalopathy.Because of a second decompensating event,she was accepted for liver transplantation,and an uneventful transplantation was carried out after clinical improvement of colitis.CONCLUSION Despite WD being a rare disorder,it is important to consider because it can present with a plethora of symptoms from childhood to an elderly age.Colitis should be recognized as a serious adverse drug reaction to trientine treatment that can result in decompensated liver disease.