Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

Τρίτη 1 Ιανουαρίου 2019

Evaluation of diagnostic accuracy: multidetector CT image noise correction improves specificity of a Gaussian model-based algorithm used for characterization of incidental adrenal nodules

Abstract

Objectives

To investigate whether the histogram analysis method of characterizing adrenal nodules as adenomas is affected by increased noise with modern CT technique, and if an extension that allows for noise correction will improve diagnostic performance.

Materials and methods

This is a HIPAA-compliant, IRB-approved retrospective study performed on 58 total patients. The first group of 29 patients had 33 adrenal lesions that were pathology-proven non-adenomas. The second group had 29 patients with 33 pathology-proven or presumed adenomas based on established imaging criteria. The nodules were evaluated using the histogram method, mean attenuation method, and a Gaussian model-based algorithm without (uncorrected Gaussian algorithm) and with correction (corrected Gaussian algorithm) for image noise. Sensitivity, specificity, and accuracy for identifying adenoma were derived.

Results

There were no significant differences in identifying adenoma from non-adenoma when using the histogram analysis method and the uncorrected Gaussian algorithm, both of which had low specificities of 42.4% and 47.0%, respectively (p = 0.30). Adding noise correction to the Gaussian algorithm resulted in a statistically significant increase in specificity relative to the histogram method (86.4% vs. 42.4%, p < 0.001). The corrected Gaussian algorithm improved sensitivity compared to the mean attenuation method (71.2% vs. 54.5%, p < 0.001), but had lower specificity (86.4% vs. 100%, p < 0.001), and similar overall accuracy (78.8% vs. 77.3%, p = 0.74).

Conclusion

With modern low-dose CT technique, the specificity scores of the histogram method for discrimination of adrenal adenomas and non-adenomas are lower than with previous higher dose scans. The specificity and accuracy of a histogram-equivalent method can be increased mathematically through image noise correction, and the corrected Gaussian algorithm has improved sensitivity to the mean attenuation with similar accuracy albeit with lower specificity. Although this suggests limited utility for histogram analysis in adrenal nodule characterization, our study demonstrates the potential mathematical application for other noise-dependent CT characterization methods.

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Letter to the Editor regarding the journal article published in Abdominal Radiology “Reuse and reduce: abdominal CT, lumbar spine MRI, and a potential 1.2 to 3.4 billion dollars in cost savings”

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Transmission of the malaria parasite requires ferlin for gamete egress from the red blood cell.

Transmission of the malaria parasite requires ferlin for gamete egress from the red blood cell.

Cell Microbiol. 2018 Dec 29;:e12999

Authors: Obrova K, Cyrklaff M, Frank R, Mair GR, Mueller AK

Abstract
Ferlins mediate calcium-dependent vesicular fusion. Although conserved throughout eukaryotic evolution, their function in unicellular organisms including apicomplexan parasites is largely unknown. Here, we define a crucial role for a ferlin-like protein (FLP) in host-to-vector transmission of the rodent malaria parasite Plasmodium berghei. Infection of the mosquito vectors requires the formation of free gametes and their fertilization in the mosquito midgut. Mature gametes will only emerge upon secretion of factors that stimulate the disruption of the red blood cell membrane and the parasitophorous vacuole membrane. Genetic depletion of FLP in sexual stages leads to a complete life cycle arrest in the mosquito. Although mature gametes form normally, mutants lacking FLP remain trapped in the red blood cell. The egress defect is rescued by detergent-mediated membrane lysis. In agreement with ferlin vesicular localization, HA-tagged FLP labels intracellular speckles, which relocalize to the cell periphery during gamete maturation. Our data define FLP as a novel critical factor for Plasmodium fertilization and transmission and suggest an evolutionarily conserved example of ferlin-mediated exocytosis.

PMID: 30597708 [PubMed - as supplied by publisher]

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Analysis of survival outcomes based on molecular subtypes in breast cancer brain metastases: A single institutional cohort.

Analysis of survival outcomes based on molecular subtypes in breast cancer brain metastases: A single institutional cohort.

Breast J. 2018 Nov;24(6):920-926

Authors: Jeon W, Jang BS, Jeon SH, Kim JH, Kim YJ, Kim SH, Kim CY, Han JH, Kim IA

Abstract
PURPOSE: To evaluate the survival outcomes based on molecular subtypes of breast cancer in patients with brain metastasis.
MATERIALS AND METHODS: We retrospectively reviewed 106 breast cancer patients treated for brain metastases, from January 2005 to May 2016. Patients were divided into four groups based on the tumor molecular subtype: luminal A (Estrogen Receptor [ER]/Progesterone Receptor [PR] positive, human epithelial growth factor receptor-2 [HER2] negative), luminal B (ER/PR positive, HER2 Positive), HER2 (HER2 positive and ER/PR negative), and Triple negative (TNBC).
RESULTS: The median follow-up time for surviving patients was 22 months (range: 11.2-51.1 months). The median survival of all patients was 14 months, with a 1-year overall survival (OS) rate of 57.5% and a 2-year OS rate of 32.1%. Thirty patients (28.3%) had a solitary brain metastasis while 62 (58.5%) patients had multiple metastases. A significant difference was observed in the survival rates of the two groups. Based on the Karnofsky performance score, the performance status of the patients at the time of brain metastasis was also found to affect survival. Patients with different molecular subtypes had different survival rates; the luminal A group showed the highest median survival (luminal A: 23.1, luminal B: 15.0, HER2: 12.5 and TNBC: 6.4 months, respectively), which was statistically significant.
CONCLUSION: In breast cancer patients with brain metastasis, survival rates were different based on the molecular subtype of the tumor, despite various local and systemic treatments. Appropriate and tailored treatment approaches should, therefore, be considered for the different molecular subtypes.

PMID: 30596408 [PubMed - in process]

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ASCO 2018: highlights in HER2-positive metastatic breast cancer.

ASCO 2018: highlights in HER2-positive metastatic breast cancer.

Memo. 2018;11(4):280-283

Authors: Bartsch R, Bergen E

Abstract
At the 2018 ASCO Annual Meeting, data from several interesting studies in HER2-positive metastatic breast cancer were presented. While not immediately practice changing, these trials indicate the future directions of drug development in this field. Early phase studies with novel antibody-drug conjugates (ADCs) such as trastuzumab-deruxtecan and trastuzumab-duocarmazine suggest relevant clinical activity of these drugs in pretreated patients; in addition, these ADCs may offer activity in low HER2-expressing tumours as well. ZW25, a bispecific HER2-directed antibody targeting the extracellular domains 2 and 4, showed excellent tolerability and considerable single-agent activity. A combination of T‑DM1 with the tyrosine-kinase inhibitor neratinib yielded high response rates, while a study of trastuzumab plus durvalumab reported disappointing results. Although formally negative, overall survival data from the PHEREXA trial suggest clinical activity of dual HER2-inhibition with trastuzumab and pertuzumab in patients with prior trastuzumab treatment for advanced disease. A combined analysis of two tucatinib studies showed that systemic therapy is active when continued in case of isolated central nervous system progression and stable extracranial disease after local therapy of brain metastases; finally, a small prospective observation in asymptomatic patients with reduced left ventricular ejection fraction suggests that anti-HER2 treatment may be reasonably safe in this population.

PMID: 30595754 [PubMed]

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21-Gene Recurrence Score Testing in HER2-positive Patients.

21-Gene Recurrence Score Testing in HER2-positive Patients.

Clin Breast Cancer. 2018 Nov 27;:

Authors: Altman AM, Marmor S, Tuttle TM, Hui JYC

Abstract
INTRODUCTION: The 21-gene recurrence score (RS) has been extensively studied and validated in patients with estrogen receptor-positive (ER+), human epidermal growth factor 2 (HER2)-negative breast cancer; however, RS testing is not routinely performed in patients with HER2-positive (HER2+) disease. We sought to determine patterns of RS testing, to characterize RS distributions, and to determine the impact of RS results on clinical decision-making for patients with ER+, HER2+ breast cancer.
MATERIALS AND METHODS: Using the Surveillance and Epidemiology End Results program database, we identified women with ER+, HER2+ breast cancer. We stratified patients using TAILORx RS cutoffs and evaluated treatment characteristics across patients. Multivariable logistic regression was performed to determine factors associated with RS testing and receipt of a high-risk RS.
RESULTS: Overall, 5% of patients with ER+, HER2+, early stage breast cancer underwent RS testing. The distribution of RS testing by TAILORx cutoffs were: high-risk, 17%; intermediate-risk, 49%; and low-risk, 34%. Chemotherapy utilization among those not tested was 66%. Among those tested, utilization was significantly associated with RS results: 67% of high-risk, 30% of intermediate-risk, and 19% of low-risk patients received chemotherapy. Progesterone receptor-negative status, larger tumor size, and high tumor grade were significantly associated with high-risk RS.
CONCLUSIONS: RS testing is used sparingly among patients with HER2+ early-stage breast cancer; however, test results appear to impact clinician's decision-making on chemotherapy use.

PMID: 30595493 [PubMed - as supplied by publisher]

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Oligomeric proanthocyanidins (OPCs) from grape seed extract suppress the activity of ABC transporters in overcoming chemoresistance in colorectal cancer cells.

Oligomeric proanthocyanidins (OPCs) from grape seed extract suppress the activity of ABC transporters in overcoming chemoresistance in colorectal cancer cells.

Carcinogenesis. 2018 Dec 29;:

Authors: Ravindranathan P, Pasham D, Goel A

Abstract
Multidrug resistance is a major hindrance in managing cancer. By performing a series of experiments in chemoresistant colorectal cancer cell lines, we demonstrate that oligomeric proanthocyanidins (OPCs) from grape seed extracts can sensitize both acquired (HCT116-FOr cells) and innately chemoresistant (H716 cells) cancer cells to chemotherapeutic drugs, 5-fluorouracil (5FU) and oxaliplatin, by inhibiting ABC transporter proteins. When combined with chemotherapeutic drugs, OPCs significantly inhibited growth of the chemoresistant cells (p<0.05 to p<0.001), and decreased the expression of several key ABC transporters. Moreover, the activity of the ABC transporters was also significantly decreased by OPCs in the cell lines (p<0.05). We further confirmed that co-treatment with OPCs sensitized the chemoresistant cells to 5FU and oxaliplatin, as observed by improvement in cell cycle arrest, double strand breaks and p53 accumulation in these cells. Additionally, we confirmed that co-administration of OPCs with chemotherapeutic drugs significantly decreased chemoresistant xenograft tumor growth in mice (p<0.05). Together, our study illuminates the downregulation of multiple ABC transporters as a mechanism by which OPCs overcome chemoresistance in cancer cells, and may serve as adjunctive treatments in patients with refractory colorectal cancer.

PMID: 30596962 [PubMed - as supplied by publisher]

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Ivermectin inhibits the growth of glioma cells by inducing cell cycle arrest and apoptosis in vitro and in vivo.

Ivermectin inhibits the growth of glioma cells by inducing cell cycle arrest and apoptosis in vitro and in vivo.

J Cell Biochem. 2019 Jan;120(1):622-633

Authors: Song D, Liang H, Qu B, Li Y, Liu J, Zhang Y, Li L, Hu L, Zhang X, Gao A

Abstract
Glioma, the most predominant primary malignant brain tumor, remains uncured due to the absence of effective treatments. Hence, it is imperative to develop successful therapeutic agents. This study aimed to explore the antitumor effects and mechanisms of ivermectin (IVM) in glioma cells in vitro and in vivo. The effects of IVM on cell viability, cell cycle arrest, apoptosis rate, and morphological characteristics were determined respectively by MTT assay/colony formation assay, flow cytometry, and transmission electron microscope. In addition, the expression levels of cycle-related and apoptosis-associated proteins were individually examined by Western blot analysis. Moreover, cell proliferation and apoptosis analyses were carried out by TUNEL, Ki-67, cleaved caspase-3, and cleaved caspase-9 immunostaining assay. Our results demonstrated that IVM has a potential dosage-dependent inhibition effect on the apoptosis rate of glioma cells. Meanwhile, the results also revealed that IVM induced apoptosis by increasing caspase-3 and caspase-9 activity, upregulating the expressions of p53 and Bax, downregulating Bcl-2, activating cleaved caspase-3 and cleaved caspase-9, and blocking cell cycle in G0/G1 phase by downregulating levels of CDK2, CDK4, CDK6, cyclin D1, and cyclin E. These findings suggest that IVM has an inhibition effect on the proliferation of glioma cells by triggering cell cycle arrest and inducing cell apoptosis in vitro and in vivo, and probably represents promising agent for treating glioma.

PMID: 30596403 [PubMed - in process]

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Cytotoxic effect of Rosa canina extract on human colon cancer cells through repression of telomerase expression.

Cytotoxic effect of Rosa canina extract on human colon cancer cells through repression of telomerase expression.

J Pharm Anal. 2018 Dec;8(6):394-399

Authors: Turan I, Demir S, Kilinc K, Yaman SO, Misir S, Kara H, Genc B, Mentese A, Aliyazicioglu Y, Deger O

Abstract
Rosa canina is a member of the genus Rosa that has long been used for medical objectives. Several studies have reported cytotoxic effects of different Rosa species, but there has been only limited investigation of the cytotoxic effect of R. canina. The purpose of the current study was to examine the potential effect of R. canina extract on cell viability, the cell cycle, apoptosis, and the expression of telomerase in human colon cancer (WiDr) cells. The cytotoxic effect of the extract was determined using MTT assay. The mechanism involved in the cytotoxic effect of the extract was then evaluated in terms of apoptosis and the cell cycle using flow cytometry. Mitochondrial membrane potential (MMP) was investigated using the fluorometric method, and expression levels of telomerase were studied using RT-PCR. R. canina extract exhibited a selective cytotoxic effect on WiDr cells compared with normal colon cells. The extract induced cell cycle arrest at the S phase and apoptosis via reduced MMP in WiDr cells. R. canina extract significantly repressed telomerase expressions at treatment times of 48 and 72 h in WiDr cells. Our results suggest that R. canina may have considerable potential for development as a novel natural product-based anticancer agent.

PMID: 30595946 [PubMed]

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Retracted: Anticancer Effects of Gingerol in Retinoblastoma Cancer Cells (RB355 Cell Line) Are Mediated via Apoptosis Induction, Cell Cycle Arrest and Upregulation of PI3K/Akt Signaling Pathway.

Retracted: Anticancer Effects of Gingerol in Retinoblastoma Cancer Cells (RB355 Cell Line) Are Mediated via Apoptosis Induction, Cell Cycle Arrest and Upregulation of PI3K/Akt Signaling Pathway.

Med Sci Monit. 2018 Dec 29;24:9465

Authors: Meng B, Ii H, Qu W, Yuan H

Abstract
<strong>ABSTRACT</strong> The article is withdrawn by the authors request.

PMID: 30595604 [PubMed - in process]

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Immunotherapy for Urothelial Carcinoma: Current Evidence and Future Directions.

Immunotherapy for Urothelial Carcinoma: Current Evidence and Future Directions.

Curr Urol Rep. 2018 Nov 07;19(12):109

Authors: Tripathi A, Plimack ER

Abstract
PURPOSE OF REVIEW: Until recently, effective treatment options for patients with advanced urothelial carcinoma were limited to platinum-based chemotherapy. In the post-platinum setting and for patients ineligible for cisplatin, minimally effective second-line chemotherapy was used and outcomes were poor. The approval of immune checkpoint inhibitors has significantly changed the treatment landscape of urothelial carcinoma. Here, we review current data demonstrating their efficacy in advanced disease and ongoing trials investigating novel combination strategies.
RECENT FINDINGS: Since May 2016, five agents targeting the programmed cell death 1 (PD-1) pathways have been approved for use after progression on platinum-based chemotherapy. Further, atezolizumab and pembrolizumab are approved for use in cisplatin-ineligible patients with high programmed death-ligand 1 (PD-L1) expression. Preliminary studies have shown their safety and efficacy as neoadjuvant therapy in muscle-invasive bladder cancer. Several ongoing trials are investigating these agents in combination with radiation therapy, platinum-based chemotherapy, other immune checkpoint inhibitors, and targeted agents. Immune checkpoint inhibitors have demonstrated durable efficacy in patients with advanced urothelial carcinoma as first- and second-line therapy. Ongoing studies will help define the optimal sequence, combination strategies, and predictive biomarkers of response.

PMID: 30406502 [PubMed - indexed for MEDLINE]

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Defective transcription elongation in a subset of cancers confers immunotherapy resistance.

Defective transcription elongation in a subset of cancers confers immunotherapy resistance.

Nat Commun. 2018 10 23;9(1):4410

Authors: Modur V, Singh N, Mohanty V, Chung E, Muhammad B, Choi K, Chen X, Chetal K, Ratner N, Salomonis N, Weirauch MT, Waltz S, Huang G, Privette-Vinnedge L, Park JS, Janssen EM, Komurov K

Abstract
The nature and role of global transcriptional deregulations in cancers are not fully understood. We report that a large proportion of cancers have widespread defects in mRNA transcription elongation (TE). Cancers with TE defects (TEdeff) display spurious transcription and defective mRNA processing of genes characterized by long genomic length, poised promoters and inducible expression. Signaling pathways regulated by such genes, such as pro-inflammatory response pathways, are consistently suppressed in TEdeff tumors. Remarkably, TEdeff correlates with the poor response and outcome in immunotherapy, but not chemo- or targeted therapy, -treated renal cell carcinoma and metastatic melanoma patients. Forced pharmacologic or genetic induction of TEdeff in tumor cells impairs pro-inflammatory response signaling, and imposes resistance to the innate and adaptive anti-tumor immune responses and checkpoint inhibitor therapy in vivo. Therefore, defective TE is a previously unknown mechanism of tumor immune resistance, and should be assessed in cancer patients undergoing immunotherapy.

PMID: 30353012 [PubMed - indexed for MEDLINE]

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CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response.

CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response.

Nat Commun. 2018 10 15;9(1):4275

Authors: Szlachta K, Kuscu C, Tufan T, Adair SJ, Shang S, Michaels AD, Mullen MG, Fischer NL, Yang J, Liu L, Trivedi P, Stelow EB, Stukenberg PT, Parsons JT, Bauer TW, Adli M

Abstract
Predicting the response and identifying additional targets that will improve the efficacy of chemotherapy is a major goal in cancer research. Through large-scale in vivo and in vitro CRISPR knockout screens in pancreatic ductal adenocarcinoma cells, we identified genes whose genetic deletion or pharmacologic inhibition synergistically increase the cytotoxicity of MEK signaling inhibitors. Furthermore, we show that CRISPR viability scores combined with basal gene expression levels could model global cellular responses to the drug treatment. We develop drug response evaluation by in vivo CRISPR screening (DREBIC) method and validated its efficacy using large-scale experimental data from independent experiments. Comparative analyses demonstrate that DREBIC predicts drug response in cancer cells from a wide range of tissues with high accuracy and identifies therapeutic vulnerabilities of cancer-causing mutations to MEK inhibitors in various cancer types.

PMID: 30323222 [PubMed - indexed for MEDLINE]

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Nuclear lamina dysfunction triggers a germline stem cell checkpoint.

Nuclear lamina dysfunction triggers a germline stem cell checkpoint.

Nat Commun. 2018 09 27;9(1):3960

Authors: Barton LJ, Duan T, Ke W, Luttinger A, Lovander KE, Soshnev AA, Geyer PK

Abstract
LEM domain (LEM-D) proteins are conserved components of the nuclear lamina (NL) that contribute to stem cell maintenance through poorly understood mechanisms. The Drosophila emerin homolog Otefin (Ote) is required for maintenance of germline stem cells (GSCs) and gametogenesis. Here, we show that ote mutants carry germ cell-specific changes in nuclear architecture that are linked to GSC loss. Strikingly, we found that both GSC death and gametogenesis are rescued by inactivation of the DNA damage response (DDR) kinases, ATR and Chk2. Whereas the germline checkpoint draws from components of the DDR pathway, genetic and cytological features of the GSC checkpoint differ from the canonical pathway. Instead, structural deformation of the NL correlates with checkpoint activation. Despite remarkably normal oogenesis, rescued oocytes do not support embryogenesis. Taken together, these data suggest that NL dysfunction caused by Otefin loss triggers a GSC-specific checkpoint that contributes to maintenance of gamete quality.

PMID: 30262885 [PubMed - indexed for MEDLINE]

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Radio-sensitizing effects of VE-821 and beyond: Distinct phosphoproteomic and metabolomic changes after ATR inhibition in irradiated MOLT-4 cells.

Radio-sensitizing effects of VE-821 and beyond: Distinct phosphoproteomic and metabolomic changes after ATR inhibition in irradiated MOLT-4 cells.

PLoS One. 2018;13(7):e0199349

Authors: Šalovská B, Janečková H, Fabrik I, Karlíková R, Čecháková L, Ondrej M, Link M, Friedecký D, Tichý A

Abstract
Current anti-cancer strategy takes advantage of tumour specific abnormalities in DNA damage response to radio- or chemo-therapy. Inhibition of the ATR/Chk1 pathway has been shown to be synthetically lethal in cells with high levels of oncogene-induced replication stress and in p53- or ATM- deficient cells. In the presented study, we aimed to elucidate molecular mechanisms underlying radiosensitization of T-lymphocyte leukemic MOLT-4 cells by VE-821, a higly potent and specific inhibitor of ATR. We combined multiple approaches: cell biology techniques to reveal the inhibitor-induced phenotypes, and quantitative proteomics, phosphoproteomics, and metabolomics to comprehensively describe drug-induced changes in irradiated cells. VE-821 radiosensitized MOLT-4 cells, and furthermore 10 μM VE-821 significantly affected proliferation of sham-irradiated MOLT-4 cells. We detected 623 differentially regulated phosphorylation sites. We revealed changes not only in DDR-related pathways and kinases, but also in pathways and kinases involved in maintaining cellular metabolism. Notably, we found downregulation of mTOR, the main regulator of cellular metabolism, which was most likely caused by an off-target effect of the inhibitor, and we propose that mTOR inhibition could be one of the factors contributing to the phenotype observed after treating MOLT-4 cells with 10 μM VE-821. In the metabolomic analysis, 206 intermediary metabolites were detected. The data indicated that VE-821 potentiated metabolic disruption induced by irradiation and affected the response to irradiation-induced oxidative stress. Upon irradiation, recovery of damaged deoxynucleotides might be affected by VE-821, hampering DNA repair by their deficiency. Taken together, this is the first study describing a complex scenario of cellular events that might be ATR-dependent or triggered by ATR inhibition in irradiated MOLT-4 cells. Data are available via ProteomeXchange with identifier PXD008925.

PMID: 30001349 [PubMed - indexed for MEDLINE]

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Inhibitors of dihydrofolate reductase as antitumor agents: design, synthesis and biological evaluation of a series of novel nonclassical 6-substituted pyrido[3,2-d]pyrimidines with a three- to five-carbon bridge.

Inhibitors of dihydrofolate reductase as antitumor agents: design, synthesis and biological evaluation of a series of novel nonclassical 6-substituted pyrido[3,2-d]pyrimidines with a three- to five-carbon bridge.

Bioorg Med Chem. 2018 05 15;26(9):2674-2685

Authors: Li H, Fang F, Liu Y, Xue L, Wang M, Guo Y, Wang X, Tian C, Liu J, Zhang Z

Abstract
Bridge homologation of the previously reported nonclassical two-carbon-bridged antifolate, 2,4-diamino-6-phenethylpyrido[3,2-d]pyrimidine (wm-5a), afforded the three-, four- and five-carbon-bridged antifolate analogues 3.1-3.5, 4.1-4.2 and 5.1-5.5. The target compounds, with substituents at various positions on the carbon bridges, were efficiently synthesized by aldol condensation or Wittig reaction and followed by reduction. Elongation of the two-carbon bridge to three-, four- or five-carbon bridges, and also saturation of the carbon bridges, provided compounds with good inhibitory activity against recombinant human DHFR (rhDHFR). Analogue 3.5, which has a three-carbon bridge, inhibited the proliferation of HL-60 and HCT116 cells to a greater extent than the other analogues. Compound 3.5 was also the most potent inhibitor of rhDHFR (IC50 = 0.06 μM), and was approximately 38-fold more potent than the two-carbon-bridged lead compound. Docking studies revealed that both the length and flexibility of the saturated carbon bridge in 3.5 were important for high potency. Flow cytometry studies indicated that compound 3.5 arrested HL-60 cells in the S-phase and induced apoptosis. Western blot analysis of HL-60 cells treated with 3.5 showed a dose-dependent upregulation of DHFR protein levels.

PMID: 29691154 [PubMed - indexed for MEDLINE]

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Single-cell RNA sequencing reveals metallothionein heterogeneity during hESC differentiation to definitive endoderm.

Single-cell RNA sequencing reveals metallothionein heterogeneity during hESC differentiation to definitive endoderm.

Stem Cell Res. 2018 04;28:48-55

Authors: Lu J, Baccei A, Lummertz da Rocha E, Guillermier C, McManus S, Finney LA, Zhang C, Steinhauser ML, Li H, Lerou PH

Abstract
Differentiation of human pluripotent stem cells towards definitive endoderm (DE) is the critical first step for generating cells comprising organs such as the gut, liver, pancreas and lung. This in-vitro differentiation process generates a heterogeneous population with a proportion of cells failing to differentiate properly and maintaining expression of pluripotency factors such as Oct4. RNA sequencing of single cells collected at four time points during a 4-day DE differentiation identified high expression of metallothionein genes in the residual Oct4-positive cells that failed to differentiate to DE. Using X-ray fluorescence microscopy and multi-isotope mass spectrometry, we discovered that high intracellular zinc level corresponds with persistent Oct4 expression and failure to differentiate. This study improves our understanding of the cellular heterogeneity during in-vitro directed differentiation and provides a valuable resource to improve DE differentiation efficiency.

PMID: 29427839 [PubMed - indexed for MEDLINE]

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Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review.

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Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review.

Ann Intern Med. 2018 01 16;168(2):121-130

Authors: Abdel-Wahab N, Shah M, Lopez-Olivo MA, Suarez-Almazor ME

Abstract
Background: Cancer immunotherapy with checkpoint inhibitors (CPIs) is associated with frequent immune-related adverse events (irAEs) and is often not recommended for patients with concomitant autoimmune disease.
Purpose: To summarize the evidence on adverse events associated with CPIs in patients with cancer and preexisting autoimmune disease.
Data Sources: MEDLINE, EMBASE, Web of Science, PubMed ePubs, and the Cochrane Central Register of Controlled Trials through September 2017 with no language restrictions.
Study Selection: Original case reports, case series, and observational studies describing patients with cancer and autoimmune disease who were receiving CPIs.
Data Extraction: 2 reviewers independently extracted data and assessed the quality of reporting.
Data Synthesis: 123 patients in 49 publications were identified; 92 (75%) had exacerbation of preexisting autoimmune disease, irAEs, or both. No differences in adverse events were observed in patients with active versus inactive disease. Patients receiving immunosuppressive therapy at initiation of CPI therapy seemed to have fewer adverse events than those not receiving treatment. Most flares and irAEs were managed with corticosteroids; 16% required other immunosuppressive therapies. Adverse events improved in more than half of patients without discontinuation of CPI therapy. Three patients died of adverse events.
Limitations: The quality and quantity of data were limited. Case reports typically describe unique manifestations and are not generalizable to the population at large. Because there were no prospective observational studies, incidence could not be determined.
Conclusion: Flares and irAEs in patients with autoimmune disease who are receiving CPIs can often be managed without discontinuing therapy, although some events may be severe and fatal. Prospective longitudinal studies are needed to establish incidence of adverse events and evaluate risk-benefit ratios and patient preferences in this population.
Primary Funding Source: National Institute of Arthritis and Musculoskeletal and Skin Diseases.

PMID: 29297009 [PubMed - indexed for MEDLINE]

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Suppression of MAPK signaling in BRAF-activated PTEN-deficient melanoma by blocking β-catenin signaling in cancer-associated fibroblasts.

Suppression of MAPK signaling in BRAF-activated PTEN-deficient melanoma by blocking β-catenin signaling in cancer-associated fibroblasts.

Pigment Cell Melanoma Res. 2018 03;31(2):297-307

Authors: Zhou L, Yang K, Dunaway S, Abdel-Malek Z, Andl T, Kadekaro AL, Zhang Y

Abstract
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment have been associated with formation of a dynamic and optimized niche for tumor cells to grow and evade cell death induced by therapeutic agents. We recently reported that ablation of β-catenin expression in stromal fibroblasts and CAFs disrupted their biological activities in in vitro studies and in an in vivo B16F10 mouse melanoma model. Here, we show that the development of a BRAF-activated PTEN-deficient mouse melanoma was significantly suppressed in vivo after blocking β-catenin signaling in CAFs. Further analysis revealed that expression of phospho-Erk1/2 and phospho-Akt was greatly reduced, effectively abrogating the activating effects and abnormal cell cycle progression induced by Braf and Pten mutations. In addition, the epithelial-mesenchymal transition (EMT)-like process was also suppressed in melanoma cells. Taken together, our data highlight an important crosstalk between CAFs and the RAF-MEK-ERK signaling cascade in BRAF-activated melanoma and may offer a new approach to abrogate host-dependent drug resistance in targeted therapy.

PMID: 29045061 [PubMed - indexed for MEDLINE]

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A Dynamical Model for Activating and Silencing the Mitotic Checkpoint.

A Dynamical Model for Activating and Silencing the Mitotic Checkpoint.

Sci Rep. 2017 06 20;7(1):3865

Authors: Henze R, Dittrich P, Ibrahim B

Abstract
The spindle assembly checkpoint (SAC) is an evolutionarily conserved mechanism, exclusively sensitive to the states of kinetochores attached to microtubules. During metaphase, the anaphase-promoting complex/cyclosome (APC/C) is inhibited by the SAC but it rapidly switches to its active form following proper attachment of the final spindle. It had been thought that APC/C activity is an all-or-nothing response, but recent findings have demonstrated that it switches steadily. In this study, we develop a detailed mathematical model that considers all 92 human kinetochores and all major proteins involved in SAC activation and silencing. We perform deterministic and spatially-stochastic simulations and find that certain spatial properties do not play significant roles. Furthermore, we show that our model is consistent with in-vitro mutation experiments of crucial proteins as well as the recently-suggested rheostat switch behavior, measured by Securin or CyclinB concentration. Considering an autocatalytic feedback loop leads to an all-or-nothing toggle switch in the underlying core components, while the output signal of the SAC still behaves like a rheostat switch. The results of this study support the hypothesis that the SAC signal varies with increasing number of attached kinetochores, even though it might still contain toggle switches in some of its components.

PMID: 28634351 [PubMed - indexed for MEDLINE]

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Genome-Wide Overexpression Screen Identifies Genes Able to Bypass p16-Mediated Senescence in Melanoma.

Publication date: February 2019

Source: Neoplasia, Volume 21, Issue 2

Author(s): J.D. Jones, B.P. Sinder, D. Paige, F.N. Soki, A.J. Koh, S. Thiele, Y. Shiozawa, L.C. Hofbauer, S. Daignault, H. Roca, L.K. McCauley

Abstract

Macrophages play a dual role in regulating tumor progression. They can either reduce tumor growth by secreting antitumorigenic factors or promote tumor progression by secreting a variety of soluble factors. The purpose of this study was to define the monocyte/macrophage population prevalent in skeletal tumors, explore a mechanism employed in supporting prostate cancer (PCa) skeletal metastasis, and examine a novel therapeutic target. Phagocytic CD68+ cells were found to correlate with Gleason score in human PCa samples, and M2-like macrophages (F4/80⁺CD206⁺) were identified in PCa bone resident tumors in mice. Induced M2-like macrophages in vitro were more proficient at phagocytosis (efferocytosis) of apoptotic tumor cells than M1-like macrophages. Moreover, soluble factors released from efferocytic versus nonefferocytic macrophages increased PC-3 prostate cancer cell numbers in vitro. Trabectedin exposure reduced M2-like (F4/80+CD206+) macrophages in vivo. Trabectedin administration after PC-3 cell intracardiac inoculation reduced skeletal metastatic tumor growth. Preventative pretreatment with trabectedin 7 days prior to PC-3 cell injection resulted in reduced M2-like macrophages in the marrow and reduced skeletal tumor size. Together, these findings suggest that M2-like monocytes and macrophages promote PCa skeletal metastasis and that trabectedin represents a candidate therapeutic target.

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An Intratumor Pharmacokinetic/Pharmacodynamic Model for the Hypoxia-Activated Prodrug Evofosfamide (TH-302): Monotherapy Activity is Not Dependent on a Bystander Effect

Publication date: February 2019

Source: Neoplasia, Volume 21, Issue 2

Author(s): Cho Rong Hong, William R. Wilson, Kevin O. Hicks

Abstract

Tumor hypoxia contributes to resistance to anticancer therapies. Hypoxia-activated prodrugs (HAPs) selectively target hypoxic cells and their activity can extend to well-oxygenated areas of tumors via diffusion of active metabolites. This type of bystander effect has been suggested to be responsible for the single agent activity of the clinical-stage HAP evofosfamide (TH-302) but direct evidence is lacking. To dissect the contribution of bystander effects to TH-302 activity, we implemented a Green's function pharmacokinetic (PK) model to simulate the spatial distribution of O₂, TH-302 and its cytotoxic metabolites, bromo-isophosphoramide mustard (Br-IPM) and its dichloro derivative isophosphoramide mustard (IPM), in two digitized tumor microvascular networks. The model was parameterized from literature and experimentally, including measurement of diffusion coefficients of TH-302 and its metabolites in multicellular layer cultures. The latter studies demonstrate that Br-IPM and IPM cannot diffuse significantly from the cells in which they are generated, although evidence was obtained for diffusion of the hydroxylamine metabolite of TH-302. The spatially resolved PK model was linked to a pharmacodynamic (PD) model that describes cell killing probability at each point in the tumor microregion as a function of Br-IPM and IPM exposure. The resulting PK/PD model accurately predicted previously reported monotherapy activity of TH-302 in H460 tumors, without invoking a bystander effect, demonstrating that the notable single agent activity of TH-302 in tumors can be accounted for by significant bioreductive activation of TH-302 even in oxic regions, driven by the high plasma concentrations achievable with this well-tolerated prodrug.

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Imaging and Clinical Features of an Unusual Unilateral Breast Enlargement Diagnosed as Fibrocystic Change: A Case Report.

Imaging and Clinical Features of an Unusual Unilateral Breast Enlargement Diagnosed as Fibrocystic Change: A Case Report.

Am J Case Rep. 2018 Dec 31;19:1550-1555

Authors: Kim SJ, Kim WG

Abstract
BACKGROUND Breasts are assumed to be symmetrical bilaterally, and abnormal findings on breast imaging are largely based on such an assumption. Clinically noticeable breast asymmetry beyond that of normal range is rarely encountered. CASE REPORT A 38-year-old female presented with unilateral enlargement of her left breast for 3 months and complained of polymenorrhea twice a month. Mammography and ultrasonography revealed that the left breast had a larger volume of fibroglandular tissue than the right breast, without accompanying signs of malignancy or abnormality. Magnetic resonance imaging demonstrated unilateral, diffuse, stippled enhancement in the left breast, which was located peripherally in the early phase and propagated centrally in the delayed phase with a persistent kinetic pattern. Ultrasonography-guided core needle biopsy was performed for the left breast, leading to a pathological diagnosis of fibrocystic change. The condition could be presumably due to a different response of the breasts to imbalance in endogenous hormones. CONCLUSIONS Based on our findings, we believe that radiologists should consider that the breast has a unique dynamic physiology and that features on breast imaging can be affected by hormonal alteration.

PMID: 30595602 [PubMed - in process]

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The “enlarged hilar periportal space sign” in liver cirrhosis

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هفت باور نادرست درباره سرقت علمی - نیتیو پیپر

هفت باور نادرست درباره سرقت علمی

۱۳۹۷/۰۷/۱۰|آموزش ها|بدون ديدگاه

مانند سایر موضوعات، بدفهمی‌ها و باورهای نادرست زیادی درباره سرقت علمی وجود دارد. با نادیده گرفتن قانون حق تألیف که به‌روشنی مجازات‌های سرقت علمی را تبیین کرده است، بسیاری از پژوهش‌گران خود را به‌طور جدی دچار دردسر می‌کنند. علی‌رغم آگاهی از نادرست بودن باورهای زیر، بسیاری از افراد آن‌ها را توجیهی برای سرقت‌های علمی می‌دانند. سرقت علمی از جمله پدیده‌هایی است که مردم دوست ندارند در کلاس درس یا محل کار درباره‌اش صحبت کنند. در اینجا، هفت باور نادرست درباره سرقت علمی مرور می‌شوند، پس با نیتیو پیپر همراه باشید.

هفت باور نادرست درباره سرقت علمی

۱- تنها محتوایی که مالکیت خصوصی دارد را نمی‌توان سرقت کرد

سرقت علمی و کپی‌رایت در این زمینه وجه اشتراک دارند. برخی فکر می‌کنند اگر اثری تحت مالکیت عمومی بوده یا مدت زمان مشخصی از انتشارش گذشته باشد، نیازی نیست به نام صاحب اثر اشاره کنند. هرچند در این حالت حق تألیف را نقض نکرده‌اید، با این حال، حتی اگر نویسنده اثر سال‌ها پیش فوت کرده باشد یا اثر تحت مالکیت عمومی باشد، باز هم باید به نام وی اشاره کنید؛ در غیر این صورت، مرتکب سرقت علمی شده‌اید.

۲- تنها باید نقل قول‌های مستقیم را ارجاع‌دهی کرد

بسیاری از دانشجویان تنبل که از ارجاع دادن بیزارند همیشه در اینجا قربانی می‌شوند. آن‌ها فکر می‌کنند تنها باید نقل قول مستقیم را ارجاع‌دهی کنند. بنابراین، با پارافریز کردن کل اثر از نقل قول مستقیم فرار می‌کنند. اما واقعیت این است که کلمات ابزارهای انتقال دادن، قرض گرفتن و اشتراک‌گذاری ایده‌ها و افکارند. ارجاع دادن کمک می‌کند سایر افراد محل دقیق منبع شما را پیدا کنند. بنابراین، حتی اگر کار را پارافریز کنید و به منبع‌تان ارجاع ندهید، مرتکب سرقت علمی شده‌اید.

۳- سرقت علمی تصادفی اهمیتی ندارد

حتی پس از پارافریز کردن، شباهت‌هایی که با متن اصلی وجود دارد قابل ردگیری‌اند. حتی اگر برای پارافریز کردن تلاش زیادی انجام دهید، باز هم سرقت علمی صورت گرفته است. برخی اوقات، مشابهت یاب‌های آنلاین مواردی از شباهت را ردیابی می‌کنند که باعث شگفتی شما می‌شود. ممکن است به علت ثبت نکردن منابع پژوهشی از ابتدای نوشتن مقاله، آن‌ها را گم کرده باشید. اینجا جایی است که ادعای بی‌گناهی می‌کنید. ممکن است از سرقت علمی اجتناب کرده باشید، اما واقعیت این است مرتکب خلاف شده‌اید و ممکن است جریمه‌ای سنگین در انتظارتان باشد. سرقت علمی تصادفی یا غیرتصادفی مهم نیست؛ مقاله همچنان سرقتی است.

۴- اینترنت یعنی دانش مشترک

بسیاری از دانشجویان گمان می‌کنند که چون اینترنت رایگان و دسترسی به آن برای همه آزاد است جزئی از دانش عمومی به حساب می‌آید و نیازی نیست اطلاعات استخراج‌ شده از آن را ارجاع‌دهی کنند. دانش مشترک تعریف خاص خود را دارد. دانش مشترک یعنی اطلاعات و حقایقی که برای همه آشناست و در تمام کتاب‌های مرجع در دسترس عموم است و به‌راحتی می‌توان آن را بازیابی کرد. بنابراین، باید تمام منابع اطلاعاتی اینترنتی را ارجاع‌دهی کرد.

۵- سرقت علمی از خود مهم نیست

بسیاری از دانشجویان عادت کرده‌اند که مقاله خود را بازنویسی و در ژورنال‌های متعدد سابمیت کنند. این کار نوعی سرقت علمی آکادمیک است. بسیاری از افراد این ادعا را که چیزی از دیگران سرقت نشده است قبول ندارند. کپی‌برداری از کارهای خودتان و بازنویسی کردن‌شان ممکن است دردسرساز شود. بیشتر نویسندگان از فرصت سوء استفاده می‌کنند و از کارهای‌شان مجدداً استفاده می‌کنند. به همین دلیل، بسیاری از نشریات قانون‌هایی دارند که مانع از استفاده مجدد از آثار پیشین می‌شوند، مگر آنکه به روشنی به آن‌ها ارجاع‌دهی شده باشد.

+بیشتر بخوانید: سرقت علمی از خود یا self-plagiarism چیست و چرا باید از آن اجتناب کرد؟

۶- هم می‌توانم از ارجاع‌دهی درون‌متنی استفاده کنم و هم از کتاب‌شناسی

بسیاری از دانشجویان فکر می‌کنند می‌توانند یکی از این دو شیوه را به کار ببرند. واقعیت این است که ژورنال‌ها هم ارجاع درون‌متنی و هم کتاب‌شناسی را الزامی می‌دانند. ارجاعات درون‌متنی نشان می‌دهند که محتوای قرض‌ گرفته‌ شده کجا آغاز می‌شود و کجا پایان می‌یابد. کتاب‌شناسی به مخاطب نشان می‌دهد که چگونه می‌توانند به منابع استفاده‌ شده دسترسی پیدا کنند.

۷- سرقت علمی تنها در کشورهای غیرانگلیسی‌زبان رایج است

fx1

To use MRCP to investigate age-related changes and gender differences of the pancreas and to correlate pancreatic gland size and duct diameter.

Methods

In this institutional review, board-approved, HIPAA-compliant study, 280 patients (age 20–88 years) without a history of pancreatic or liver disease who had undergone MRI/MRCP from 2004 to 2015 were identified. The anteroposterior size and main duct diameter of the pancreatic head, body, and tail were measured. The pancreatic gland and duct sizes were compared between genders, and among seven age subgroups (20–29, 30–39, 40–49, 50–59, 60–69, 70–79, 80–89).

Results

The pancreatic head and body were significantly larger in males than females (head, p < 0.01; body, p = 0.03), while the tail and the duct diameters of the pancreatic head, body, and tail showed no gender difference. As the age of male participants increased, there was an associated increase in size of the pancreatic gland initially (largest at age 50–59 (body) and 60–69 (head)), followed by subsequent decline in size thereafter. Additionally, the pancreatic duct diameter was found to increase gradually. In females, the size of the pancreatic gland decreased, while the diameter of the pancreatic duct increased with age. Moderate positive correlation for gland size and strong positive correlation for duct diameter among different pancreatic regions were found. Weak negative correlation was found between gland size and duct diameter.

Conclusions

There are gender differences in the gland size of the pancreatic head and body. The pancreatic gland size increases until the sixth decade in males, with a more continuous decrease in gland size with age in females. Both males and females demonstrate a marked decrease in gland size after the eighth decade. The duct diameter increases with age in both males and females.

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Fishbone migration to bile ducts after pancreaticoduodenectomy: a case series

Abstract

We reviewed six cases suspected of having fish bones in the bile ducts on follow-up CT following pancreaticoduodenectomy. The period from surgery to CT examination in which fishbone migration was first suspected ranged from 282 to 1157 days with a median of 517 days. The fish bone in the bile duct disappeared in five out of six cases on subsequent CT. One case was complicated by hepatolithiasis, and the other five cases showed no biliary complications. In two cases, wandering of fish bones in the jejunal limb was observed on CT images before their migration into the bile ducts. Asymptomatic migration of fish bones to the bile ducts following pancreaticoduodenectomy is not rare, but serious complications can occasionally occur. Indications of intervention may be controversial in asymptomatic cases, but once fish bones are observed in the biliary tree or the jejunal limb, dietary instructions advising not to swallow fish bones may be a good option to prevent complications.

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The Courvoisier’s sign

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Prenatal planning of placenta previa: diagnostic accuracy of a novel MRI-based prediction model for placenta accreta spectrum (PAS) and clinical outcome

Abstract

Purpose

To investigate the diagnostic accuracy of MRI for placenta accreta spectrum (PAS) and clinical outcome prediction in women with placenta previa, using a novel MRI-based predictive model.

Methods

Thirty-eight placental MRI exams performed on a 1.5T scanner were retrospectively reviewed by two radiologists in consensus. The presence of T2 dark bands, myometrial thinning, abnormal vascularity, uterine bulging, placental heterogeneity, placental protrusion sign, placental recess, and percretism signs was scored using a 5-point scale. Pathology and clinical intrapartum findings were the standard of reference for PAS, while intrapartum/peripartum bleeding and emergency hysterectomy defined the clinical outcome. Receiver-operating characteristic (ROC) analysis and discriminant function analysis were performed to test the predictive power of MRI findings for both PAS and clinical outcome prediction.

Results

Abnormal vascularity and percretism signs were the two most predictive MRI features of PAS. The area under the curve (AUC) of the predictive function was 0.833 (cutoff 0.39, 67% sensitivity, 100% specificity, p = 0.001). Percretism signs and myometrial thinning were the two most predictive MRI features of poor outcome. AUC of the predictive function was 0.971 (cutoff − 0.55, 100% sensitivity, 77% specificity, p < 0.001).

Conclusion

The diagnostic accuracy of MRI, especially considering the combination of the most predictive MRI findings, is higher when the target of the prediction is the clinical outcome rather than the PAS.

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Δευτέρα 31 Δεκεμβρίου 2018

Malignant mesothelioma: A histomorphological and immunohistochemical study of 24 cases from a tertiary care hospital in Southern India

Monalisa Hui, Shantveer Gurulingappa Uppin, Kakarla Bhaskar, Narahari Narendra Kumar, Gongati Kruparao Paramjyothi

Indian Journal of Cancer 2018 55(2):190-195

BACKGROUND: Malignant mesotheliomas are histologically heterogeneous neoplasms. Definite diagnosis requires a varied panel of immunohistochemical (IHC) markers to differentiate these from histological mimics. Only a few case series have been reported in the Indian literature where mesotheliomas have been analyzed on routine histology and IHC. AIM: To evaluate the histological features of malignant mesothelioma and to elucidate the best possible immunomarker combination useful in different scenarios. MATERIALS AND METHODS: A total of 24 cases of malignant mesotheliomas of different sites encountered over a 6-year period were retrospectively analyzed with regard to their histomorphology and IHC findings. RESULTS: The pleura was the most common site of involvement (16 cases) followed by peritoneum (5 cases) and pericardium (3 cases). Epithelioid mesothelioma was the most common histological type (15 cases, 62.5%) followed by sarcomatoid (5 cases, 20.84%), deciduoid (2 cases, 8.34%), and 1 case each of desmoplastic and biphasic mesothelioma. Among the mesothelial markers, WT1 was positive in 17 of 20 (85%) cases and calretinin was positive in 20 of 21 (95.23%) cases. D2-40 and CK5/6 were positive in all cases where they were studied. Adenocarcinoma markers TTF-1, napsin A, and CEA had very high negative predictive value in ruling out mesothelioma. CONCLUSION: The differential diagnosis of mesotheliomas varies with histological type and tumor location. Judicious use of various combinations of IHC markers in different situation has been highlighted in this article.

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Stereotactic body radiotherapy for lung tumors: Dosimetric analysis and clinical outcome

Kaustav Talapatra, Dipanjan Majumder, Pranav Chadha, P Shaju, Sandeep Goyle, BK Smruti, Rajesh Mistry

Indian Journal of Cancer 2018 55(2):170-175

INTRODUCTION: Stereotactic body radiotherapy (SBRT) has emerged as an important modality in malignant lung tumor treatment both in early localized primary and oligometastatic setting. This study aims to present the results of lung SBRT both in terms of dosimetry and clinical outcome. MATERIALS AND METHODS: Twenty-seven patients were assessed from 2012 to 2016. Both the primary and oligometastatic lung tumors were evaluated. Respiratory motion management was done employing ANZAI (Siemens, Germany) based four-dimensional computed tomography (CT). Commonly used fractionations were 60 Gy/5 fractions for peripheral tumors and 48 Gy/6 fractions for central tumors. Radiation Therapy Oncology Group toxicity criteria were used for toxicity and whole-body positron emission tomography-CT scan was done at follow-up for response evaluation. RESULTS: Twenty-seven patients were evaluated, 18 (66.7%) patients had a primary, and 9 (33.3%) patients had metastatic lung tumors. The male-to-female ratio for the entire cohort was 2:1. The median age at diagnosis was 65.8 years. Mean planning target volume (PTV) D2cc was 54.9 ± 9.04 Gy and mean internal target volume diameter was 3.0 ± 1.07 cm. Mean V20 Gy, V10 Gy, and V5 Gy of (lungs total-PTV) and (Lung ipsilateral - PTV) were 5.4 ± 4% and 10.9 ± 7.9%, 11.7 ± 5.8% and 24.2 ± 14.0%, and 22.05 ± 12.4% and 33.2 ± 15.3%, respectively. In total 21 (84%) patients and 4 patients (16%) showed a complete and partial response, respectively. One (3%) patient developed Gr 3 radiation pneumonitis. One year local control was in 18 (81%) patients whereas 4 (14%) patients progressed and three patients did not report. A higher prescribed dose significantly correlated with 1 year tumor control (P = 0.036). CONCLUSION: This study infers the feasibility and a favorable outcome for lung cancer amenable to SBRT in addition to being one of the largest clinical experiences for lung stereotactic treatment in our country.

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Radical radiotherapy or chemoradiotherapy for inoperable, locally advanced, non-small cell lung cancer: Analysis of patient profile, treatment approaches, and outcomes for 213 patients at a tertiary cancer center

Raj Kumar Shrimali, Chandran Nallathambi, Animesh Saha, Avipsa Das, Sriram Prasath, Anurupa Mahata, B Arun, Indranil Mallick, Rimpa Achari, Deepak Dabkara, Robin Thambudorai, Sanjoy Chatterjee

Indian Journal of Cancer 2018 55(2):125-133

INTRODUCTION: Radical radiotherapy (RT) with curative intent, with or without chemotherapy, is the standard treatment for inoperable, locally advanced nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: We retrospectively reviewed the data for all 288 patients who presented with inoperable, locally advanced NSCLC at our institution, between May 2011 and December 2016. RESULTS: RT alone or sequential chemoradiotherapy (SCRT) or concurrent chemoradiotherapy (CCRT) was used for 213 patients. Median age was 64 years (range: 27–88 years). Stage-III was the biggest stage group with 189 (88.7%) patients. Most patients with performance status (PS) 0 or 1 received CCRT, whereas most patients with PS 2 received RT alone (P < 0.001). CCRT, SCRT, and RT alone were used for 120 (56.3%), 24 (11.3%), and 69 (32.4%) patients, respectively. A third of all patients (32.4%) required either volumetric-modulated arc radiotherapy (VMAT) or tomotherapy. Median follow-up was 16 months. The median progression-free survival and median overall survival (OS) were 11 and 20 months, respectively. One-year OS and 2-year OS were 67.9% and 40.7%, respectively. Patients treated using CCRT lived significantly longer with a median survival of 28 months, compared with 13 months using SCRT and RT alone (P < 0.001). On multivariate analysis, OS was significantly affected by age, stage group, treatment approach, and response to treatment. CONCLUSION: RT including CCRT is feasible, safe, and well tolerated in our patient population and results in survival benefits comparable with published literature. CCRT should be considered for all patients with inoperable, locally advanced NSCLC, who are fit and have good PS.

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Carcinoma cervix – No role for surgery in stages IB2-IIB?

Prasanth Ganesan

Indian Journal of Cancer 2018 55(2):123-124

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Primary cutaneous B-cell lymphoma: A single-center 5-year experience

Linu Abraham Jacob, Vikas Asati, KC Lakshmaiah, Babu K Govind, Dasappa Lokanatha, Suresh MC Babu, KN Lokesh, AH Rudresh, LK Rajeev, Nikita J Mulchandani, Abhishek Anand, Deepak Koppaka, Suma Narayana Mysore

Indian Journal of Cancer 2018 55(2):134-137

BACKGROUND: Skin is the second most common site for extranodal non-Hodgkin's lymphoma (NHL). Most primary cutaneous NHLs are of T-cell origin (70%). Primary cutaneous B-cell lymphoma (PCBCL) is a rare entity. MATERIALS AND METHODS: Patients diagnosed with PCBCL between January 2012 and July 2017 at our center were retrospectively analyzed. RESULTS: Eight patients of PCBCL were diagnosed. Three patients (37.5%) were males while 5 patients (62.5%) were females. The median age at diagnosis was 45 years (range, 18–60 years). Scalp was the most common site of involvement (50% of the patients). Diffuse large B-cell lymphoma (DLBCL) was the most common histology (63%), with leg-type DLBCL diagnosed in 1 patient. Two patients had primary cutaneous follicle center lymphoma, whereas the remaining 1 patient had precursor B-lymphoblastic lymphoma. All 5 DLBCL cases were treated with CHOP chemotherapy, and rituximab was given to 3 patients. Of the primary cutaneous follicle center lymphomas, 1 patient with stage II disease was treated with CHOP and is alive without recurrence for the past 5 years, whereas the other patient is on observation alone. The patient with precursor B-lymphoblastic lymphoma was started on MCP-841 protocol; however, the patient did not complete the treatment and died after 11 months. CONCLUSIONS: PCBCL is a heterogeneous group of diseases and dividing them into subtypes, based on morphology and immunophenotype, has therapeutic implications.

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Impact of gene polymorphism of TNF-α rs 1800629 and TNF-β rs 909253 on plasma levels of South Indian breast cancer patients

Karuvaje Thriveni, Anisha Raju, Girija Ramaswamy, S Krishnamurthy

Indian Journal of Cancer 2018 55(2):179-183

AIM: Inflammation plays a lead role in the tumor microenvironment and promotes metastasis. Single-nucleotide polymorphism (SNP) in the tumor necrosis factor (TNF) gene locus may alter the expression of genes and proteins. The objective of the study is to find the distribution of genetic polymorphism in the sites of TNF-α −308G>A and TNF- β +252A>G in breast cancer and evaluate polymorphism effects on plasma levels. MATERIALS AND METHODS: The study group consisted of 109 invasive ductal primary breast cancer patients and 75 age-matched healthy female controls. Plasma cytokine concentrations were measured by the MILLIPLEX® MAP Human Cytokine/Chemokine Panel magnetic bead kits. The genotyping procedure for SNP included allele-specific polymerase chain reaction for TNFα and restriction fragment length polymorphism for TNFβ. RESULTS: Odds ratio with 95% confidence interval showed that these polymorphisms were not a causative risk factor, and both polymorphisms were consistent with Hardy–Weinberg equilibrium. Plasma TNFα and TNFβ median concentrations were significantly higher in cases when compared to controls (P < 0.01). When plasma TNFα levels were grouped under polymorphic subtypes, patients with mutant TNF- α −308A allele showed significantly higher values (P < 0.001). In addition, plasma TNFα values were significantly elevated in mutant TNF-β +252G allele (P < 0.01). CONCLUSION: This study demonstrated that there is no significant association between SNPs and breast cancer susceptibility in South Indian population. However, plasma TNFα level is significantly elevated with mutant-recessive TNF-α −308 A and TNF-β +252 G alleles of patients.

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Treatment practices for metastatic pancreatic cancer: Can we deliver an appropriately efficacious and safe regimen in Indian patients?

Anant Ramaswamy, Vikas Ostwal, Alok Goel, Prabhat Bhargava, Sujay Srinivas, Sanyo Dsouza, Shailesh V Shrikhande

Indian Journal of Cancer 2018 55(2):138-143

INTRODUCTION: The median overall survival (mOS) in metastatic pancreatic cancers (PCs) hovers between 6 months to 11 months. MATERIALS AND METHODS: The study is a retrospective analysis of metastatic PC patients who were evaluated from August 2013 to August 2016 in the Department of Gastrointestinal (GI) Medical Oncology, Tata Memorial Hospital (TMH). RESULTS: Out of 218 patients, 24 patients (11%) were not planned for chemotherapy and referred to the Department of Palliative Care for further supportive care. One hundred and fifty-three patients received palliative chemotherapy in TMH with median age of 56 years (range: 23–79), male (60.1%), and nonresident in Maharashtra (60.1%). Regimens used most commonly were gemcitabine–nab-paclitaxel in 60 patients (39.2%), gemcitabine–erlotinib in 25 patients (16.3%), and modified FOLFIRINOX in 21 patients (13.7%). A total of 58 patients (43%; n = 135) had Grade 3/4 toxicities. As of cutoff date for the analysis of outcomes, 139 patients (90.8%) patients had ceased first-line chemotherapy, due to radiologically proven progressive disease (PD) in 89 patients (64%), repeated Grades 3 and 4 adverse events in 26 patients (18.7%), and clinically PD in 18 patients (12.9%). With a median follow-up of 278 days, the mOS was 217 days (95% confidence interval [CI]: 175–258), and the median event-free survival was 125 days (95% CI: 107–122). CONCLUSION: Dose modifications for chemotherapy are required commonly when treating metastatic PC, with common reasons for dose reduction being toxicities, Eastern Cooperative Oncology Group performance status >=2, and low albumin levels. Studies evaluating logistic and financial aspects of treating metastatic PC with chemotherapy in India are warranted.

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Gamna–Gandy bodies in a solid pseudopapillary tumor of the pancreas

Anita Nangia, Shivali Sehgal

Indian Journal of Cancer 2018 55(2):201-202

Gamna gandy bodies are sclerosiderotic granules composed of various amounts of calcium and hemosiderin in hyalinised fibrous tissue. We report a case of an 18 year old girl with solid pseudopapillary tumor of the pancreas in which numerous gamna gandy bodies were present. The pathogenesis of such a finding is unclear. To the best of our knowledge, this is the first report of Gamna Gandy bodies occurring in a solid pesudopapillary tumor of the pancreas.

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Τρίτη 1 Ιανουαρίου 2019

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هفت باور نادرست درباره سرقت علمی

هفت باور نادرست درباره سرقت علمی

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Δευτέρα 31 Δεκεμβρίου 2018

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