Cancer by Sfakianakis Alexandros: 04/04/17

Τρίτη 4 Απριλίου 2017

Down-regulation of LncRNA TUG1 enhances radiosensitivity in bladder cancer via suppressing HMGB1 expression

Long non-coding RNAs (lncRNAs) have been reported to regulate the sensitivity of different cancer cells to chemoradiotherapy. Aberrant expression of lncRNA Taurine-upregulated gene 1 (TUG1) has been found to b...

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An integrated strategy of biological and physical constraints in biological optimization for cervical carcinoma

For cervical carcinoma cases, this study aimed to evaluate the quality of intensity-modulated radiation therapy (IMRT) plans optimized by biological constraints. Furthermore, a new integrated strategy in biolo...

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Effects of patient-centered communication on anxiety, negative affect, and trust in the physician in delivering a cancer diagnosis: A randomized, experimental study

BACKGROUND

When bad news about a cancer diagnosis is being delivered, patient-centered communication (PCC) has been considered important for patients' adjustment and well-being. However, few studies have explored how interpersonal skills might help cancer patients cope with anxiety and distress during bad-news encounters.

METHODS

A prospective, experimental design was used to investigate the impact of the physician communication style during a bad-news encounter. Ninety-eight cancer patients and 92 unaffected subjects of both sexes were randomly assigned to view a video of a clinician delivering a first cancer diagnosis with either an enhanced patient-centered communication (E-PCC) style or a low patient-centered communication (L-PCC) style. Participants rated state anxiety and negative affect before and immediately after the video exposure, whereas trust in the physician was rated after the video exposure only. Main and interaction effects were analyzed with generalized linear models.

RESULTS

Viewing the disclosure of a cancer diagnosis resulted in a substantial increase in state anxiety and negative affect among all participants. This emotional response was moderated by the physician's communication style: Participants viewing an oncologist displaying an E-PCC style were significantly less anxious than those watching an oncologist displaying an L-PCC style. They also reported significantly higher trust in the physician.

CONCLUSIONS

Under a threatening, anxiety-provoking disclosure of bad news, a short sequence of empathic PCC influences subjects' psychological state, insofar that they report feeling less anxious and more trustful of the oncologist. Video exposure appears to be a valuable method for investigating the impact of a physician's communication style during critical encounters. Cancer 2017. © 2017 American Cancer Society.

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Unusual clinical umbilical hernia: pitfall

Description

A 75-year-old alcoholic male patient with severe malnutrition was admitted to the hospital with the diagnosis of pneumonia. The finding of a symptomatic umbilical hernia on patient examination mandated a surgical consultation with the question of an operative hernia repair.

Clinically, the abdomen was distended with spider angiomas. Palpation of the umbilical hernia was painless. The hernia content was not reducible. A suspicious murmur (Cruveilhier-Baumgarten murmur) was identified on auscultation of the umbilicus (figure 1). The abdominal CT scan showed signs of portal hypertension. A large recanalised paraumbilical vein coursing from the left side of the portal vein through the falciform ligament and draining into a large umbilical varicose vein was visible. An enlarged right inferior epigastric vein originating from the umbilical varicose vein drained into the right femoral vein. The hernial sac contained only the umbilical varicose (figure 2A,B,C). On further investigation,...

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Biologics,Biologic Response Modifiers,Biopharmaceutical.

http://otorhinolarygology.blogspot.com/2017/04/biologicsbiologic-response.html

Major kinds of biopharmaceuticals include:

Blood factors (Factor VIII and Factor IX)

Thrombolytic agents (tissue plasminogen activator)

Hormones (insulin, glucagon, growth hormone, gonadotrophins)

Haematopoietic growth factors (Erythropoietin, colony stimulating factors)

Interferons (Interferons-α, -β, -γ)

Interleukin-based products (Interleukin-2)

Vaccines (Hepatitis B surface antigen)

Monoclonal antibodies (Various)

Additional products (tumour necrosis factor, therapeutic enzymes)

Research and development investment in new medicines by the biopharmaceutical industry stood at $65.2 billion in 2008.[11] A few examples of biologics made with recombinant DNA technology include:

USAN/INN Trade name Indication Technology Mechanism of action

abatacept Orencia rheumatoid arthritis immunoglobin CTLA-4 fusion protein T-cell deactivation

adalimumab Humira rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Ulcerative Colitis, Crohn's disease monoclonal antibody TNF antagonist

alefacept Amevive chronic plaque psoriasis immunoglobin G1 fusion protein incompletely characterized

erythropoietin Epogen anemia arising from cancer chemotherapy, chronic renal failure, etc. recombinant protein stimulation of red blood cell production

etanercept Enbrel rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis recombinant human TNF-receptor fusion protein TNF antagonist

infliximab Remicade rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Ulcerative Colitus, Crohn's disease monoclonal antibody TNF antagonist

trastuzumab Herceptin breast cancer humanized monoclonal antibody HER2/neu (erbB2) antagonist

ustekinumab Stelara psoriasis humanized monoclonal antibody IL-12 and IL-23 antagonist

denileukin diftitox Ontak cutaneous T-cell lymphoma (CTCL) Diphtheria toxin engineered protein combining Interleukin-2 and Diphtheria toxin Interleukin-2 receptor binder

golimumab Simponi rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Ulcerative colitis monoclonal antibody TNF antagonist

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

The p53/p21 complex regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins

The tumor suppressor p53 binds pro-survival Bcl-2 family proteins such as Bcl-w and Bcl-XL to liberate Bax, which in turn exerts pro-apoptotic or anti-invasive functions depending on stress context. Based on our previous finding that p53 interacts with p21, we investigated the possible involvement of p21 in these functions. Here we report that although p53 can bind Bcl-w alone, it requires p21 to liberate Bax to suppress cell invasion and promote cell death. p21 bound Bcl-w, forming a p53/p21/Bcl-w complex in a manner that maintained all pairwise p53/p21, p21/Bcl-w, and p53/Bcl-w interactions. This allowed Bax liberation from the complex. Accordingly, a p53 derivative incapable of binding p21 failed to mediate radiotherapy-induced tumor cell death in mice. Bcl-XL also served as a target of the cooperative action of p53 and p21. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple cell components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21.

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Combination therapy targeting BCL6 and phospho-STAT3 defeats intra-tumor heterogeneity in a subset of non-small cell lung cancers

Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, K-RAS, and MYC-oncogenic alterations commonly found in non-small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1 and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 up-regulation and another with SMAD2/3 down-regulation. Treatment with a STAT3 inhibitor eliminated the up-regulated STAT3 subpopulation, but left a large surviving subpopulation with down-regulated SMAD2/3. A bioinformatics search identified BCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes and tumor suppressors may provide a potent way to defeat intra-tumor heterogeneity.

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Cellular prion protein PRPC and ecto-5'-nucleotidase are markers of the cellular stress response to aneuploidy

Aneuploidy is a hallmark of most human tumors, but the molecular physiology of aneuploid cells is not well characterized. In this study, we screened cell surface biomarkers of ~300 proteins by multiparameter flow cytometry using multiple aneuploid model systems such as cell lines, patient samples and mouse models. Several new biomarkers were identified with altered expression in aneuploid cells, including overexpression of the cellular prion protein CD230/PRPC and the immunosuppressive cell surface enzyme ecto-5'-nucleotidase CD73. Functional analyses associated these alterations with increased cellular stress. An increased number of CD73+ cells was observed in confluent cultures in aneuploid cells relative to their diploid counterparts. An elevated expression in CD230/PRPC was observed in serum-deprived cells in association with increased generation of reactive oxygen species. Overall, our work identified biomarkers of aneuploid karyotypes which suggest insights into the underlying molecular physiology of aneuploid cells.

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Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma

Elevated plasma concentrations of soluble VEGFA isoforms are associated with poor prognosis in parallel with improved response to treatment with the anti-VEGFA antibody bevacizumab. To uncover the underlying mechanism to these observations, we administered anti-VEGFA therapy to mice bearing luminescent mouse fibrosarcomas expressing single VEGFA isoforms or their wild type counterparts expressing all isoforms (fs120, fs164, fs188 or fsWT). Expression of the more soluble isoforms conferred an advantage for lung metastasis from subcutaneous tumors (fs120/164 versus fs188/WT); fs120 cells also produced more lung colonies than fs188 cells when injected intravenously. Metastasis from subcutaneous fs120 tumors was more sensitive than fs188 to treatment with the anti-VEGFA antibody B20-4.1.1. Despite elevated plasma levels of VEGFA in fs120 tumor-bearing mice and a dependence on VEGF receptor 1 activity for metastasis to the lung, B20-4.1.1 did not affect survival in the lung on intravenous injection. B20-4.1.1 inhibited subcutaneous tumor growth and decreased vascular density in both fs120 and fs188 tumors. However, migration of fs120, but not fs188 cells in vitro was inhibited by B20-4.1.1. The greater survival of fs120 cells in the lung was associated with VEGFR1-dependent accumulation of CD11b positive myeloid cells and higher expression of the VEGFR1 ligand, PlGF2, by the fs120 cells in vitro and in the plasma and lungs of fs120 tumor-bearing mice. We conclude that soluble VEGFA isoform expression increases fibrosarcoma metastasis through multiple mechanisms that vary in their sensitivity to anti-VEGF/VEGFR inhibition, with VEGFA-targeted therapy suppressing metastasis through effects on the primary tumor rather than the metastatic site

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CCR7 mediates human breast cancer cell invasion, migration by inducing epithelial–mesenchymal transition and suppressing apoptosis through AKT pathway

Abstract

Chemokine and the chemokine receptor have a key role in the tumor progress. Here, we supposed that CCR7 might induce the invasion, migration, and epithelial–mesenchymal transition (EMT) process of breast cancer. In this research, human breast cancer MCF-7 and MDA-MB-231cells were treated with CCL19 and small-interfering RNA (CCR7 siRNA) for activation and inhibition of CCR7, respectively. Cell invasion and transwell assays were used to detect the effect of CCR7 on invasion and migration. The results demonstrated that CCL19 mediated cell invasion and migration by inducing the EMT, with downregulation of E-cadherin and up-regulation of N-cadherin and vimentin levels. On the other hand, knockdown of CCR7 revealed the changes compared with CCL19 group and the control group. Knockdown of CCR7 inhibits CCL19-induced breast cancer cell proliferation, the cell cycle, migration, invasion and EMT. Moreover, we demonstrated that CCL19-induced AKT phosphorylation; however, CCR7 siRNA suppressed CCL19-induced AKT phosphorylation, a key regulator of tumor metastasis. In conclusion, all findings demonstrated that CCL19/CCR7 axis regulated EMT progress in breast cancer cells and mediated the tumor cell invasion and migration process via activation of AKT signal pathway. Our results suggested that CCR7 may regard as a therapeutic target for the breast cancer treatment.

All findings demonstrated that CCL19/CCR7 axis regulated EMT progress in breast cancer cells and mediated the tumor cell invasion and migration process via activation of AKT signal pathway. Our results suggested that CCR7 may regard as a therapeutic target for the breast cancer treatment.

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A systematic investigation of the association between HPV and the clinicopathological parameters and prognosis of oral and oropharyngeal squamous cell carcinomas

Abstract

Human papillomavirus (HPV), the causal factor of cervical cancers, was closely linked to the etiology and prognosis of oropharyngeal squamous cell carcinoma (OPSCC), but its role in oral squamous cell carcinoma (OSCC) was unclear. In addition, few researches based on Chinese population were documented. Hence, we sought to investigate the relationship of HPV marker P16 protein to the clinicopathological parameters and survival of OPSCC and OSCC patients systematically to assess the influence of ethnic, regional difference on HPV susceptibility. Specimens from 93 OPSCC patients and 95 OSCC patients were recut, and P16 immunohistochemistry (IHC) was performed. Moreover, survival analysis was conducted to confirm the independent factors that influenced the prognosis. The P16 results were positive in 25.8% and 9.5% of patients with OPSCC and OSCC, respectively. The overall survival (OS) of HPV-positive OPSCC patients was significantly longer than that of HPV-negative OPSCC patients (P = 0.004). Conversely, statistical significance was not observed regarding the OS of OSCC patients (P = 0.343). Cox regression analysis indicated that T stage and P16 status were independent factors that affected the prognosis of OPSCC patients, and the smoking index influenced the prognosis of OSCC patients. Among OPSCC patients who received radiochemotherapy (RCT), HPV-positive patients had a better survival rate than their HPV-negative counterparts (P = 0.015). Conversely, no significant difference was observed between HPV-positive and HPV-negative OSCC patients who received RCT (P = 0.237). P16 is a credible surrogate by which to define HPV status. HPV expression had a favorable effect on OPSCC patients as opposed to their OSCC counterparts in this single center population-based study.

The research regarding to the relationship between HPV and clinicopathological parameters and paprognosis of oral and oropharyngeal squamous cell carcinomas is emerging as a hotspot in the world. Taking account of the difference between The East and The West, we conduct this systematic retrospective investigation including consultation of medical records, collection of specimen, statistical analysis and postoperative follow-up.

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The positive clinical therapeutically effects of Escin on advanced thyroid cancer

Abstract

The incidences of thyroid cancer keep rising worldwide over the past few decades. Although most thyroid cancers are indolent and highly curable, the treatment for advanced thyroid cancer remains challengeable in clinical practice. We performed two separate cohorts to evaluate the safety and efficiency of Escin in patients with advanced thyroid cancer . In cohort 1, 120 patients were divided into four groups equally and were administrated with placebo or different dosages of Escin. The pharmacokinetics of Escin and the side effects were evaluated. In cohort 2, 120 patients were treated with Escin. Several biomarkers related to the progression of thyroid cancer were evaluated. Kaplan–Meier (KM) analyses were performed to evaluate progression-free survival (PFS) and overall survival (OS). The serum Escin concentrations were stable during the treatment. Escin (0.6 mg/kg/day for 9 days, intravenous injection) was tolerable for patients with thyroid cancer . Escin significantly reduced the serum levels of TSH, TgAb, Tg, and calcitonin and prolonged the PFS and OS for patients with advanced thyroid cancer. This study showed Escin is efficient and well tolerated in patients with advanced thyroid cancer. Future studies are needed to investigate the mechanism of Escin on thyroid cancer and the proper dosage of Escin clinically.

This study showed Escin is efficient and well tolerated in patients with advanced thyroid cancer. Based on the safety, and pharmacokinetic and efficacy profiles of our study, it was concluded that Escin 0.6 mg/kg/day i.v. for 9 days was tolerable.

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A cross-sectional study on HPV testing with type 16/18 genotyping for cervical cancer screening in 11,064 Chinese women

Abstract

Cytology-based cervical cancer screening is restricted because of a lack of cytologists. Thus, HPV-based instead of cytology-based screening may be a more suitable strategy in China. Here, we assessed the effectiveness of HPV testing (Cobas^® 4800 Test, Roche) and HPV-based programs to detect high-grade cervical intraepithelial neoplasia (CIN) or cancer compared with cytology (Thinprep, Hologic) and cytology-based programs through a cross-sectional study in 11,064 Chinese women aged 21–65 years who were enrolled from Longyou County in Zhejiang Province, China. The rates of HPV positivity and cytology abnormality were 9.8% and 6.1%, respectively. The HPV positivity rate had two age peaks, 21–24 (15.4%) and 60–65 (14.4%) years. According to adjusted data, HPV testing demonstrated significantly higher sensitivity and negative predictive value (NPV) than cytology for detecting CIN2 or worse (90.0% vs. 66.7%, 99.9% vs. 99.5%), and there was an acceptable specificity (91.3%) and positive predictive value (PPV, 12.5%). Furthermore, primary HPV testing with type 16/18 genotyping showed the highest sensitivity (78.6%) and NPV (99.7%) among four screening strategies, and there was similar specificity (96.8%) and PPV (23.9%) compared with co-testing screening to detect CIN2+, while there were fewer colposcopies (4.2) and tests (106.3) performed than with co-testing and primary cytology screening to detect a case of high-grade CIN. The differences in effectiveness were approximately similar when CIN3+ was the identifying target. Our findings suggest that primary HPV testing with type 16/18 genotyping has a higher sensitivity and NPV, possesses optimal cost/effectiveness in the first round of screening and is a feasible strategy of cervical cancer screening for Chinese women.

Cytology-based cervical cancer screening is restricted in China because of a lack of cytologists. We assessed, for the first time in China, the effectiveness of Cobas^® HPV testing and HPV-based programs to detect high-grade cervical intraepithelial neoplasia (CIN) or cancer through a population-based cross-sectional study, and found that primary HPV testing with type 16/18 genotyping demonstrated higher sensitivity and negative predictive value (NPV), possessed optimal cost/effectiveness in the first round of screening and could be a feasible strategy of cervical cancer screening for Chinese women.

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DNA methylation epigenotype and clinical features of NRAS-mutation(+) colorectal cancer

Abstract

Sporadic colorectal cancer (CRC) is classified into several molecular subtypes. We previously established two groups of DNA methylation markers through genome-wide DNA methylation analysis to classify CRC into distinct subgroups: high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME, respectively). HME CRC, also called CpG island methylator phenotype (CIMP)-high CRC, shows methylation of both Group 1 markers (CIMP markers) and Group 2 markers, while IME/CIMP-low CRC shows methylation of Group 2, but not of Group 1 markers, and LME CRC shows no methylation of either Group 1 or Group 2 markers. While BRAF- and KRAS-mutation(+) CRC strongly correlated with HME and IME, respectively, clinicopathological features of NRAS-mutation(+) CRC, including association with DNA methylation, remain unclear. To characterize NRAS-mutation(+) CRC, the methylation levels of 19 methylation marker genes (6 Group 1 and 13 Group 2) were analyzed in 61 NRAS-mutation(+) and 144 NRAS-mutation(−) CRC cases by pyrosequencing, and their correlation with clinicopathological features was investigated. Different from KRAS-mutation(+) CRC, NRAS-mutation(+) CRC significantly correlated with LME. NRAS-mutation(+) CRC showed significantly better prognosis than KRAS-mutation(+) CRC (P = 3 × 10⁻⁴). NRAS-mutation(+) CRC preferentially occurred in elder patients (P = 0.02) and at the distal colon (P = 0.006), showed significantly less lymph vessel invasion (P = 0.002), and correlated with LME (P = 8 × 10⁻⁵). DNA methylation significantly accumulated at the proximal colon. NRAS-mutation(+) CRC may constitute a different subgroup from KRAS-mutation(+) CRC, showing significant correlation with LME, older age, distal colon, and relatively better prognosis.

Genetic and epigenetic analyses of colorectal cancer (CRC) were conducted to clarify molecular and clinicopathological features of NRAS-mutation(+) CRC compared to KRAS-mutation(+) and other subgroups of CRC. NRAS-mutation(+) CRC presented a low-methylation epigenotype, occurred in elder patients and at the distal colon, and showed relatively better prognosis

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Preclinical activity of the novel anti-Prolactin Receptor (PRLR) antibody drug-conjugate REGN2878-DM1 in PRLR positive breast cancers

The Prolactin Receptor (PRLR) is a type 1 cytokine receptor that is expressed in a subset of breast cancers and may contribute to its pathogenesis. It is relatively over-expressed in ~25% of human breast tumors while expressed at low levels in some normal human tissues including the mammary gland. We developed an anti-PRLR antibody-drug conjugate (ADC), to target PRLR positive breast cancer. REGN2878-DM1 is comprised of a fully human high affinity function-blocking anti-PRLR IgG1 antibody (REGN2878) conjugated via a non-cleavable SMCC linker to the cytotoxic maytansine derivative DM1. Both unconjugated REGN2878 and conjugated REGN2878-DM1 block PRL mediated activation in vitro and are rapidly internalized into lysosomes. REGN2878-DM1 induces potent cell cycle arrest and cytotoxicity in PRLR-expressing tumor cell lines. In vivo, REGN2878-DM1 demonstrated significant antigen-specific anti-tumor activity against breast cancer xenograft models. In addition, REGN2878-DM1 showed additive activity when combined with the anti-estrogen agent fulvestrant. These results illustrate promising anti-tumor activity against PRLR positive breast cancer xenografts and support the evaluation of anti-PRLR ADCs as potential therapeutic agents in breast cancer.

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Biological role and therapeutic targeting of TGF-{beta}3 in glioblastoma

Transforming growth factor (TGF)-β contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-β1 and TGF-β2 isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-β3 in glioblastoma has not been defined yet. Here we studied the expression and functional role of endogenous and exogenous TGF-β3 in glioblastoma models. TGF-β3 mRNA is expressed in human and murine long-term glioma cell lines as well as in human glioma-initiating cell cultures with expression levels lower than TGF-β1 or TGF-β2 in most cell lines. Inhibition of TGF-β3 mRNA expression by ISTH2020 or ISTH2023, two different isoform-specific phosphorothioate locked nucleic acid (LNA)-modified antisense oligonucleotide gapmers, blocks down-stream SMAD2 and SMAD1/5 phosphorylation in human LN-308 cells, without affecting TGF-β1 or TGF-β2 mRNA expression or protein levels. Moreover, inhibition of TGF-β3 expression reduces invasiveness in vitro. Interestingly, depletion of TGF-β3 also attenuates signaling evoked by TGF-β1 or TGF-β2. In orthotopic syngeneic (SMA-560) and xenograft (LN-308) in vivo glioma models, expression of TGF-β3 as well of the down-stream target, plasminogen-activator-inhibitor (PAI)-1, was reduced while TGF-β1 and TGF-β2 levels were unaffected following systemic treatment with TGF-β3-specific antisense oligonucleotides. We conclude that TGF-β3 might function as a gatekeeper controlling down-stream signaling despite high expression of TGF-β1 and TGF-β2 isoforms. Targeting TGF-β3 in vivo may represent a promising strategy interfering with aberrant TGF-β signaling in glioblastoma.

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U1 Adaptors suppress the KRAS-MYC oncogenic axis in human pancreatic cancer xenografts

Targeting KRAS and MYC has been a tremendous challenge in cancer drug development. Genetic studies in mouse models have validated the efficacy of silencing expression of both KRAS and MYC in mutant KRAS driven tumors. We investigated the therapeutic potential of a new oligonucleotide-mediated gene silencing technology (U1 Adaptor) targeting KRAS and MYC in pancreatic cancer. Nanoparticles in complex with anti-KRAS U1 Adaptors (U1-KRAS) showed remarkable inhibition of KRAS in different human pancreatic cancer cell lines in vitro and in vivo. As a nanoparticle-free approach is far easier to develop into a drug, we refined the formulation of U1 Adaptors by conjugating them to tumor targeting peptides (iRGD and cRGD). Peptides coupled to fluorescently tagged U1 Adaptors showed selective tumor localization in vivo. Efficacy experiments in pancreatic cancer xenograft models showed highly potent (>90%) anti-tumor activity of both iRGD and (cRGD)₂-KRAS Adaptors. U1 Adaptors targeting MYC inhibited pancreatic cancer cell proliferation caused apoptosis in vitro (40-70%) and tumor regressions in vivo. Comparison of iRGD conjugated U1 KRAS and U1 MYC Adaptors in vivo revealed a significantly greater degree of cleaved caspase-3 staining and decreased Ki67 staining as compared with controls. There was no significant difference in efficacy between the U1 KRAS and U1 MYC Adaptor groups. Our results validate the value in targeting both KRAS and MYC in pancreatic cancer therapeutics and provide evidence that the U1 Adaptor technology can be successfully translated using a nanoparticle free delivery system to target two undruggable genes in cancer.

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Vulvar squamous cell carcinoma (VSCC) as two diseases: HPV status identifies distinct mutational profiles including oncogenic fibroblast growth factor receptor 3

Purpose: Patients with advanced or recurrent invasive vulvar squamous cell carcinoma (VSCC) have limited treatment options and a grave prognosis. Understanding the genomic landscape may facilitate the identification of new therapies and improve clinical outcomes. Experimental design: A retrospective chart review and molecular analysis of patients with VSCC from 2000-2016 was performed at the Ottawa Hospital Research Institute. The presence of oncogenic HPV was determined by nested PCR and amplified DNA was sequenced using the Ion AmpliSeq Cancer Hotspot v2 Panel. The patients were divided into two groups according to HPV status (HPV-positive versus HPV-negative) and clinical outcome correlated with mutation status using descriptive statistics. Results: In 43 VSCC patients, there was a high mutation rate in both HPV-positive (73%) and HPV-negative (90%) disease with the two subgroups expressing distinct genetic profiles. HPV-positive tumors were characterized by oncogenic mutations in PIK3CA (27%), FGFR3 (14%) and PTEN (9%), while HPV-negative tumors were found to have mutations in TP53 (57%), HRAS (24%), PI3KCA (19%) and CDKN2A (14%). Mutation S249C in FGFR3 occurred in 14% of HPV-positive tumors. While there were notable differences in the occurrence of TP53, HRAS, PTEN, and FGFR3 mutations according to HPV status, only the rate of TP53 mutations was statistically significant (p=0.0004). No significant difference in prognosis was found between patients with HPV-positive and HPV-negative VSCC. Conclusions: HPV-positive VSCC is characterized by oncogenic FGFR3 mutations which helps classify this subtype as a separate disease. Inhibitors of FGFR3 merit consideration as a therapeutic strategy in this neglected woman's cancer.

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Characterization of an Immunogenic Mutation in a Patient with Metastatic Triple Negative Breast Cancer.

Purpose: The administration of autologous tumor infiltrating lymphocytes (TIL) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There is limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic non-synonymous mutations in a patient with triple-negative breast cancer (TNBC) in order to identify and isolate mutation-reactive TIL for possible use in adoptive cell transfer. Experimental Design: A TNBC metastasis was resected for TIL generation and whole exome sequencing. Tandem minigenes or long 25mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNg ELISPOT. The nature of the T cell response against a unique non-synonymous mutation was characterized. Results: We identified 72 non-synonymous mutations from the tumor of a patient with TNBC. CD4⁺and HLA-DRB1^*1501-restricted TIL isolated from this tumor recognized a single mutation in RBPJ (recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples. Conclusion: Breast cancers can express naturally processed and presented unique non-synonymous mutations that are recognized by a patient's immune system. TIL recognizing these immunogenic mutations can be isolated from a patient's tumor suggesting that adoptive cell transfer of mutation-reactive TIL could be a viable treatment option for patients with breast cancer.

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Phase Ib/II study of safety & efficacy of combination therapy with multikinase VEGF inhibitor Pazopanib and MEK inhibitor Trametinib in advanced soft tissue sarcoma

Purpose: Pazopanib, a multi-receptor tyrosine kinase inhibitor targeting primarily vascular endothelial growth factor receptors 1-3 (VEGFRs1-3), is approved for advanced soft tissue sarcoma and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using a trametinib would synergize with pazopanib in advanced soft tissue sarcoma (STS). Experimental Design: In an open-label, multicenter, investigator-initiated NCCN-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate and disease control rate. Results: Twenty-five patients were enrolled. The median age was 49 years (range 22-77 years) and 52% were male. Median PFS was 2.27 months (95% confidence interval [CI] 1.9-3.9), and the 4-month PFS rate was 21.1% (95% CI 9.7-45.9%), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% (p = 0.79). Median overall survival was 9.0 months (95% CI 5.7-17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI 1.0-26.0%), one with PIK3CA E542K mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI 34.9-75.6%). The most common adverse events were diarrhea (84%), nausea (64%), and fatigue (56%). Conclusion: The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas.

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Use of expansion cohorts in phase 1 trials and probability of success in phase 2 for 381 anticancer drugs

Purpose Evaluate the association between the use of phase 1 (P1) expansion cohorts (ECs) and drug performance in phase 2 (P2) as well as time to approval by the U.S. Food and Drug Administration (FDA). Methods We performed a systematic search of MEDLINE for single-agent dose-finding adult oncology P1 trials published 2006-2011 and subsequent P2 trials. Successful P2 trials were those that met their primary endpoints. Dates of approval were obtained from the Drugs@FDA website April 2014. A logistic regression model was used to determine the associations between variables and success in P2. Results We identified 533 P1 trials evaluating 381 drugs; 112 drugs had at least one P1 trial with an EC. P1 trials with ECs of 2-20 patients were associated with a higher rate of successful P2 trials than those with no EC (48% vs 27%, OR 2.1, 95%CI 1.1-4.0, p = 0.037). P2 success rates were the same for EC with 2-20 and more than 20 patients (48% vs 52%). Other positive associations were: disease-specific trials (OR 1.7, 95%CI 1.0-2.9, p=0.037), industry sponsorship (OR 2.9, 95%CI 1.5-5.7, p = 0.0024) and response rate of 6%-20% (OR 2.89, 95%CI 1.6-5.2, p = 0.0007). Drugs tested in P1 trials with ECs had a higher rate of 5-year-approval (19% vs 5%, HR 4.4, 95% CI 2.2-8.8, p < 0.001). Conclusion The use of ECs in P1 trials was associated with success of subsequent P2 trials. However, confounders may play a role in this association.

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A Phase II study of Dovitinib in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma

Purpose: Genetic and preclinical studies have implicated fibroblast growth factor receptor (FGFR) signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor FGFR activity, may be active in ACC. Methods: In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate (ORR) and change in tumor growth rate (TGR). Progression-free survival (PFS), overall survival (OS), metabolic response, biomarker and QOL were secondary endpoints. Results: Of thirty-four evaluable patients, two (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on-treatment (p<0.001). Toxicity was moderate; 63% of patients developed grade 3-4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on ¹⁸FDG-PET scans was seen in 3/15 patients but did not correlate with RECIST response. MYB gene translocation was observed and significantly correlated with over-expression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib. Conclusion: Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably to those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine if FGFR signaling is a valid therapeutic target in ACC.

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The prognostic value of simultaneous tumor and serum RAS/RAF mutations in localized colon cancer

Abstract

The impact of RAS/RAF mutations in localized colon cancer needs clarification. Based on analysis of tumor-specific DNA, this study aimed at elucidating the prognostic influence of mutational status in tumor and serum using an extended panel of mutations.

The study retrospectively included 294 patients with curatively resected stage I–III adenocarcinoma of the colon. Mutations in tumor and serum were determined at time of surgery. Analyses were performed with droplet digital PCR technology. Hazard ratio (HR) for the association between mutational status and survival was estimated in multivariate analysis taking known prognostic factors into account.

Mutational status in tumor did not on its own have significant prognostic impact (P = 0.22). Patients with a RAS mutation simultaneously in tumor and serum had a significantly worse prognosis, overall survival (OS) (HR = 2.30, 95% CI = 1.27–4.15, P = 0.0057), and disease-free survival (DFS) (HR = 2.18, 95%CI = 1.26–3.77, P = 0.0053). BRAF mutation in the serum and proficient mismatch repair (pMMR) protein in tumor also indicated significantly worse prognosis, OS (HR = 3.45, 95% CI = 1.52–7.85, P = 0.0032) and DFS (HR = 3.61, 95% CI = 1.70–7.67, P = 0.0008). In conclusion, RAS mutations in serum, and BRAF mutation in serum combined with pMMR in tumor were strong independent prognostic factors in patients with RAS/RAF mutated tumors.

This work is the first to demonstrate simultaneous RAS/RAF mutational status in tumor and serum in localized colon cancer patients to be a potent prognostic marker.

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Diffusion of digital breast tomosynthesis among women in primary care: associations with insurance type

Abstract

Digital breast tomosynthesis (DBT) has shown potential to improve breast cancer screening and diagnosis compared to digital mammography (DM). The FDA approved DBT use in conjunction with conventional DM in 2011, but coverage was approved by CMS recently in 2015. Given changes in coverage policies, it is important to monitor diffusion of DBT by insurance type. This study examined DBT trends and estimated associations with insurance type. From June 2011 to September 2014, DBT use in 22 primary care centers in the Dartmouth -Brigham and Women's Hospital Population-based Research Optimizing Screening through Personalized Regimens research center (PROSPR) was examined among women aged 40–89. A longitudinal repeated measures analysis estimated the proportion of DBT performed for screening or diagnostic indications over time and by insurance type. During the study period, 93,182 mammograms were performed on 48,234 women. Of these exams, 16,506 DBT tests were performed for screening (18.1%) and 2537 were performed for diagnosis (15.7%). Between 2011 and 2014, DBT utilization increased in all insurance groups. However, by the latest observed period, screening DBT was used more frequently under private insurance (43.4%) than Medicaid (36.2%), Medicare (37.8%), other (38.6%), or no insurance (32.9%; P < 0.0001). No sustained differences in use of DBT for diagnostic testing were seen by insurance type. DBT is increasingly used for breast cancer screening and diagnosis. Use of screening DBT may be associated with insurance type. Surveillance is required to ensure that disparities in breast cancer screening are minimized as DBT becomes more widely available.

Digital breast tomosynthesis (DBT) is increasingly used for breast cancer screening and diagnosis. Our study finds screening DBT to be associated with insurance type, with lowest use among those with Medicaid and the uninsured. Surveillance is required to ensure that insurance-related disparities in breast cancer screening are minimized as DBT becomes more widely available.

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Risk and associated risk factors of hospitalization for specific health problems over time in childhood cancer survivors: a medical record linkage study

Abstract

Childhood cancer survivors (CCS) experience higher hospitalization rates compared to the general population for neoplasms, circulatory diseases, endocrine/nutritional/metabolic diseases and eye disorders. We studied trends in hospitalization rates and associated patient and treatment-specific risk factors for diagnosis subgroups among these four diseases. We performed medical record linkage of a ≥5-year CCS cohort with national registers, and obtained a random reference sample matched on age, gender and calendar year per CCS. For each diagnosis subgroup we compared hospitalization rates and trends over time in CCS and the reference population. Further, we analyzed risk factors for hospitalizations within the four CCS diagnosis groups. We used multivariate Poisson regression for all models. We retrieved hospitalization data from 1382 CCS and 26,583 reference persons. CCS had increased hospitalization rates for almost all diagnosis subgroups examined. Hospitalization rates for endocrine/nutritional/metabolic diseases appeared to increase with longer time since primary cancer diagnosis up to 30 years after primary cancer diagnosis. Survivors initially treated with radiotherapy had increased hospitalization rates for neoplasms (P < 0.001), those initially treated with anthracyclines (2.5 [1.1–5.5]) and radiotherapy to thorax and/or abdomen (9.3 [2.4–36.6]) had increased hospitalization rates for diseases of the circulatory system, and those initially treated with radiotherapy to head and/or neck had increased hospitalization rates for endocrine/nutritional/metabolic diseases (6.7 [3.5–12.7]) and diseases of the eye (3.6 [1.5–8.9]). Our study highlights that long-term health problems resulting in hospitalizations are still clinically relevant later in life of CCS. The identified treatment-related risk factors associated with hospitalizations support targeted follow-up care for these risk groups of CCS.

Childhood cancer survivors experience higher hospitalization rates compared to the general population for almost all diagnosis subgroups within neoplasms, circulatory diseases, endocrine/nutritional/metabolic diseases and eye disorders. This study supports the prioritization of follow-up care for the risk groups we identified, namely those survivors originally treated with anthracyclines and radiotherapy to thorax and/or abdomen and head and/or neck.

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Effective nasal mask ventilation of a difficult airway in a patient with advanced salivary gland cancer

We report a case of successful nasal mask ventilation in a patient with a difficult airway and advanced salivary cancer.

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Use of the Laryngeal Mask Airway (LMA) Protector™ for shoulder surgeries in beach-chair position

The use of supraglottic airway devices in the management of airway for patients in beach-chair positions for shoulder surgeries is often appropriate and increasingly favoured over tracheal intubation due to the potential complications associated with the latter [1,2]. We report our initial experience and satisfactory performance of the Laryngeal Mask Airway (LMA) Protector™ in three patients scheduled for elective shoulder surgeries performed in beach-chair positions. Recently introduced in 2016, the LMA Protector™ is a single-use second-generation supraglottic airway device complete with a pharyngeal chamber and dual gastric access ports.

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Up-regulation of autophagy is a mechanism of resistance to chemotherapy and can be inhibited by pantoprazole to increase drug sensitivity

Abstract

Background

Autophagy is a survival mechanism that allows recycling of cellular breakdown products, particularly in stressed cells. Here we evaluate the hypotheses that up-regulation of autophagy is a common mechanism of resistance to chemotherapy, and that drug resistance can be reversed by inhibiting autophagy with a proton pump inhibitor.

Methods

We exposed human PC3, LNCaP and MCF7 cells to seven clinically-used chemotherapy drugs ± pantoprazole, examined the up-regulation of autophagy and the effect on cellular proliferation by Western Blots, MTS assay and colony-forming assay. The distribution of drug effects and of autophagy was quantified in LNCaP tumor sections in relation to blood vessels and hypoxia by immunohistochemistry using γH2AX, cleaved caspase-3 and p62.

Results

All anticancer drugs led to up-regulation of autophagy in cultured tumor cells. Pantoprazole inhibited the induction of autophagy in a time- and dose-dependent manner, and sensitized cancer cells to the seven anti-cancer drugs. Treatment of LNCaP xenografts with paclitaxel induced both DNA damage and autophagy; autophagy was inhibited and markers of toxicity were increased by pantoprazole.

Conclusions

Induction of autophagy is a general mechanism associated with resistance to anticancer drugs and that its inhibition is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes.

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Down-regulation of LncRNA TUG1 enhances radiosensitivity in bladder cancer via suppressing HMGB1 expression

Abstract

Background

Long non-coding RNAs (lncRNAs) have been reported to regulate the sensitivity of different cancer cells to chemoradiotherapy. Aberrant expression of lncRNA Taurine-upregulated gene 1 (TUG1) has been found to be involved in the development of bladder cancer, however, its function and underlying mechanism in the radioresistance of bladder cancer remains unclear.

Methods

Quantitative real-time PCR (qRT-PCR) was conducted to measure the expression of TUG1 and HMGB1 mRNA in bladder cancer tissues and cell lines. HMGB1 protein levels were tested by western blot assays. Different doses of X-ray were used for radiation treatment of bladder cancer cells. Colony survival and cell viability were detected by clonogenic assay and CCK-8 Kit, respectively. Cell apoptosis was determined by flow cytometry. A xenograft mouse model was constructed to observe the effect of TUG1 on tumor growth in vivo.

Results

The levels of TUG1 and HMGB1 were remarkably increased in bladder cancer tissues and cell lines. Radiation treatment markedly elevated the expression of TUG1 and HMGB1. TUG1 knockdown inhibited cell proliferation, promoted cell apoptosis and decreased colony survival in SW780 and BIU87 cells under radiation. Moreover, TUG1 depletion suppressed the HMGB1 mRNA and protein levels. Furthermore, overexpression of HMGB1 reversed TUG1 knockdown-induced effect in bladder cancer cells. Radiation treatment dramatically reduced the tumor volume and weight in xenograft model, and this effect was more obvious when combined with TUG1 silencing.

Conclusion

LncRNA TUG1 knockdown enhances radiosensitivity of bladder cancer by suppressing HMGB1 expression. TUG1 acts as a potential regulator of radioresistance of bladder cancer, and it may represent a promising therapeutic target for bladder cancer patients.

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An integrated strategy of biological and physical constraints in biological optimization for cervical carcinoma

Abstract

Background

Methods

Twenty patients of advanced stage cervical carcinoma were enrolled in this study. For each patient, dose volume optimization (DVO), biological model optimization (BMO) and integrated strategy optimization (ISO) plans were created using same treatment parameters. Different biological models were also used for organ at risk (OAR) in BMO plans, which include the LKB and Poisson models. Next, BMO plans were compared with their corresponding DVO plans, in order to evaluate BMO plan quality. ISO plans were also compared with DVO and BMO plans, in order to verify the performance of the integrated strategy.

Results

BMO plans produced slightly inhomogeneity and less coverage of planning target volume (PTV) (V95=96.79, HI = 0.10: p < 0.01). However, the tumor control probability (TCP) value, both from DVO and BMO plans, were comparable. For the OARs, BMO plans produced lower normal tissue complication probability (NTCP) of rectum (NTCP = 0.11) and bladder (NTCP = 0.14) than in the corresponding DVO plans (NTCP = 0.19 and 0.18 for rectum and bladder; p < 0.01 for rectum and p = 0.03 for bladder). V95, D98, CI and HI values that were produced by ISO plans (V95 = 98.31, D98 = 54.18Gy, CI = 0.76, HI = 0.09) were greatly better than BMO plans (V95 = 96.79, D98 = 53.42Gy, CI = 0.71, HI = 0.10) with significant differences. Furthermore, ISO plans produced lower NTCP values of rectum (NTCP = 0.14) and bladder (NTCP = 0.16) than DVO plans (NTCP = 0.19 and 0.18 for rectum and bladder, respectively) with significant differences.

Conclusions

BMO plans produced lower NTCP values of OARs compared to DVO plans for cervical carcinoma cases, and resulted in slightly less target coverage and homogeneity. The integrated strategy, proposed in this study, could improve the coverage, conformity and homogeneity of PTV greater than the BMO plans, as well as reduce the NTCP values of OARs greater than the DVO plans.

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Metastasis from Hepatocellular Carcinoma Masquerading as a Jugular Paraganglioma

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Characteristics and Impacts of Venous Thromboembolism in Patients with Hepatocellular Carcinoma

Abstract

Introduction

Venous thromboembolism (VTE) is a common complication in cancer patients, and is associated with worse prognosis in such population. Hepatocellular carcinoma (HCC) poses high risk for VTE; however, data is scarce regarding the characteristics and consequences of VTE in HCC patients.

Method

We retrospectively reviewed the electronic medical records (EMR) of 270 patients diagnosed with HCC from 2000 to 2015 in Cook County Health and Hospitals System. We report the cumulative incidence of VTE in the present cohort, and identified through multivariate logistic regression the independent risk factors of the development of VTE. Overall prognosis of patients with and without VTE were presented and compared.

Results

Sixteen cases (5.93%) of VTE were documented in the present study. In multivariate analysis, obesity, Child B cirrhosis, intra-hepatic lesions more than 3, and multi-organ extrahepatic metastasis were significantly associated with VTE development (p < 0.05). The presence of VTE was an independent risk factor for mortality in multivariate analysis (HR = 3.62, p = 0.021), together with male gender, Child C cirrhosis, and extrahepatic metastasis.

Conclusions

Obesity, Child B cirrhosis, more intra-hepatic lesions, and multi-organ extrahepatic metastasis are associated with cancer-associated VTE. VTE will adversely affect the prognosis of patients with HCC; therefore, primary thromboprophylaxis may be warranted in such population.

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New doxorubicin nanocarriers based on cyclodextrins

Summary

Polymeric nanoparticles and fibrin gels (FBGs) are attractive biomaterials for local delivery of a variety of biotherapeutic agents, from drugs to proteins. We combined these different drug delivery approaches by preparing nanoparticle-loaded FBGs characterized by their intrinsic features of drug delivery rate and antiproliferative/apoptotic activities. Inclusion complexes of doxorubicin (DOXO) with oligomeric β-cyclodextrins (oCyD) functionalized with different functional groups were studied. These nanocarriers were able to interact with FBGs as shown by a decreased release rate of DOXO. One of these complexes, oCyDNH₂/DOXO, demonstrated good antiproliferative and apoptotic activity in vitro, reflecting a higher drug uptake by cells. As hypothesized, the nanocarrier/FBG complexes showed a lower drug release rate than similar FBGs loaded with the corresponding non-functionalized oCyD/DOXO. Taken together, our results provide experimental evidence that oCyDNH₂/DOXO complexes may be useful components in enhanced FBGs and further build support for the great promise these complex molecules hold for clinical use in localized anticancer therapy of inoperable or surgically removable tumors of different histological origin.

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A case of gastric metastasis from renal cell cancer during the sequential targeted therapy

Abstract

Historically, gastric metastasis from renal cell cancer (RCC) has been extremely rare. As RCC is now being treated with various agents of targeted therapy, however, the rate of unusual visceral metastases might increase as outcomes improve and follow-up periods grow longer. Here we present a valuable case of gastric metastasis from RCC detected in a routine CT scan during sequential targeted therapy. A 73-year-old man was referred to our hospital, presenting with left renal cell cancer with multiple lung metastases at stage cT1bN0M1. He received first-line targeted therapy consisting of sunitinib and subsequently underwent left radical nephrectomy. He then underwent sequential therapy consisting of interferon-alpha, sunitinib, everolimus, and axitinib for multiple lung metastases. Five years after nephrectomy, a follow-up computed tomography scan revealed a 2.2 × 1.6 cm mass in the stomach without any symptoms. Gastrointestinal endoscopy disclosed a polypoid lesion at the gastric fundus. Endoscopic submucosal resection was performed. Microscopic diagnosis revealed gastric metastasis from RCC. As various new therapeutic agents increase survival periods for metastatic RCC patients in this era of targeted therapy, clinicians must watch for metastasis in the stomach, though this was formerly a rare event.

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Granuloma-forming interstitial pneumonia induced by nivolumab: a possible immune-related adverse event of the lung

Abstract

Nivolumab, a monoclonal antibody targeting the PD-1, has recently been used as a standard treatment for lung cancer, melanoma and renal cell carcinoma. We herein report the case of a patient undergoing treatment for non-small cell lung cancer (NSCLC) who developed interstitial pneumonia which featured nivolumab-induced granuloma formation. An 82-year-old male patient with NSCLC was initially treated with radiation therapy and chemotherapy. Five years later, however, he developed metastatic carcinoma in a hilar lymph node accompanied by ground glass opacity (GGO), suggesting tumor cell invasion. Treatment with nivolumab was initiated. At 21 days after the first dose of nivolumab, he complained of cough and dyspnea. Chest computed tomography scans demonstrated tumor progression and newly formed GGO in the area surrounding the primary tumor. Fibrosing active alveolitis with granuloma formation and organizing pneumonia findings were observed in the pathological examination of a transbronchial lung biopsy (TBLB) specimen. No malignant cells were found in TBLB. A bacteriological analysis of cultures, a PCR, and special staining did not reveal any infections. The patient's pneumonitis improved after treatment with systemic corticosteroids. Granuloma-forming interstitial pneumonia may be a feature of nivolumab-associated pneumonitis.

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Gangliocytic Paraganglioma: a Diagnostic Pitfall of Rare Neuroendocrine Tumor

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Comparison of Health Communication Channels for Reaching Hispanics About Biobanking: a Pilot Trial

Abstract

Cancer education is essential for improving cancer prevention and biobanking knowledge among racial-ethnic minorities, with the goal of increasing diversity and representativeness of biospecimen collections. However, little is known about the communication modalities for optimal delivery of information. We examined feasibility of recruitment and compared communication modalities for delivering cancer prevention and biobanking education to Hispanics. Communication modalities were evaluated using participation rates and change in knowledge, attitudes, self-efficacy, intention, receptivity, and trust. Enrollment in a biobanking registry was a behavioral outcome. Community members in Ponce, Puerto Rico and Tampa, Florida were recruited. Participants (N = 254) were randomized to one of three communication modalities: standard dissemination (mailed materials); enhanced dissemination (mailed materials plus follow-up call); and 'charla' (face-to-face group discussion). Participants completed questionnaires about their knowledge, attitudes, self-efficacy, intentions, receptivity, and trust regarding biobanking and cancer prevention pre- and post-intervention. Knowledge, attitudes, and self-efficacy were improved among all three modalities. Although the greatest increases in knowledge were observed when the information was delivered via charla, the charla had the lowest participation rate. The standard and enhanced dissemination modalities were more feasible for delivering cancer prevention and biobanking education to Hispanics. Lack of differences among the three modalities suggests culturally tailored education may be sufficient to capture the community's intention to participate in biobanking research, regardless of the delivery method for the education. Results from this study contribute to the limited knowledge regarding Hispanics knowledge and intentions for biospecimen collection, and in the future may improve participation in this underrepresented group.

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Management of GBM: a problem of local recurrence

Abstract

Forty years ago, adjuvant treatment of patients with GBM using fractionated radiotherapy following surgery was shown to substantially improve survival compared to surgery alone. However, even with the addition of temozolomide to radiotherapy, overall survival is quite limited and local failure remains a fundamental problem, despite multiple attempts to increase dose to the tumor target. This review presents the historical background and clinical rationale leading to the current standard of care consisting of 60 Gy total dose in 2 Gy fractions to the MRI-defined targets in younger, high performance status patients and more hypofractionated regimens in elderly and/or debilitated patients. Particle therapies offer the potential to increase local control while reducing dose and, potentially, long-term neurocognitive toxicity. However, improvements in systemic therapies for GBM will need to be implemented before the full benefits of improved local control can be realized.

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Bone marrow myeloid cells in regulation of multiple myeloma progression

Abstract

Survival, growth, and response to chemotherapy of cancer cells depends strongly on the interaction of cancer cells with the tumor microenvironment. In multiple myeloma, a cancer of plasma cells that localizes preferentially in the bone marrow, the microenvironment is highly enriched with myeloid cells. The majority of myeloid cells are represented by mature and immature neutrophils. The contribution of the different myeloid cell populations to tumor progression and chemoresistance in multiple myeloma is discussed.

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SABCS 2016: systemic therapy for metastatic breast cancer

Summary

At the 2016 San Antonio Breast Cancer Symposium, several interesting phase II and phase III studies investigating systemic therapies for metastatic breast cancer were presented. The PrEGOC 0102 trial demonstrated that the combination of fulvestrant plus everolimus is safe and effective and could be an alternative to exemestane plus everolimus for selected patients with hormone-receptor positive, HER2-negative disease. The pan-PI3K inhibitor buparlisib showed some activity in combination with fulvestrant after failure of everolimus in the BELLE-3 trial. PIK3CA mutation detected in circulating tumor DNA (ctDNA) was predictive for a buparlisib efficacy. Unfortunately, the unfavorable toxicity profile precludes further development of this drug. Nonetheless, PI3K seems to be a valid target in tumors resistant to mTOR inhibition. The BROCADE phase II trial failed to show a statistically significant benefit by the addition of the PARP inhibitor veliparib to carboplatin and paclitaxel in patients with BRCA1/2 germline mutation. The overall response rate, however, was statistically significant higher in the veliparib arm compared to the placebo arm. Data from the phase III trial BROCADE-3 are awaited. Finally, the TNT trial did not identify further biomarkers, in addition to BRCA1/2 germline mutation, for carboplatin benefit in patients with metastatic triple-negative breast cancer.

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A case of gastric metastasis from renal cell cancer during the sequential targeted therapy

Abstract

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Granuloma-forming interstitial pneumonia induced by nivolumab: a possible immune-related adverse event of the lung

Abstract

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Up-regulation of autophagy is a mechanism of resistance to chemotherapy and can be inhibited by pantoprazole to increase drug sensitivity

Abstract

Background

Methods

Results

Conclusions

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Surgical site infection: clean surgery and antimicrobials

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Feasibility, reliability, and validity of the Japanese version of the 12-item World Health Organization Disability Assessment Schedule-2 in preoperative patients

Abstract

Purpose

The avoidance of postoperative functional disability is one of the most important concerns of patients facing surgery, but methods to evaluate disability have not been definitively established. The aim of our study was to evaluate the feasibility, reliability, and validity of the Japanese version of the 12-item World Health Organization Disability Assessment Schedule-2 (WHODAS 2.0-J) in preoperative patients.

Methods

Individuals aged ≥55 years who were scheduled to undergo surgery in a tertiary-care hospital in Japan between April 2016 and September 2016 were eligible for enrolment in the study. All patients were assessed preoperatively using the WHODAS 2.0-J, the 8-Item Short Form (SF-8) questionnaire, and the Tokyo Metropolitan Institute of Gerontology Index (TMIG Index). The feasibility, reliability, and validity of WHODAS2.0-J were evaluated using response rate, Cronbach's alpha (a measure of reliability), and the correlation between the WHODAS 2.0-J and the SF-8 questionnaire and TMIG Index, respectively.

Results

A total of 934 patients were enrolled in the study during the study period, of whom 930 completed the WHODAS 2.0-J (response rate 99.5%) preoperatively. Reliability and validity were assessed in the 898 patients who completed all three assessment tools (WHODAS 2.0-J, SF-8 questionnaire, and TMIG Index) and for whom all demographic data were available. Cronbach's alpha was 0.92. The total score of the WHODAS 2.0-J showed a mild or moderate correlation with the SF-8 questionnaire and TMIG Index (r = −0.63 to −0.34).

Conclusion

The WHODAS 2.0-J is a feasible, reliable, and valid instrument for evaluating preoperative functional disability in surgical patients.

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Cleavage and phosphorylation: important post-translational modifications of galectin-3

Abstract

As the unique chimeric member of the β-galactoside-binding protein family, galectin-3 is a multivalent and multifunctional oncogenic protein involved in multiple physiological and pathological processes, including cell growth, cell differentiation, cell adhesion, RNA splicing, cell apoptosis, and malignant transformation. Post-translational modifications can effectively increase a protein's functional diversity, either by degradation or adding chemical modifications, thus regulating activity, localization, and ligand interaction. In order to clearly understand the functional mechanisms of galectin-3 involved in normal cell biology and pathogenesis, here, we have summarized the previously reported post-translational modifications of galectin-3, including cleavage and phosphorylation. Cleavage of galectin-3 by MMPs, PSA, and proteases from parasites generated intact carbohydrate-recognition domain and N-terminal peptides of varying lengths that retained lectin binding activity but lost multivalence. Serine and tyrosine phosphorylation of galectin-3 by c-Abl, CKI, and GSK-3β could regulate its localization and associated signal transduction. Accordingly, cleavage and phosphorylation play an important role in regulating galectin-3 function via altering its multivalence, localization, and ligand interaction.

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iRECIST: A clarification of tumour response assessment in the immunotherapy era

Publication date: Available online 4 April 2017
Source:European Journal of Cancer
Author(s): Charles Ferté, Aurélien Marabelle

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Rituximab maintenance improves overall survival of patients with follicular lymphoma—Individual patient data meta-analysis

Publication date: May 2017
Source:European Journal of Cancer, Volume 76
Author(s): Liat Vidal, Anat Gafter-Gvili, Gilles Salles, Sami Bousseta, Bernice Oberman, Carmit Rubin, Marinus H.J. van Oers, Catherine Fortpied, Michele Ghielmini, Ruth Pettengell, Mathias Witzens-Harig, Peter Dreger, Umberto Vitolo, Maria Gomes da Silva, Andrea Evangelista, Hailun Li, Laurence Freedman, Thomas M. Habermann, Ofer Shpilberg
BackgroundRandomised trials of rituximab maintenance (MR) for patients with follicular lymphoma support improved progression-free survival (PFS), but the effect on overall survival has been inconclusive. To evaluate the effect of MR on overall survival according to patient and disease characteristics, and to explore certain adverse events, we performed an individual patient data (IPD) meta-analysis.MethodsAll investigators of randomised controlled trials that compared MR therapy with observation or treatment only at relapse (no MR) for patients with follicular lymphoma were invited to participate in an IPD meta-analysis. We obtained baseline patient and disease characteristics and time to progression and death for each patient. All analyses took into account the trial and original randomised treatment group. We analysed data in two ways: a two-stage analysis and a multivariate model including patient and disease characteristics.FindingsSeven trials including 2315 patients were analysed. Overall survival of patients improved with MR compared with no MR (hazard ratio [HR] 0.79, 95% CI 0.66–0.96). We could not detect any patient or disease characteristics that were associated with a survival benefit with MR. In all of the models, MR had a beneficial effect on overall survival compared with observation for all types of patients, which was not shown in a particular subgroup in which the patient had already received rituximab in the induction phase and received first-line therapy. MR improved PFS compared with observation (HR 0.57, 95% CI 0.51–0.64). The risk of adverse events was higher with MR, specifically infection of any grade and grade 3–4 infections.InterpretationBased on IPD from randomised controlled trials, MR improves overall survival consistently in all patients, regardless of patient and disease characteristics when compared with observation, and should be prescribed after a successful induction with R-CVP or R-CHOP for patients with follicular lymphoma. It is still uncertain if that holds when the patient has already received rituximab in his/hers first induction. The effect of MR after bendamustine-rituximab induction compared with rituximab at progression should be further explored.

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Improving treatment results with reference centres for rare cancers: Where do we stand?

Publication date: May 2017
Source:European Journal of Cancer, Volume 77
Author(s): Isabelle Ray-Coquard, Eric Pujade Lauraine, Axel Le Cesne, Patricia Pautier, Marie Cecile Vacher Lavenue, Annalisa Trama, Paolo Casali, Jean Michel Coindre, Jean Yves Blay
Rare adult cancer (RAC) is characterised by an incidence of less than six cases per 100,000 people per annum; Four-million three-hundred thousand patients in the European Union are living with some or other rare cancer (22% of all new human cancers). These cancers are linked with worse survival rates than 'frequent' tumours (5-year survival: 47% for RAC against 65% for 'common' cancers), mainly because of: (1) delays in obtaining an accurate diagnosis, (2) inadequate treatments given in curative phases and (3) restricted opportunities for patients to participate in clinical trials because of the lack of support for dedicated trials for this disease group from both academic and industrial sponsors. Although quantitative studies to measure the socioeconomic burden of RACs as a whole are still lacking, the increasing fragmentation of all cancers into molecular subgroups implies a substantial increase in the number of RACs and their associated socioeconomic burden. To answer this urgent and growing need, some countries, cooperative groups, and cancer institutes delineated national and/or regional organisations to promote quality management for RACs. Currently, the European Union (EU) is supporting an official EU call to organise a European network dedicated to RACs. The goals will be to pool the vast knowledge and expertise of the 67 EU clinical reference centres and to cover ten rare adult solid cancer domains across more than 18 countries in order to deploy an integrated, EU-wide capacity towards accelerated innovative treatments and care for RACs while empowering patients. This article will summarise these experiences and potential benefit for patients.

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Bone marrow myeloid cells in regulation of multiple myeloma progression

Abstract

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Epigenetic approach for angiostatic therapy: promising combinations for cancer treatment

Abstract

Cancer cells are often dependent on epigenetic pathways for their survival. Consequently, drugs that target the epigenome, rather than the underlying DNA sequence, are currently attracting considerable attention. In recent years, the first epigenetic drugs have been approved for cancer chemotherapy, mainly for hematological applications. Limitations in single-drug efficacies have thus far limited their application in the treatment of solid tumors. Nevertheless, promising activity for these compounds has been suggested when combined with other, distinctly targeted agents. In this review, we discuss the anti-angiogenic activity of histone deacetylase and DNA methyltransferase inhibitors and their combinations with other targeted (anti-angiogenic) therapeutics in treatment of solid tumors. The role that these inhibitors play in the inhibition of tumor angiogenesis, particularly in combination with other targeted agents, and the advantages they present over broad acting anticancer agents, are critically discussed.

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Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

Abstract

Apigenin (4′,5,7,-trihydroxyflavone) is a flavonoid found in certain herbs, fruits, and vegetables. Apigenin can attenuate inflammation, which is associated with many chronic diseases of aging. Senescent cells—stressed cells that accumulate with age in mammals—display a pro-inflammatory senescence-associated secretory phenotype (SASP) that can drive or exacerbate several age-related pathologies, including cancer. Flavonoids, including apigenin, were recently shown to reduce the SASP of a human fibroblast strain induced to senesce by bleomycin. Here, we confirm that apigenin suppresses the SASP in three human fibroblast strains induced to senesce by ionizing radiation, constitutive MAPK (mitogen-activated protein kinase) signaling, oncogenic RAS, or replicative exhaustion. Apigenin suppressed the SASP in part by suppressing IL-1α signaling through IRAK1 and IRAK4, p38-MAPK, and NF-κB. Apigenin was particularly potent at suppressing the expression and secretion of CXCL10 (IP10), a newly identified SASP factor. Further, apigenin-mediated suppression of the SASP substantially reduced the aggressive phenotype of human breast cancer cells, as determined by cell proliferation, extracellular matrix invasion, and epithelial-mesenchymal transition. Our results support the idea that apigenin is a promising natural product for reducing the impact of senescent cells on age-related diseases such as cancer.

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Cognitive status, fast walking speed and walking speed reserve—the Gait and Alzheimer Interactions Tracking (GAIT) study

Abstract

The aims of this study were to (1) determine if older people at their fast walking speed (FWS) are able to reach the speed required at pedestrian crossings (>1.2 m/s) and (2) determine the role of cognitive impairment on the ability to alter speed and walk quickly. Participants were recruited from the Angers Memory Clinic, France. Gait speed was assessed at preferred and FWS using a GAITRite walkway. Walking speed reserve (WSR) was calculated as the difference between FWS and preferred speeds. Participants were classified into cognitive stages (cognitively healthy, mild cognitive impairment, mild and moderate dementia) based on neuropsychological evaluations. The proportion of participants with a FWS of <1.2 m/s was reported. The association between cognitive stage and preferred, fast and walking speed reserve was assessed using multivariable regression, adjusting for covariates. The mean age of the sample (n = 681) was 73.3 (SD 5.8) years. At preferred speed 73.7%, and at FWS 12.8%, of participants had speeds less than 1.2 m/s. Poorer cognitive stage was associated with slower preferred speed (β −0.08, 95% CI −0.10, −0.06), FWS (β −0.13, 95% CI −0.16, −0.10) and also with smaller WSR (m/s) (β −0.05, 95% CI −0.07, −0.03), but not WSR (%) (β −1.73, 95% CI −4.38, 0.93). In older people, worse stages of cognitive impairment were associated with poorer ability to increase speed and walk quickly. Such limitations may result in reduced ability to access the community.

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Three-dimensional computed tomographic volumetry precisely predicts the postoperative pulmonary function

Abstract

Purpose

It is important to accurately predict the patient's postoperative pulmonary function. The aim of this study was to compare the accuracy of predictions of the postoperative residual pulmonary function obtained with three-dimensional computed tomographic (3D-CT) volumetry with that of predictions obtained with the conventional segment-counting method.

Methods

Fifty-three patients scheduled to undergo lung cancer resection, pulmonary function tests, and computed tomography were enrolled in this study. The postoperative residual pulmonary function was predicted based on the segment-counting and 3D-CT volumetry methods. The predicted postoperative values were compared with the results of postoperative pulmonary function tests.

Results

Regarding the linear correlation coefficients between the predicted postoperative values and the measured values, those obtained using the 3D-CT volumetry method tended to be higher than those acquired using the segment-counting method. In addition, the variations between the predicted and measured values were smaller with the 3D-CT volumetry method than with the segment-counting method. These results were more obvious in COPD patients than in non-COPD patients.

Conclusions

Our findings suggested that the 3D-CT volumetry was able to predict the residual pulmonary function more accurately than the segment-counting method, especially in patients with COPD. This method might lead to the selection of appropriate candidates for surgery among patients with a marginal pulmonary function.

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Bone marrow myeloid cells in regulation of multiple myeloma progression

Abstract

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Solute carrier organic anion transporter family member 4A1 (SLCO4A1) as a prognosis marker of colorectal cancer

Abstract

Purpose

Solute carrier organic anion transporter family member 4A1 (SLCO4A1) is involved in the transport of various compounds, including sugars, bile salts, organic acids, metal ions, amine compounds, and estrogen. SLCO4A1 is highly expressed in several cancers and a gender bias has been observed in colorectal cancer (CRC). We investigated SLCO4A1 expression, its prognostic value in patients with CRC, and its role in CRC cell proliferation and metastasis.

Methods

SLCO4A1 expression was assessed by immunohistochemistry (IHC) on specimens from 84 patients with CRC. The association of SLCO4A1 expression with clinicopathological features was examined. To confirm the biological role of SLCO4A1 in CRC, four CRC cell lines expressing SLCO4A1 were used and SLCO4A1 expression was knocked down by siRNA. Cell proliferation, MTT, migration, invasion, and semisolid agar colony formation assays were performed.

Results

SLCO4A1 was overexpressed in 32% of the CRC samples. SLCO4A1 overexpression and pathologic T stage were independent prognostic factors of decreased survival (P = 0.021). Kaplan–Meier analysis indicated a decreased cumulative survival for patients highly expressing SLCO4A1 compared to patients showing low SLCO4A1 expression (Log-rank test, P = 0.025). In cell lines, SLCO4A1 knockdown resulted in a significant decrease of viability, invasion, and migration when compared to control cells. Semisolid colony formation assay indicated that SLCO4A1-knocked down cells presented poor carcinogenic abilities compared to control cells.

Conclusions

SLCO4A1 may be a valuable marker of poor prognostic for CRC. Furthermore, SLCO4A1 plays an important role in CRC cell proliferation, migration, invasion, and carcinogenesis.

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Effect of magnolol on cerebral injury and blood brain barrier dysfunction induced by ischemia-reperfusion in vivo and in vitro

Abstract

Magnolol, a neolignan compound isolated from traditional Chinese medicine Magnolia officinalis, has a potentially therapeutic influence on ischemic stroke. Previous studies have demonstrated that cerebral ischemia-reperfusion (I-R) and blood–brain barrier (BBB) are involved in the pathogeneses of stroke. Therefore, in vivo and in vitro studies were designed to investigate the effects of magnolol on I-R-induced neural injury and BBB dysfunction. In cerebral I-R model of mice, cerebral infarct volumes, brain water content, and the exudation of Evans blue were significantly reduced by intravenous injection with magnolol at the doses of 1.4, 7.0, and 35.0 μg/kg. When primary cultured microglial cells were treated with 1 μg/ml lipopolysaccharide (LPS) plus increasing concentrations of magnolol, ranging from 0.01 to 10 μmol/L, magnolol could statistically inhibit LPS-induced NO release, TNF-α secretion, and expression of p65 subunit of NF-κB in the nucleus of microglial cells. In the media of brain microvascular endothelial cells (BMECs), oxygen and glucose deprivation-reperfusion (OGD-R) could remarkably lead to the elevation of TNF-α and IL-1β levels, while magnolol evidently reversed these effects. In BBB model in vitro, magnolol dose- and time-dependently declined BBB hyperpermeability induced by oxygen and glucose deprivation (OGD), OGD-R, and ephrin-A1 treatment. More importantly, magnolol could obviously inhibit phosphorylation of EphA2 (p-EphA2) not only in ephrin-A1-treated BMECs but also in cerebral I-R model of mice. In contrast to p-EphA2, magnolol significantly increased ZO-1 and occludin levels in BMECs subjected to OGD. Taken together, magnolol can protect neural damage from cerebral ischemia- and OGD-reperfusion, which may be associated with suppressing cerebral inflammation and improving BBB function.

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Plasminogen activator inhibitor links obesity and thrombotic cerebrovascular diseases: The roles of PAI-1 and obesity on stroke

Abstract

One of the global socioeconomic phenomena occurred during the last decades is the increased prevalence of obesity, with direct consequence on the risk of developing thrombotic disorders. As the physiological inhibitor of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1) is well known for its role in fibrinolysis. More and more evidences have shown that PAI-1 involves in physiopathologic mechanisms of many diseases and metabolic disorder. Increased serum level of PAI-1 has been observed in obesity and it also contributes to the development of adipose tissue and then has effects on obesity. Meantime, obesity affects also the PAI-1 levels. These evidences indicate the complicated interaction between PAI-1 and obesity. Many clinic studies have confirmed that obesity relates to the stroke outcome although there are many contradictory results. Simultaneously, correlation is found between plasma PAI-1 and thrombotic cerebrovascular diseases. This article reviews contemporary knowledge regarding the complex interplay of obesity, PAI-1 and stroke.

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Tracking dendritic cell migration into lymph nodes by using a novel PET probe 18 F-tetrafluoroborate for sodium/iodide symporter

Abstract

Background

Recently, ¹⁸F-tetrafluoroborate (TFB) was used as a substrate for the human sodium/iodide symporter (hNIS) reporter gene. This study evaluated the feasibility of performing molecular-genetic imaging by using the new radiotracer (¹⁸F-TFB) for the hNIS gene, to track dendritic cell (DC) migration in live mice. A murine dendritic cell line (DC2.4) co-expressing the hNIS and effluc genes (DC/NF) was established. To confirm the functional cellular expression of both effluc and NIS in the inoculated DC/NF cells by bio-medical imaging, combined bioluminescence imaging (BLI) and ¹⁸F-TFB positron emission tomography/computed tomography (PET/CT) imaging was performed after intramuscular injection with parental DCs and DC/NF cells. For DC-tracking, parental DCs or DC/NF cells were injected in the left or right mouse footpad, respectively, and ¹⁸F-TFB PET/CT and BLI were performed to monitor these cells in live mice.

Results

In vivo PET/CT and BLI showed a clear signal in DC/NF injection sites but not in parental DC injection sites. The signal intensity in DC/NF cells was correlated with time. In vivo ¹⁸F-TFB PET/CT imaging showed higher radiotracer activity in the draining popliteal lymph nodes (DPLNs) in DC/NF injection sites than those in DC injection sites on day 2. BLI also showed DC/NF cell migration to the DPLNs on day 2 after the injection.

Conclusions

Migration of DCs to the lymph nodes was successfully monitored using ¹⁸F-TFB PET/CT imaging of the NIS gene and optical imaging of the effluc gene in live mice. These data support the feasibility of using ¹⁸F-TFB as a substrate for hNIS reporter gene imaging to track the migration of DCs to the lymph nodes in live animals. The use of ¹⁸F-TFB may facilitate enhanced PET imaging of the hNIS reporter gene in small animals and humans in future studies.

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Severe Murine Typhus Presenting with Acalculous Cholecystitis: A Case Report and Literature Review

A 54-year-old otherwise healthy male, who was being evaluated for prolonged fever, developed clinical and ultrasonographic signs compatible with acute acalculous cholecystitis. Diagnosis of murine typhus was confirmed by serology and the patient was treated with doxycycline. He improved rapidly and all clinical and laboratory abnormalities returned to normal. The present case dictates that knowledge of the local epidemiology and keeping a high index of clinical suspicion can help recognize uncommon manifestations of murine typhus, in order to treat appropriately and avoid unnecessary investigations and interventions.

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Down-regulation of Talin1 promotes hepatocellular carcinoma progression via activation of the ERK1/2 pathway

Abstract

Talin1 is an adaptor protein that conjugates integrins to the cytoskeleton and regulates integrins and focal adhesion signaling. Several studies have found that Talin1 is over-expressed in several tumor types and promotes tumor progression. However, the explicit role of Talin1 in hepatocellular carcinoma (HCC) progression is still unclear and its functional mechanism remains largely unknown. In this study, we showed a trend of gradually decreasing expression of Talin1 from normal liver tissues to hepatocirrhosis, liver hyperplasia, the corresponding adjacent non-tumor, primary HCC and eventually metastatic foci, indicating that Talin1 maybe correlate with HCC initiation to progression. Meanwhile, Talin1 was significantly down-regulated in HCC tissues compared with adjacent non-tumor tissues and low Talin1 expression was associated with HCC progression and poor prognosis. Furthermore, Talin1 knockdown induced epithelial-NDASH-mesenchymal transition (EMT) and promoted migration and invasion in SK-Hep-1 cells and HepG2 cells. Mechanistically, we found that the ERK pathway was responsible for these promoting effects of Talin1 knockdown in HCC cells. The promoting effects of Talin1 knockdown on EMT, migration, and invasion were reversed by U0126, a specific ERK1/2 inhibitor. Taken together, our results suggested that Talin1 might serve as a tumor suppressor in HCC and a potential prognostic biomarker for HCC patients.

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Herpes Simplex Proctitis Mimicking Inflammatory Bowel Disease in a Teenaged Male

We report the case of a 17-year-old male who was initially assessed for pain with defecation, bloody rectal discharge, and diarrhea, consistent with proctitis. Though proctitis is most commonly due to inflammatory bowel disease (IBD), infectious etiologies must also be considered, including sexually transmitted causes of infectious proctitis. In discussion of his sexual history, he identified as homosexual and acknowledged engaging in receptive anal intercourse. Rectal biopsies obtained via colonoscopy were culture-positive for herpes simplex virus (HSV), leading to a diagnosis of HSV proctitis and treatment with an appropriate antiviral medication. HSV proctitis is more common in individuals with high-risk sexual practices, including men who have sex with men. While this may be an uncommon diagnosis for pediatricians to make in practice, a high clinical index of suspicion for sexually transmitted infectious proctitis in those with risk factors must be maintained in order to facilitate appropriate testing, treatment, and counseling of affected individuals.

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