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from Cancer via ola Kala on Inoreader http://ift.tt/2pk199N
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Issue Information

from Cancer via ola Kala on Inoreader http://ift.tt/2q3QbmL
via IFTTT

Prospective unbiased experience with three acellular dermal matrices in breast reconstruction

Background

The use of acellular dermal matrix (ADM) has become the standard of care in breast reconstruction. However, the majority of current studies are biased or combine large databases introducing inherent flaws. Here, we present a prospective single surgeon experience comparing three ADM.

Methods

All expander based breast reconstructions between 2014 and 2015 using ADM were included.

Results

Eighteen patients (32 breasts) underwent reconstruction using Flex Pliable, 15 patients (22 breasts) used Alloderm, and 14 patients (20 breasts) had Dermacell. There were no significant differences in patient demographics or comorbidities. All expanders were placed into a subpectoral position, and there were no direct to implant cases. Average intraoperative fill was comparable, (Flex: 225 cc, Alloderm: 180 cc, Dermacell: 130 cc). There were no differences in seroma, infection, or mastectomy skin flap necrosis rates. There were no cases of red breast, expander explanation or failed reconstruction in any cohort. Time to drain removal was significantly shorter in Flex and Dermacell patients compared to Alloderm (20 days vs 15 days vs 26 days, respectively; P = 0.01).

Conclusions

While there are differences between available ADM, successful outcomes can be achieved with proper patient selection, sound surgical technique, and diligent post-operative management.

http://ift.tt/2ouCRe7

Implantable Doppler monitoring of buried free flaps during vascularized lymph node transfer

Background and Objectives

Reliable flap monitoring is crucial to the success of free tissue transfer, including vascularized lymph node transfer (VLNT). However, no large-scale study has examined implantable Doppler monitoring in VLNT. We aimed to determine whether an implantable Doppler system can reliably monitor flap perfusion during VLNT and also to calculate the sensitivity and specificity of this system for detecting compromise in the monitored vessel.

Methods

An analysis of prospectively collected data of patients who underwent buried VLNT with implantable Doppler monitoring between 2014 and 2015 was performed.

Results

A consecutive series of 100 patients underwent VLNT with implantable Doppler monitoring. Five cases required return to the operating room for flap exploration due to a change in Doppler signal quality. All compromised flaps were salvaged. The sensitivity of the implantable Doppler system for flap monitoring was 100%, the specificity was 97.9%, the positive predictive value was 60%, and the negative predictive value was 100%. The false-positive rate was 2%.

Conclusions

This is the largest reported series of implantable Doppler monitoring of free flap perfusion during VLNT. Our experience suggests that this is a safe and effective technique for postoperative monitoring of VLNT.

http://ift.tt/2pgSwuI

Factors associated with local recurrence in operated osteosarcomas: A retrospective evaluation of 95 cases from a tertiary care center in a resource challenged environment

Background and Objectives

Local control of disease is one of the main goals of osteosarcoma management. We conducted a retrospective evaluation of 95 operated cases of osteosarcoma over 7 years to know about the factors associated with local recurrence in resource-challenged environment of the developing world.

Methods

The factors which were evaluated and compared between local recurrence and non-local recurrence groups included demographic profile, site of tumor, whether biopsy done outside, type of surgery (limb salvage or amputation), presence of pathological fracture, vicinity of neurovascular bundle, tumor volume, histological subtype, chemotherapy induced necrosis, surgical margins, and delay in surgery. The time to local recurrence after surgery was also noted in the local recurrence group.

Results

At a mean follow-up of 2.8 years, biopsy done from outside the treating center and delay in surgery after completion of neo-adjuvant chemotherapy emerged as significant risk factors for local recurrence. Most of the local recurrences (80%) occurred within 12 months of the primary surgery.

Conclusions

Lack of financial resources and availability of few tertiary care centers dealing with musculoskeletal oncology in the developing countries, lead to overburden with a long waiting list for tumor surgery making the scenario different from the Western world.

http://ift.tt/2ouniD8

Genome Wide Association Studies of Chemotherapeutic Toxicities: Genomics of Inequality

With an estimated global population of cancer survivors exceeding 32 million and growing, there is a heightened awareness of the long-term toxicities resulting from cancer treatments and their impact on quality of life. Unexplained heterogeneity in the persistence and development of toxicities, as well as an incomplete understanding of their mechanisms have generated a growing need for the identification of predictive pharmacogenomic markers. Early studies addressing this need used a candidate gene approach; however, over the last decade, unbiased and comprehensive genome-wide association studies (GWAS) have provided markers of phenotypic risk and potential targets to explore the mechanistic and regulatory pathways of biological functions associated with chemotherapeutic toxicity. In this review, we provide the current status of GWAS of chemotherapeutic toxicities with an emphasis on examining the ancestral diversity of the representative cohorts within these studies. Persistent calls to incorporate both ancestrally diverse and/or admixed populations into genomic efforts resulted in a recent rise in the number of studies utilizing cohorts of East Asian descent; however, few pharmacogenomic studies to date include cohorts of African, Indigenous American, Southwest Asian, and admixed populations. Through comprehensively evaluating sample size, composition by ancestry, genome-wide significant variants, and population-specific minor allele frequencies as reported by HapMap/dbSNP using NCBI PubMed, and the NHGRI-EBI GWAS Catalog, we illustrate allele frequencies and effect sizes tend to vary among individuals of differing ancestries. In an era of Personalized Medicine, the lack of diversity in genome-wide studies of anticancer agent toxicity may contribute to the health disparity gap.

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Ribonucleotide reductase large subunit (RRM1) as a novel therapeutic target in multiple myeloma

Purpose: To investigate the biologic and clinical significance of ribonucleotide reductase (RR) in multiple myeloma (MM). <p>Experimental Design: We assessed the impact of RR expression on patient outcome in MM. We then characterized the effect of genetic and pharmacological inhibition of RRM1 on MM growth and survival using siRNA and clofarabine (CLO), respectively, both in vitro and in vivo mouse xenograft model.</p> <p>Results: Newly diagnosed MM patients with higher RRM1 expression have shortened survival. Knockdown of RRM1 triggered significant growth inhibition and apoptosis in MM cells, even in the context of the bone marrow microenvironment. Gene expression profiling showed upregulation of DNA damage response genes and p53 regulated genes after RRM1 knockdown. Immunoblot and QRT-PCR analysis confirmed that -H2A.X, ATM, ATR, Chk1, Chk2, RAD51, 53BP1, BRCA1, and BRCA2 were upregulated/activated. Moreover, immunoblots showed that p53, p21, Noxa, and Puma were activated in p53 wild-type MM cells. Clofarabine (CLO), a purine nucleoside analog that inhibits RRM1, induced growth arrest and apoptosis in p53 wild-type cell lines. Although CLO did not induce cell death in p53 mutant cells, it did trigger synergistic toxicity in combination with DNA damaging agent melphalan. Finally, we demonstrated that tumor growth of RRM1-knockdown MM cells was significantly reduced in a murine human MM cell xenograft model.</p> Conclusions: Our results therefore demonstrate that RRM1 is a novel therapeutic target in MM in preclinical setting, and provide the basis for clinical evaluation of RRM1 inhibitor, alone or in combination with DNA damaging agents, to improve patient outcome in MM.

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Characterization of the tumor T-cell receptor repertoire and immune microenvironment in patients with locoregionally advanced squamous cell carcinoma of the head and neck

Purpose: Squamous cell carcinoma of the head and neck (SCCHN) is a lethal cancer with a suboptimal 5-year overall survival of approximately 50% with surgery and/or definitive chemoradiotherapy. Novel treatments are thus urgently awaited. Immunotherapy with checkpoint blockade has emerged as a promising option for patients with recurrent/metastatic SCCHN, however it has not been investigated in the curative-intent setting yet. The purpose of this study was to investigate the T-cell receptor repertoire and the tumor microenvironment in tumor tissues of SCCHN patients with locoregionally advanced disease. <br />Experimental design: We performed T-cell receptor sequencing of tumor tissues from 44 patients with locoregionally advanced SCCHN prior to treatment with definitive chemoradiotherapy and correlated the T-cell clonality and the mRNA expression levels of immune-related genes with clinicopathological parameters. <br />Results: Clonal expansion of T-cells was significantly higher in HPV-negative compared to HPV-positive tumors, signifying more robust antigen presentation in HPV-negative tumors. The latter was supported by the higher percentage of HPV-negative tumors expressing HLA-A protein compared to HPV-positive tumors (p=0.049). Higher GRZB levels correlated significantly with longer recurrence-free survival (log-rank, p=0.003) independent of tumor size, nodal stage and HPV status. <br />Conclusion: Our findings support clonal expansion of T-cells in SCCHN patients with locoregionally advanced disease and imply differences in the antigen presentation capacity between HPV-negative and HPV-positive tumors. Elevated GRZB mRNA levels may also serve as a favorable and independent predictor of outcome in SCCHN patients treated with chemoradiotherapy. These data provide rationale for the introduction of immunotherapeutic approaches in the curative-intent setting.

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Molecular pathways: targeting the protein kinase Wee1 in cancer

Wee1 is a protein kinase that regulates the G2 checkpoint and prevents entry into mitosis in response to DNA damage. Cyclin-dependent kinases (CDKs) are a family of 14 serine/threonine protein kinases, which coordinate the progression through the cell cycle. The Cdc2/cyclin B complex controls the progression from G2 into mitosis. There are two mechanisms by which the G2 checkpoint is initiated in response to DNA damage: phosphorylation of Cdc25c by CHK1 and of Wee1 kinase, which phosphorylates Cdc2. Blockade at the G2 checkpoint is especially important for p53 mutant cells because these tumors mainly rely on DNA repair at the G2 checkpoint. AZD1775 (formerly MK-1775) is a small molecule pyrazol-pyrimidine derivative and potent and ATP-competitive specific inhibitor of the Wee1 kinase. Several preclinical and clinical studies demonstrated encouraging anti-tumor effects with manageable side effects of the combination of Wee1 inhibition and DNA-damaging agents.  Promising combination schedules are being investigated at the moment, e.g. combining PARP-inhibition and Wee1 inhibition. Also a weekly schedule with carboplatin and AZD1775 warrants investigation aimed at further improving the anti-tumor effect.

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Overexpressed fatty acid synthase in gastrointestinal stromal tumors: Targeting a progression-associated metabolic driver enhances the antitumor effect of imatinib

Purpose: In gastrointestinal stromal tumors (GISTs), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN). <p>Experimental Design: Forty GISTs were quantitated for FASN mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known KIT/PDGFRA/BRAF genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, KIT transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNA interference or myristoylated-AKT transfection. The therapeutic relevance of dual blockade of FASN and KIT was evaluated in vivo.</p> <p>Results: FASN mRNA abundance significantly increased from very low/low-risk to high-risk levels of NCCN guidelines (p<0.0001). FASN overexpression was associated with a nongastric location (p = 0.05), unfavorable genotype (p=0.005), and increased risk level (p<0.001) and independently predicted shorter disease-free survival (p<0.001). In vitro, FASN knockdown inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and re-sensitized resistant GIST cells to imatinib. C75 transcriptionally repressed the KIT promoter, downregulated KIT expression and phosphorylation, induced LC3-II and myristoylated AKT-suppressible activity of caspases 3 and 7, attenuated the PI3K/AKT/mTOR/RSP6/4E-BP1 pathway activation, and exhibited dose-dependent therapeutic additivism with imatinib. Compared with both monotherapies, the C75/imatinib combination more effectively suppressed the growth of xenografts, exhibiting decreased KIT, Ki-67, and phosphorylated PIK3/AKT/mTOR levels and increased TUNEL labeling.          </p> <p>Conclusions: We have characterized the prognostic, biological, and therapeutic implications of overexpressed FASN in GISTs. C75 represses KIT transactivation, abrogates PI3K/AKT/mTOR activation, and provides a rationale for dual blockade of KIT and FASN in treating imatinib-resistant GISTs.

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Genome Wide Association Studies of Chemotherapeutic Toxicities: Genomics of Inequality

With an estimated global population of cancer survivors exceeding 32 million and growing, there is a heightened awareness of the long-term toxicities resulting from cancer treatments and their impact on quality of life. Unexplained heterogeneity in the persistence and development of toxicities, as well as an incomplete understanding of their mechanisms have generated a growing need for the identification of predictive pharmacogenomic markers. Early studies addressing this need used a candidate gene approach; however, over the last decade, unbiased and comprehensive genome-wide association studies (GWAS) have provided markers of phenotypic risk and potential targets to explore the mechanistic and regulatory pathways of biological functions associated with chemotherapeutic toxicity. In this review, we provide the current status of GWAS of chemotherapeutic toxicities with an emphasis on examining the ancestral diversity of the representative cohorts within these studies. Persistent calls to incorporate both ancestrally diverse and/or admixed populations into genomic efforts resulted in a recent rise in the number of studies utilizing cohorts of East Asian descent; however, few pharmacogenomic studies to date include cohorts of African, Indigenous American, Southwest Asian, and admixed populations. Through comprehensively evaluating sample size, composition by ancestry, genome-wide significant variants, and population-specific minor allele frequencies as reported by HapMap/dbSNP using NCBI PubMed, and the NHGRI-EBI GWAS Catalog, we illustrate allele frequencies and effect sizes tend to vary among individuals of differing ancestries. In an era of Personalized Medicine, the lack of diversity in genome-wide studies of anticancer agent toxicity may contribute to the health disparity gap.

http://ift.tt/2q364tP

Ribonucleotide reductase large subunit (RRM1) as a novel therapeutic target in multiple myeloma

Purpose: To investigate the biologic and clinical significance of ribonucleotide reductase (RR) in multiple myeloma (MM). <p>Experimental Design: We assessed the impact of RR expression on patient outcome in MM. We then characterized the effect of genetic and pharmacological inhibition of RRM1 on MM growth and survival using siRNA and clofarabine (CLO), respectively, both in vitro and in vivo mouse xenograft model.</p> <p>Results: Newly diagnosed MM patients with higher RRM1 expression have shortened survival. Knockdown of RRM1 triggered significant growth inhibition and apoptosis in MM cells, even in the context of the bone marrow microenvironment. Gene expression profiling showed upregulation of DNA damage response genes and p53 regulated genes after RRM1 knockdown. Immunoblot and QRT-PCR analysis confirmed that -H2A.X, ATM, ATR, Chk1, Chk2, RAD51, 53BP1, BRCA1, and BRCA2 were upregulated/activated. Moreover, immunoblots showed that p53, p21, Noxa, and Puma were activated in p53 wild-type MM cells. Clofarabine (CLO), a purine nucleoside analog that inhibits RRM1, induced growth arrest and apoptosis in p53 wild-type cell lines. Although CLO did not induce cell death in p53 mutant cells, it did trigger synergistic toxicity in combination with DNA damaging agent melphalan. Finally, we demonstrated that tumor growth of RRM1-knockdown MM cells was significantly reduced in a murine human MM cell xenograft model.</p> Conclusions: Our results therefore demonstrate that RRM1 is a novel therapeutic target in MM in preclinical setting, and provide the basis for clinical evaluation of RRM1 inhibitor, alone or in combination with DNA damaging agents, to improve patient outcome in MM.

http://ift.tt/2ou7AYO

Characterization of the tumor T-cell receptor repertoire and immune microenvironment in patients with locoregionally advanced squamous cell carcinoma of the head and neck

Purpose: Squamous cell carcinoma of the head and neck (SCCHN) is a lethal cancer with a suboptimal 5-year overall survival of approximately 50% with surgery and/or definitive chemoradiotherapy. Novel treatments are thus urgently awaited. Immunotherapy with checkpoint blockade has emerged as a promising option for patients with recurrent/metastatic SCCHN, however it has not been investigated in the curative-intent setting yet. The purpose of this study was to investigate the T-cell receptor repertoire and the tumor microenvironment in tumor tissues of SCCHN patients with locoregionally advanced disease. <br />Experimental design: We performed T-cell receptor sequencing of tumor tissues from 44 patients with locoregionally advanced SCCHN prior to treatment with definitive chemoradiotherapy and correlated the T-cell clonality and the mRNA expression levels of immune-related genes with clinicopathological parameters. <br />Results: Clonal expansion of T-cells was significantly higher in HPV-negative compared to HPV-positive tumors, signifying more robust antigen presentation in HPV-negative tumors. The latter was supported by the higher percentage of HPV-negative tumors expressing HLA-A protein compared to HPV-positive tumors (p=0.049). Higher GRZB levels correlated significantly with longer recurrence-free survival (log-rank, p=0.003) independent of tumor size, nodal stage and HPV status. <br />Conclusion: Our findings support clonal expansion of T-cells in SCCHN patients with locoregionally advanced disease and imply differences in the antigen presentation capacity between HPV-negative and HPV-positive tumors. Elevated GRZB mRNA levels may also serve as a favorable and independent predictor of outcome in SCCHN patients treated with chemoradiotherapy. These data provide rationale for the introduction of immunotherapeutic approaches in the curative-intent setting.

http://ift.tt/2q3oAlH

Molecular pathways: targeting the protein kinase Wee1 in cancer

Wee1 is a protein kinase that regulates the G2 checkpoint and prevents entry into mitosis in response to DNA damage. Cyclin-dependent kinases (CDKs) are a family of 14 serine/threonine protein kinases, which coordinate the progression through the cell cycle. The Cdc2/cyclin B complex controls the progression from G2 into mitosis. There are two mechanisms by which the G2 checkpoint is initiated in response to DNA damage: phosphorylation of Cdc25c by CHK1 and of Wee1 kinase, which phosphorylates Cdc2. Blockade at the G2 checkpoint is especially important for p53 mutant cells because these tumors mainly rely on DNA repair at the G2 checkpoint. AZD1775 (formerly MK-1775) is a small molecule pyrazol-pyrimidine derivative and potent and ATP-competitive specific inhibitor of the Wee1 kinase. Several preclinical and clinical studies demonstrated encouraging anti-tumor effects with manageable side effects of the combination of Wee1 inhibition and DNA-damaging agents.  Promising combination schedules are being investigated at the moment, e.g. combining PARP-inhibition and Wee1 inhibition. Also a weekly schedule with carboplatin and AZD1775 warrants investigation aimed at further improving the anti-tumor effect.

http://ift.tt/2oujodL

Overexpressed fatty acid synthase in gastrointestinal stromal tumors: Targeting a progression-associated metabolic driver enhances the antitumor effect of imatinib

Purpose: In gastrointestinal stromal tumors (GISTs), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN). <p>Experimental Design: Forty GISTs were quantitated for FASN mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known KIT/PDGFRA/BRAF genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, KIT transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNA interference or myristoylated-AKT transfection. The therapeutic relevance of dual blockade of FASN and KIT was evaluated in vivo.</p> <p>Results: FASN mRNA abundance significantly increased from very low/low-risk to high-risk levels of NCCN guidelines (p<0.0001). FASN overexpression was associated with a nongastric location (p = 0.05), unfavorable genotype (p=0.005), and increased risk level (p<0.001) and independently predicted shorter disease-free survival (p<0.001). In vitro, FASN knockdown inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and re-sensitized resistant GIST cells to imatinib. C75 transcriptionally repressed the KIT promoter, downregulated KIT expression and phosphorylation, induced LC3-II and myristoylated AKT-suppressible activity of caspases 3 and 7, attenuated the PI3K/AKT/mTOR/RSP6/4E-BP1 pathway activation, and exhibited dose-dependent therapeutic additivism with imatinib. Compared with both monotherapies, the C75/imatinib combination more effectively suppressed the growth of xenografts, exhibiting decreased KIT, Ki-67, and phosphorylated PIK3/AKT/mTOR levels and increased TUNEL labeling.          </p> <p>Conclusions: We have characterized the prognostic, biological, and therapeutic implications of overexpressed FASN in GISTs. C75 represses KIT transactivation, abrogates PI3K/AKT/mTOR activation, and provides a rationale for dual blockade of KIT and FASN in treating imatinib-resistant GISTs.

http://ift.tt/2q35ZX3

Successful treatment of a rare case of ameloblastic fibrosarcoma with radiation therapy

Abstract

Sarcomas are rare diseases of the head and neck region, representing around 1% of all malignancies. Amongst them, ameloblastic fibrosarcoma (AFS) is of even greater rarity, with less than 100 cases reported in the literature. Consequently, no standard treatment or guidelines have been made available. Surgery is often performed as primary therapy, but may be limited due to anatomical or functional reasons. We present a case of AFS successfully treated by postoperative radiation therapy. A detailed case study is provided, followed by a review of the English-language literature focusing on the role of radiation therapy.

http://ift.tt/2oJdocY

The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series

Abstract

Melanomas in Chinese patients show relatively higher rates of acral and mucosal types than in other populations. However, the efficacy of checkpoint inhibitor therapies against these melanoma subtypes is not well defined. We analyzed 52 patients treated with ipilimumab, pembrolizumab, or a combination of both to evaluate the efficacy and safety of checkpoint inhibitors in Chinese patients with advanced melanoma, particularly those with acral and mucosal types. The objective response rates (ORRs) were 0, 25, and 20% for ipilimumab, pembrolizumab, and pembrolizumab plus ipilimumab, respectively. Pembrolizumab contained therapy was as effective in acral and mucosal melanoma patients (ORR 26.7 and 20%, respectively) as in non-acral cutaneous melanoma patients (ORR 26.7%). Baseline lactate dehydrogenase levels and relative lymphocyte counts were independent prognostic factors for PFS and OS. The incidences of grade 3–4 adverse events were 14% in the two monotherapy groups and 30% in the combined therapy group. The most frequent adverse events were elevation of aminotransferase, skin toxicity, thyroid dysfunction, pyrexia, and fatigue. Treatment-related rash or vitiligo was associated with a better prognosis. In summary, pembrolizumab-based therapy resulted in meaningful efficacy and good tolerability in Chinese patients with melanoma, including those with acral and mucosal types.

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Epstein-Barr virus infection and breast invasive ductal carcinoma in Egyptian women: A single center experience

Publication date: Available online 24 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Noha ED Hassab El-Naby, Hameda Hassan Mohamed, Asmaa Mohamed Goda, Ahmed El Sayed Mohamed
BackgroundA controversy of the role of Epstein-Barr virus (EBV) infection in breast carcinomas has been reported in the literature.ObjectivesWe carried on this research to explore possible association between EBV infection and breast invasive ductal carcinoma (IDC) in Egyptian women attending our center.Study designThis study carried out at Sohag university hospital on 84 paraffin embedded samples of breast tissue, of them 42 breast IDC as the case group and 42 breast fibroadenomas as the control group. Nested PCRand immunohistochemistry (IHC) done separately for all samples to identify the Epstein-Barr nuclear antigen-1 (EBNA-1) gene and EBV latent membrane protein-1 (LMP-1) respectively, in breast cancer cells and controls.ResultsSpecimen considered positive when both (EBNA-1) gene and LMP-1 were detected using PCR and IHC separately for the same sample, this was achieved by 10/42 (23.81%) of breast IDC (case group) and 6/42 (14.29%) of breast fibro-adenomas (control group) (P-value=0.4). Nodal involvement was the only parameter that demonstrated a significant statistical relationship with EBV presence in cancerous tissue with p-value=0.003.ConclusionOur research could not find a significant statistical association between EBV infection and breast IDC in Egyptian women attending our center, but, there might be an association between the existence of EBV and tumor aggressiveness.



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Breaking the ritual metabolic cycle in order to save acetyl CoA: A potential role for mitochondrial humanin in T2 bladder cancer aggressiveness

Publication date: Available online 24 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Nesreen Nabil Omar, Reham Fathy Tash, Youssef Shoukry, Karim Omar ElSaeed
Introduction: Cancer cells may exhibit outsourcing of their high energy need in order to avoid the intrinsic mitochondrial apoptosis. Reduced mitochondrial respiration and accumulation of mitochondrial genome mutations are among metabolic transformations in this regard. Mitochondrial humanin (MT-RNR2) is a small peptide with anti-apoptotic activities attributed to binding some pro-apoptotic proteins. Aim of the work: The current study aims at investigating the expression of mitochondrial humanin in bladder tumor cells and the possible casting of humanin anti-apoptotic action through orchestrating some of the mitochondrial metabolic enzymes. Material and methods: Here messenger RNA of humanin, succinate dehydrogenase, glutaminase, isocitrate dehydrogenase were compared in tissues from patients with T2 bladder carcinoma in comparison to tumor associated normal tissues from the same patients. Levels of lactate and mitochondrial pyruvate carrier (MPC1) mRNA were determined to scrutinize the prevalence of aerobic glycolysis. Results: The present study found that tumor cells had suppressed aerobic glycolysis, augmented mitochondrial respiration and interrupted tricarboxylic acid cycle, all of which were suggested to serve tumor aggressiveness. MT-RNR2 was found closely related to the alterations in mitochondrial activity. Conclusion: MT-RNR2 plays its anti-apoptotic role partly by avoiding deploying energy from complete oxidation of organic compounds to inorganic wastes. Thus MT-RNR2 can potentially serve as a new biomarker in the diagnosis of bladder carcinoma especially that it is present in blood circulation.



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Outcome of resectable pediatric Ewing sarcoma of the ribs

Publication date: Available online 24 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Gehad Ahmed, Manal Zamzam, Mohamed S. Zaghloul, Ahmed Kamel, Ranin Soliman, Iman Zaky, Asmaa Salama, Nehal Kamal, Maged ElShafiey
PurposeWas to evaluate the outcome of multimodality treatment in resectable primary Ewing sarcoma/primitive neuroectodermal tumor ES/PNET of the ribs and role of thoracoscopy in facilitating resection of these tumors.Patients and methodsThis was a retrospective study including 22 patients with primary ES/PNET of the ribs surgically treated at Children's Cancer Hospital Egypt (CCHE) between January 2008 until the end of December 2014.ResultsMedian age was 8.5years (range 5months to 16years.). All patients received neoadjuvant chemotherapy. Thoracoscopic exploration was performed in 15 (68%) patients. Resection included 1,2,3 and 4 ribs in (7,4,8 and 3 patients) respectively, parts of the diaphragm (3 patients), wedge resection of the lung (10 patients) and pleural nodules (2 patients). Primary closure was feasible in 11 patients and rib transposition was done in one patient. Reconstruction by proline mesh covered by muscle flap was done in 10 patients. Margins were microscopically positive in 3 patients and close in 2 patients. Postoperative radiotherapy was given in 8 patients. With a median follow-up of 38.5months, the 3-year event -free survival (EFS) and overall survival(OS) rates were 31.6% and 55.6%, respectively.ConclusionMultimodality treatment is essential in the management of ES-PNET of the ribs. Neoadjuvant chemotherapy facilitates adequate resection. The role of thoracoscopy and the indications of postoperative radiotherapy need further evaluation.



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The profile of extremity and trunk soft tissue sarcoma in a tertiary referral center

Publication date: Available online 24 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Ahmed Mostafa Ahmed Mahmoud, Mohammed Mahmoud, Ahmed Charaf, Manar Mohamed Moneer
BackgroundProper surgery with adequate safety margin and adjuvant radiotherapy is the main line of treatment of extremity and trunk soft tissue sarcoma (STS). In spite of improved management, the long term follow up is still not satisfactory.ObjectiveTo evaluate long term outcome of STS of extremities and trunk regarding adequacy of resection, recurrence and survival.Patients and methodsThis prospective study included 25 patients with STS involving extremity and trunk. All patients were treated with wide radical excision and had adjuvant irradiation and followed up for a median of 26months.ResultsThe mean age was 40.0±15.3years. They were 16 males and 9 females. Eight patients (32%) had positive or close surgical margins. The median overall survival (OS) was 26.5months. In univariate analysis, lower limb tumors, stage III and grade 3 were significantly associated with worse overall survival (OS) (p=0.007, 0.02, and 0.020, respectively) and disease free survival (DFS) (p=0.005, 0.001, and 0.001, respectively). On multivariate analysis the only independent factor that affects the OS and DFS was the stage (p value=0.029, Hazard ratio: 3.64, 95% confidence interval: 1.14–11.61 and p value=0.003, Hazard ratio: 5.75, 95% confidence interval: 1.82–18.18 respectively).ConclusionDespite adequate surgery and adjuvant irradiation, 5years follow up results of treatment of extremity and trunk soft tissue sarcoma is still poor. This highlights the importance of early detection of small STS in extremity and trunk.



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Editor’s perspective: How rare is rare?

Publication date: Available online 25 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Emad Shash




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Epstein-Barr virus infection and breast invasive ductal carcinoma in Egyptian women: A single center experience

Publication date: Available online 24 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Noha ED Hassab El-Naby, Hameda Hassan Mohamed, Asmaa Mohamed Goda, Ahmed El Sayed Mohamed
BackgroundA controversy of the role of Epstein-Barr virus (EBV) infection in breast carcinomas has been reported in the literature.ObjectivesWe carried on this research to explore possible association between EBV infection and breast invasive ductal carcinoma (IDC) in Egyptian women attending our center.Study designThis study carried out at Sohag university hospital on 84 paraffin embedded samples of breast tissue, of them 42 breast IDC as the case group and 42 breast fibroadenomas as the control group. Nested PCRand immunohistochemistry (IHC) done separately for all samples to identify the Epstein-Barr nuclear antigen-1 (EBNA-1) gene and EBV latent membrane protein-1 (LMP-1) respectively, in breast cancer cells and controls.ResultsSpecimen considered positive when both (EBNA-1) gene and LMP-1 were detected using PCR and IHC separately for the same sample, this was achieved by 10/42 (23.81%) of breast IDC (case group) and 6/42 (14.29%) of breast fibro-adenomas (control group) (P-value=0.4). Nodal involvement was the only parameter that demonstrated a significant statistical relationship with EBV presence in cancerous tissue with p-value=0.003.ConclusionOur research could not find a significant statistical association between EBV infection and breast IDC in Egyptian women attending our center, but, there might be an association between the existence of EBV and tumor aggressiveness.



http://ift.tt/2pgF6yK

Breaking the ritual metabolic cycle in order to save acetyl CoA: A potential role for mitochondrial humanin in T2 bladder cancer aggressiveness

Publication date: Available online 24 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Nesreen Nabil Omar, Reham Fathy Tash, Youssef Shoukry, Karim Omar ElSaeed
Introduction: Cancer cells may exhibit outsourcing of their high energy need in order to avoid the intrinsic mitochondrial apoptosis. Reduced mitochondrial respiration and accumulation of mitochondrial genome mutations are among metabolic transformations in this regard. Mitochondrial humanin (MT-RNR2) is a small peptide with anti-apoptotic activities attributed to binding some pro-apoptotic proteins. Aim of the work: The current study aims at investigating the expression of mitochondrial humanin in bladder tumor cells and the possible casting of humanin anti-apoptotic action through orchestrating some of the mitochondrial metabolic enzymes. Material and methods: Here messenger RNA of humanin, succinate dehydrogenase, glutaminase, isocitrate dehydrogenase were compared in tissues from patients with T2 bladder carcinoma in comparison to tumor associated normal tissues from the same patients. Levels of lactate and mitochondrial pyruvate carrier (MPC1) mRNA were determined to scrutinize the prevalence of aerobic glycolysis. Results: The present study found that tumor cells had suppressed aerobic glycolysis, augmented mitochondrial respiration and interrupted tricarboxylic acid cycle, all of which were suggested to serve tumor aggressiveness. MT-RNR2 was found closely related to the alterations in mitochondrial activity. Conclusion: MT-RNR2 plays its anti-apoptotic role partly by avoiding deploying energy from complete oxidation of organic compounds to inorganic wastes. Thus MT-RNR2 can potentially serve as a new biomarker in the diagnosis of bladder carcinoma especially that it is present in blood circulation.



http://ift.tt/2q53iqQ

Outcome of resectable pediatric Ewing sarcoma of the ribs

Publication date: Available online 24 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Gehad Ahmed, Manal Zamzam, Mohamed S. Zaghloul, Ahmed Kamel, Ranin Soliman, Iman Zaky, Asmaa Salama, Nehal Kamal, Maged ElShafiey
PurposeWas to evaluate the outcome of multimodality treatment in resectable primary Ewing sarcoma/primitive neuroectodermal tumor ES/PNET of the ribs and role of thoracoscopy in facilitating resection of these tumors.Patients and methodsThis was a retrospective study including 22 patients with primary ES/PNET of the ribs surgically treated at Children's Cancer Hospital Egypt (CCHE) between January 2008 until the end of December 2014.ResultsMedian age was 8.5years (range 5months to 16years.). All patients received neoadjuvant chemotherapy. Thoracoscopic exploration was performed in 15 (68%) patients. Resection included 1,2,3 and 4 ribs in (7,4,8 and 3 patients) respectively, parts of the diaphragm (3 patients), wedge resection of the lung (10 patients) and pleural nodules (2 patients). Primary closure was feasible in 11 patients and rib transposition was done in one patient. Reconstruction by proline mesh covered by muscle flap was done in 10 patients. Margins were microscopically positive in 3 patients and close in 2 patients. Postoperative radiotherapy was given in 8 patients. With a median follow-up of 38.5months, the 3-year event -free survival (EFS) and overall survival(OS) rates were 31.6% and 55.6%, respectively.ConclusionMultimodality treatment is essential in the management of ES-PNET of the ribs. Neoadjuvant chemotherapy facilitates adequate resection. The role of thoracoscopy and the indications of postoperative radiotherapy need further evaluation.



http://ift.tt/2pgwubp

The profile of extremity and trunk soft tissue sarcoma in a tertiary referral center

Publication date: Available online 24 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Ahmed Mostafa Ahmed Mahmoud, Mohammed Mahmoud, Ahmed Charaf, Manar Mohamed Moneer
BackgroundProper surgery with adequate safety margin and adjuvant radiotherapy is the main line of treatment of extremity and trunk soft tissue sarcoma (STS). In spite of improved management, the long term follow up is still not satisfactory.ObjectiveTo evaluate long term outcome of STS of extremities and trunk regarding adequacy of resection, recurrence and survival.Patients and methodsThis prospective study included 25 patients with STS involving extremity and trunk. All patients were treated with wide radical excision and had adjuvant irradiation and followed up for a median of 26months.ResultsThe mean age was 40.0±15.3years. They were 16 males and 9 females. Eight patients (32%) had positive or close surgical margins. The median overall survival (OS) was 26.5months. In univariate analysis, lower limb tumors, stage III and grade 3 were significantly associated with worse overall survival (OS) (p=0.007, 0.02, and 0.020, respectively) and disease free survival (DFS) (p=0.005, 0.001, and 0.001, respectively). On multivariate analysis the only independent factor that affects the OS and DFS was the stage (p value=0.029, Hazard ratio: 3.64, 95% confidence interval: 1.14–11.61 and p value=0.003, Hazard ratio: 5.75, 95% confidence interval: 1.82–18.18 respectively).ConclusionDespite adequate surgery and adjuvant irradiation, 5years follow up results of treatment of extremity and trunk soft tissue sarcoma is still poor. This highlights the importance of early detection of small STS in extremity and trunk.



http://ift.tt/2q54zOv

Editor’s perspective: How rare is rare?

Publication date: Available online 25 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Emad Shash




http://ift.tt/2pgwqZd

Multi-institutional analysis of radiation modality use and postoperative outcomes of neoadjuvant chemoradiation for esophageal cancer

Relative radiation dose exposure to vital organs in the thorax could influence clinical outcomes in esophageal cancer (EC). We assessed whether the type of radiation therapy (RT) modality used was associated with postoperative outcomes after neoadjuvant chemoradiation (nCRT).

http://ift.tt/2p2gtYs

Defining a Leader Role curriculum for radiation oncology: A global Delphi consensus study

The need for radiation oncologists and other radiation oncology (RO) professionals to lead quality improvement activities and contribute to shaping the future of our specialty is self-evident. Leadership knowledge, skills and behaviours, like other competencies, can be learned (Blumenthal et al., 2012). The objective of this study was to define a globally applicable competency set specific to radiation oncology for the CanMEDS Leader Role (Frank et al., 2015).

http://ift.tt/2pjcW8q

Targeting NTRK fusion in non-small cell lung cancer: rationale and clinical evidence

Abstract

In the era of personalized medicine, the identification of targetable genetic alterations represented a major step forward in anticancer therapy. NTRK rearrangements represent the molecular driver of a subset of solid tumors, including 3% of non-small-cell lung cancers (NSCLCs). Preliminary data indicate that molecularly selected NSCLC patients harboring NTRK fusions derive an unprecedented clinical benefit from Trk-directed targeted therapies. The aim of this review is to describe the molecular biology of NTRK signaling pathway and to summarize the preclinical data on novel Trk inhibitors, touching upon the clinical development of these inhibitors for the treatment of advanced NSCLC, which have already shown encouraging anticancer activity and acceptable safety profile in early phase I clinical trials.

http://ift.tt/2oHIaSL

Confused reference in the article entitle: pharmacogenomics of platinum-based chemotherapy in non-small cell lung cancer—focusing on DNA repair systems

http://ift.tt/2p23aao

Treatment adherence in chronic myeloid leukaemia patients receiving tyrosine kinase inhibitors

Abstract

Failure to comply with treatment recommendations is very common in patients, but still poorly recognised by doctors. The current practice of using oral therapy on a large scale has been increasingly adopted for cancer patients. Chronic myeloid leukaemia (CML) is just such an example, where the introduction of taking new oral medications, the tyrosine kinase BCR-ABL inhibitors (TKI), has now revolutionised the treatment. The aim of our study was to assess treatment adherence in a group of Polish CML patients (a survey was conducted on 140 patient aged ≥18 years) treated with oral TKI (imatinib, dasatinib and nilotinib) taking into account the following variables: gender, age, education, place of residence, family circumstances and duration of therapy. In addition, we evaluated whether there is a relationship between how patients perceive their level of adherence to treatment recommendations with how subjectively the required dosage regimen was followed. Half the patients admitted to skipping at least one drug dose during the entire course of treatment and 39% did so within their last treatment month. Patients were also found to overestimate their own adherence assessment; around 60% of those missing at least 1 drug dose within the last treatment month believed they 'always' followed recommendations. The study demonstrated that adherence deteriorates over time. Furthermore, patients aged >65 years and patients suffering at least one comorbid disease had better adherence (p < 0.011). There were no differences in adherence among patients treated with imatinib, dasatinib and nilotinib (p = 0.249).

http://ift.tt/2oHSoCN

Targeting NTRK fusion in non-small cell lung cancer: rationale and clinical evidence

Abstract

In the era of personalized medicine, the identification of targetable genetic alterations represented a major step forward in anticancer therapy. NTRK rearrangements represent the molecular driver of a subset of solid tumors, including 3% of non-small-cell lung cancers (NSCLCs). Preliminary data indicate that molecularly selected NSCLC patients harboring NTRK fusions derive an unprecedented clinical benefit from Trk-directed targeted therapies. The aim of this review is to describe the molecular biology of NTRK signaling pathway and to summarize the preclinical data on novel Trk inhibitors, touching upon the clinical development of these inhibitors for the treatment of advanced NSCLC, which have already shown encouraging anticancer activity and acceptable safety profile in early phase I clinical trials.

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Confused reference in the article entitle: pharmacogenomics of platinum-based chemotherapy in non-small cell lung cancer—focusing on DNA repair systems

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Treatment adherence in chronic myeloid leukaemia patients receiving tyrosine kinase inhibitors

Abstract

Failure to comply with treatment recommendations is very common in patients, but still poorly recognised by doctors. The current practice of using oral therapy on a large scale has been increasingly adopted for cancer patients. Chronic myeloid leukaemia (CML) is just such an example, where the introduction of taking new oral medications, the tyrosine kinase BCR-ABL inhibitors (TKI), has now revolutionised the treatment. The aim of our study was to assess treatment adherence in a group of Polish CML patients (a survey was conducted on 140 patient aged ≥18 years) treated with oral TKI (imatinib, dasatinib and nilotinib) taking into account the following variables: gender, age, education, place of residence, family circumstances and duration of therapy. In addition, we evaluated whether there is a relationship between how patients perceive their level of adherence to treatment recommendations with how subjectively the required dosage regimen was followed. Half the patients admitted to skipping at least one drug dose during the entire course of treatment and 39% did so within their last treatment month. Patients were also found to overestimate their own adherence assessment; around 60% of those missing at least 1 drug dose within the last treatment month believed they 'always' followed recommendations. The study demonstrated that adherence deteriorates over time. Furthermore, patients aged >65 years and patients suffering at least one comorbid disease had better adherence (p < 0.011). There were no differences in adherence among patients treated with imatinib, dasatinib and nilotinib (p = 0.249).

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Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: Recommendations on incorporating patient-reported outcomes in clinical trials in epithelial ovarian cancer

Publication date: June 2017
Source:European Journal of Cancer, Volume 78
Author(s): Florence Joly, Felix Hilpert, Aikou Okamoto, Gavin Stuart, Kasunori Ochiai, Michael Friedlander
Despite the support for including patient-reported outcomes (PROs) and health-related quality of life in clinical trials, there have been deficiencies in how these have been assessed and reported in epithelial ovarian cancer (EOC) clinical trials. To redress this, the 5th Ovarian Cancer Consensus Conference, included a plenary session entitled 'How to include PROs in clinical trials'. The perspective is a summary of the recommendations made by the Gynecologic Cancer InterGroup unanimously agreed on the importance of PROs and PRO end-points in EOC clinical trials. They recognised that effort must be made to ensure the integrity of collection of PRO data and to avoid missing data. PRO end-points should be based on the PRO hypotheses, be context specific and reflect the patient population and the objectives of treatment (e.g. first line, maintenance therapy, early or late relapse). The PRO end-points inform the choice of PRO measures used in the trial and how the results are analysed and reported. There was agreement that progression-free survival should be supported by PROs among patients with late relapse (platinum sensitive) and that progression-free survival alone was not sufficient as the primary end-point of clinical trials in patients with platinum resistant/refractory EOC and PROs should be included as either the primary/co-primary end-point in this subset of patients. Novel approaches to measure the benefit of palliative chemotherapy such as time until definitive deterioration of Health-Related Quality of Life were recommended. There was consensus to endorse the ISOQOL and CONSORT-PRO guidelines on the inclusion and reporting of PRO endpoints in protocols and that all future EOC Gynecologic Cancer InterGroup trials should adhere to these.



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Hypopharyngeal and upper esophageal ulceration after cervical spine radiotherapy concurrent with crizotinib

Abstract

Herein, the authors describe the case of a 31-year-old female patient with primary metastatic adenocarcinoma of the lung referred for radiation therapy of newly diagnosed intramedullary spinal cord metastasis at C4/5 and an adjacent osteolytic lesion. Radiotherapy of the cervical spine level C3 to C5, including the whole vertebra, was performed with 30 Gy in 10 fractions. The patient's systemic therapy with crizotinib 250 mg twice daily was continued. After 8 fractions of radiation the patient developed increasing dysphagia. Ulceration of the hypopharynx and the upper esophagus were obvious in esophagoscopy and CT. Hospitalization for analgesia and percutaneous endoscopic gastrostomy (PEG) was required. First oral intake was possible 3 weeks after the onset of symptoms. The early onset, severity, and duration of mucositis seemed highly unusual in this case. A review of the literature failed to identify any reference to increased mucositis after radiation therapy concurrent with crizotinib, although references to such an effect with other tyrosine kinase inhibitors (TKI) were found. Nevertheless, the authors presume that a considerable risk of unexpected interactions exists. When crizotinib and radiotherapy are combined, heightened attention toward intensified reactions seems to be warranted.

http://ift.tt/2p0yhms

Successful treatment of a rare case of ameloblastic fibrosarcoma with radiation therapy

Abstract

Sarcomas are rare diseases of the head and neck region, representing around 1% of all malignancies. Amongst them, ameloblastic fibrosarcoma (AFS) is of even greater rarity, with less than 100 cases reported in the literature. Consequently, no standard treatment or guidelines have been made available. Surgery is often performed as primary therapy, but may be limited due to anatomical or functional reasons. We present a case of AFS successfully treated by postoperative radiation therapy. A detailed case study is provided, followed by a review of the English-language literature focusing on the role of radiation therapy.

http://ift.tt/2oJdocY

Diagnostic value of the dual-luciferase report assay for predicting response to glucocorticoid in children with acute lymphoblastic leukemia

Abstract

Objective

Resistance to glucocorticoid (GC) is a significant clinical problem in some cases of acute lymphoblastic leukemia (ALL). Current methods of assessing GC resistance are time consuming and have limited reproducibility; in this study, we sought to define a new method of evaluating GC sensitivity and resistance in vitro.

Methods

Based on the mechanisms of GC resistance, we hypothesized that the dual-luciferase report (DLR) assay could reflect the transcription effects of GC downstream of the GC-glucocorticoid receptor signaling pathway, thereby allowing the evaluation of reactions to GC. Sixty-two patients with differential GC response were included in this study. The prednisone induction test was used to divide the children with ALL into two groups: GC sensitive (GCS) and GC resistant (GCR). DLR assay was later conducted on those patients to evaluate its value for diagnosis of the GC reactivity. Receiver operating characteristic curves were used to identify the optimal assay cutoff for identifying response to GC.

Results

Using the DLR assay analysis, we found that GCR subjects showed significantly lower reporter/control ratios for luciferase, as compared with GCS subjects. The optimal cutoff value for GC response was 0.67, with sensitivity of 77.1% and specificity of 93.3%. The DLR assay results were consistent with prednisone induction test results. Further, the DLR assay was simpler, more sensitive, and less time-consuming than the prednisone induction test.

Conclusions

Our study showed that the DLR assay is relatively fast, simple, and sensitive. Accordingly, it could be useful for detecting GC response in children with ALL.

http://ift.tt/2q13zIx

Breast self-exam and patient interval associate with advanced breast cancer and treatment delay in Mexican women

Abstract

Purpose

The objective of this study was to compare treatment intervals in breast cancer patients according to the detection method (breast self-exam vs screening).

Patients and methods

We conducted a retrospective analysis including 291 breast cancer patients at a Mexican tertiary referral hospital.

Results

Breast cancer detection method was mostly breast self-exam (60%). The median patient interval was 60.5 days, and was associated with marital status and socioeconomic level. Differences between the two groups were statistically significant for global interval, p = 0.002; however, health system interval was not statistically different.

Conclusion

In our country, breast cancer screening is opportunistic, with several weaknesses within its management and quality systems. Our study showed that even in specialized health care centers, breast cancer is detected by self-exam in up to 2/3 of patients, which can explain the advanced stages at diagnosis in our country. In developing countries, the immediate health care access for breast cancer patients should be prioritized as an initial step to reduce the global treatment initiation interval in order to reduce mortality.

http://ift.tt/2oscQfF

Correlation of preoperative ROMA scores with clinical stage in epithelial ovarian cancer patients

Abstract

Purpose

The significance of the Risk of Ovarian Malignancy Algorithm (ROMA) in differentiating benign and malignant ovarian lesions has been evidenced. In our clinical work, we found that advanced ovarian cancer were accompanied commonly with high ROMA scores. Thus, this study aimed to clarify the performance of ROMA in different disease stage of epithelial ovarian cancer (EOC) prior to surgery.

Methods

Carbohydrate antigen (CA125) and human epididymis protein 4 (HE4) levels and ROMA scores in 221 patients with FIGO stage I, II or III/IV stage EOC were analyzed. The positive rates of CA125, HE4 and ROMA at each disease stage were calculated. Their cutoff values, sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) for distinguishing patients with FIGO stage I/II from those with FIGO stage III/IV were estimated via ROC curves.

Results

Serum CA125 and HE4 levels and ROMA scores rose significantly with advancing stage. ROMA and CA125 were significantly elevated more frequently in comparing with HE4 in EOC patients at with the same stage. Based on ROC curves, the cutoff values for FIGO stage III/IV EOC were 110 IU/mL, 126 pmol/L, 78 and 68% for CA125, HE4, premenopausal and postmenopausal ROMA, respectively. ROMA was the strongest predictor of FIGO stage, with the highest specificity, accuracy, and PPV, which were 84.4, 82.5, and 87.0% for postmenopausal patients, 89.3, 85.6, and 74.3% for premenopausal patients.

Conclusions

Our data suggest high ROMA scores correlated with advanced ovarian cancer prior to surgery. These observations suggest potential utility of ROMA in the comprehensively preoperative evaluation of EOC patients.

http://ift.tt/2q0VV0C

Diagnostic value of the dual-luciferase report assay for predicting response to glucocorticoid in children with acute lymphoblastic leukemia

Abstract

Objective

Resistance to glucocorticoid (GC) is a significant clinical problem in some cases of acute lymphoblastic leukemia (ALL). Current methods of assessing GC resistance are time consuming and have limited reproducibility; in this study, we sought to define a new method of evaluating GC sensitivity and resistance in vitro.

Methods

Based on the mechanisms of GC resistance, we hypothesized that the dual-luciferase report (DLR) assay could reflect the transcription effects of GC downstream of the GC-glucocorticoid receptor signaling pathway, thereby allowing the evaluation of reactions to GC. Sixty-two patients with differential GC response were included in this study. The prednisone induction test was used to divide the children with ALL into two groups: GC sensitive (GCS) and GC resistant (GCR). DLR assay was later conducted on those patients to evaluate its value for diagnosis of the GC reactivity. Receiver operating characteristic curves were used to identify the optimal assay cutoff for identifying response to GC.

Results

Using the DLR assay analysis, we found that GCR subjects showed significantly lower reporter/control ratios for luciferase, as compared with GCS subjects. The optimal cutoff value for GC response was 0.67, with sensitivity of 77.1% and specificity of 93.3%. The DLR assay results were consistent with prednisone induction test results. Further, the DLR assay was simpler, more sensitive, and less time-consuming than the prednisone induction test.

Conclusions

Our study showed that the DLR assay is relatively fast, simple, and sensitive. Accordingly, it could be useful for detecting GC response in children with ALL.

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Breast self-exam and patient interval associate with advanced breast cancer and treatment delay in Mexican women

Abstract

Purpose

The objective of this study was to compare treatment intervals in breast cancer patients according to the detection method (breast self-exam vs screening).

Patients and methods

We conducted a retrospective analysis including 291 breast cancer patients at a Mexican tertiary referral hospital.

Results

Breast cancer detection method was mostly breast self-exam (60%). The median patient interval was 60.5 days, and was associated with marital status and socioeconomic level. Differences between the two groups were statistically significant for global interval, p = 0.002; however, health system interval was not statistically different.

Conclusion

In our country, breast cancer screening is opportunistic, with several weaknesses within its management and quality systems. Our study showed that even in specialized health care centers, breast cancer is detected by self-exam in up to 2/3 of patients, which can explain the advanced stages at diagnosis in our country. In developing countries, the immediate health care access for breast cancer patients should be prioritized as an initial step to reduce the global treatment initiation interval in order to reduce mortality.

from Cancer via ola Kala on Inoreader http://ift.tt/2oscQfF
via IFTTT

Correlation of preoperative ROMA scores with clinical stage in epithelial ovarian cancer patients

Abstract

Purpose

The significance of the Risk of Ovarian Malignancy Algorithm (ROMA) in differentiating benign and malignant ovarian lesions has been evidenced. In our clinical work, we found that advanced ovarian cancer were accompanied commonly with high ROMA scores. Thus, this study aimed to clarify the performance of ROMA in different disease stage of epithelial ovarian cancer (EOC) prior to surgery.

Methods

Carbohydrate antigen (CA125) and human epididymis protein 4 (HE4) levels and ROMA scores in 221 patients with FIGO stage I, II or III/IV stage EOC were analyzed. The positive rates of CA125, HE4 and ROMA at each disease stage were calculated. Their cutoff values, sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) for distinguishing patients with FIGO stage I/II from those with FIGO stage III/IV were estimated via ROC curves.

Results

Serum CA125 and HE4 levels and ROMA scores rose significantly with advancing stage. ROMA and CA125 were significantly elevated more frequently in comparing with HE4 in EOC patients at with the same stage. Based on ROC curves, the cutoff values for FIGO stage III/IV EOC were 110 IU/mL, 126 pmol/L, 78 and 68% for CA125, HE4, premenopausal and postmenopausal ROMA, respectively. ROMA was the strongest predictor of FIGO stage, with the highest specificity, accuracy, and PPV, which were 84.4, 82.5, and 87.0% for postmenopausal patients, 89.3, 85.6, and 74.3% for premenopausal patients.

Conclusions

Our data suggest high ROMA scores correlated with advanced ovarian cancer prior to surgery. These observations suggest potential utility of ROMA in the comprehensively preoperative evaluation of EOC patients.

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The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series

Abstract

Melanomas in Chinese patients show relatively higher rates of acral and mucosal types than in other populations. However, the efficacy of checkpoint inhibitor therapies against these melanoma subtypes is not well defined. We analyzed 52 patients treated with ipilimumab, pembrolizumab, or a combination of both to evaluate the efficacy and safety of checkpoint inhibitors in Chinese patients with advanced melanoma, particularly those with acral and mucosal types. The objective response rates (ORRs) were 0, 25, and 20% for ipilimumab, pembrolizumab, and pembrolizumab plus ipilimumab, respectively. Pembrolizumab contained therapy was as effective in acral and mucosal melanoma patients (ORR 26.7 and 20%, respectively) as in non-acral cutaneous melanoma patients (ORR 26.7%). Baseline lactate dehydrogenase levels and relative lymphocyte counts were independent prognostic factors for PFS and OS. The incidences of grade 3–4 adverse events were 14% in the two monotherapy groups and 30% in the combined therapy group. The most frequent adverse events were elevation of aminotransferase, skin toxicity, thyroid dysfunction, pyrexia, and fatigue. Treatment-related rash or vitiligo was associated with a better prognosis. In summary, pembrolizumab-based therapy resulted in meaningful efficacy and good tolerability in Chinese patients with melanoma, including those with acral and mucosal types.

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The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series

Abstract

Melanomas in Chinese patients show relatively higher rates of acral and mucosal types than in other populations. However, the efficacy of checkpoint inhibitor therapies against these melanoma subtypes is not well defined. We analyzed 52 patients treated with ipilimumab, pembrolizumab, or a combination of both to evaluate the efficacy and safety of checkpoint inhibitors in Chinese patients with advanced melanoma, particularly those with acral and mucosal types. The objective response rates (ORRs) were 0, 25, and 20% for ipilimumab, pembrolizumab, and pembrolizumab plus ipilimumab, respectively. Pembrolizumab contained therapy was as effective in acral and mucosal melanoma patients (ORR 26.7 and 20%, respectively) as in non-acral cutaneous melanoma patients (ORR 26.7%). Baseline lactate dehydrogenase levels and relative lymphocyte counts were independent prognostic factors for PFS and OS. The incidences of grade 3–4 adverse events were 14% in the two monotherapy groups and 30% in the combined therapy group. The most frequent adverse events were elevation of aminotransferase, skin toxicity, thyroid dysfunction, pyrexia, and fatigue. Treatment-related rash or vitiligo was associated with a better prognosis. In summary, pembrolizumab-based therapy resulted in meaningful efficacy and good tolerability in Chinese patients with melanoma, including those with acral and mucosal types.

http://ift.tt/2peIri9

Phyllodes tumors are an uncommon differential diagnosis of axillary mass

Abstract

Phyllodes tumors are rare fibroepithelial neoplasm that account for less than 0.5% of all breast tumors and presentation in ectopic breast tissue is even rarer. In this paper, we describe a case of a phyllodes tumor in the ectopic breast tissue of the axilla. A 40-year-old woman presented with a well-circumscribed, firm, and freely mobile mass in the left axilla from 1 year ago. Ultrasound revealed a 5.5 × 4.5 × 4.5 cm homogenous and hypoecho lesion. The histopathologic analysis revealed that it was a benign phyllodes tumor. Phyllodes tumors in ectopic breast tissue may be confirmed to be a diagnostic difficulty, and this concept must be kept in mind while dealing with an axillary mass.

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Clinical Sequencing Using a Next-Generation Sequencing-Based Multiplex Gene Assay in Patients with Advanced Solid Tumors

Abstract

Advances in next-generation sequencing (NGS) technologies have enabled physicians to test for genomic alterations in multiple cancer-related genes at once in daily clinical practice. In April 2015, we introduced clinical sequencing using an NGS-based multiplex gene assay (OncoPrime^™) certified by the Clinical Laboratory Improvement Amendment. This assay covers the entire coding regions of 215 genes and the rearrangement of 17 frequently rearranged genes with clinical relevance in human cancers. The principal indications for the assay were cancers of unknown primary site, rare tumors, and any solid tumors that were refractory to standard chemotherapy. A total of 85 patients underwent testing with multiplex gene assay between April 2015 and July 2016. The most common solid tumor types tested were pancreatic (n = 19; 22.4%), followed by biliary tract (n = 14; 16.5%), and tumors of unknown primary site (n = 13; 15.3%). Samples from 80 patients (94.1%) were successfully sequenced. The median turnaround time was 40 days (range, 18–70 days). Potentially actionable mutations were identified in 69 of 80 patients (86.3%) and were most commonly found in TP53 (46.3%), KRAS (23.8%), APC (18.8%), STK11 (7.5%), and ATR (7.5%). Nine patients (13.0%) received a subsequent therapy based on the NGS assay results. Implementation of clinical sequencing using an NGS-based multiplex gene assay was feasible in the clinical setting and identified potentially actionable mutations in more than 80% of patients. Current challenges are to incorporate this genomic information into better therapeutic decision making.

This article is protected by copyright. All rights reserved.

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Roles of the PDZ-binding motif of HPV 16 E6 protein in oncogenic transformation of human cervical keratinocytes

Abstract

The high-risk human papillomavirus E6 proteins have been shown to interact with and lead degradation of PDZ-domain-containing proteins through its carboxy-terminal motif. This PDZ-binding motif plays important roles in transformation of cultured cells and carcinogenesis of E6-transgenic mice. However, its biological effects on the natural host cells have not been elucidated. We have examined its roles in an in vitro carcinogenesis model for cervical cancer, in which E6 and E7 together with activated HRAS (HRAS^G12V) can induce tumorigenic transformation of normal human cervical keratinocytes. In this model, E6Δ151 mutant, which is defective in binding to PDZ domains, almost lost tumorigenic ability, whereas E6SAT mutant which is defective in p53 degradation showed activity close to wild-type E6. Interestingly, we found decreased expression of PAR3 in E6-expressing cells independently of E6AP, which has not been previously recognized. Therefore, we knocked down several PDZ-domain containing proteins including PAR3 in human cervical keratinocytes expressing E7, HRAS^G12V and E6Δ151 to examine whether depletion of these proteins can restore the tumorigenic ability. Single knockdown of SCRIB, MAGI1 or PAR3 significantly but partially restored the tumorigenic ability. The combinatorial knockdown of SCRIB and MAGI1 cooperatively restored the tumorigenic ability, and additional depletion of PAR3 further enhanced the tumorigenic ability surpassing that induced by wild-type E6. These data highlight the importance of the carboxy-terminal motif of the E6 protein and downregulation of PAR3 in tumorigenic transformation of human cervical keratinocytes.

This article is protected by copyright. All rights reserved.

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Clinical Sequencing Using a Next-Generation Sequencing-Based Multiplex Gene Assay in Patients with Advanced Solid Tumors

Abstract

Advances in next-generation sequencing (NGS) technologies have enabled physicians to test for genomic alterations in multiple cancer-related genes at once in daily clinical practice. In April 2015, we introduced clinical sequencing using an NGS-based multiplex gene assay (OncoPrime^™) certified by the Clinical Laboratory Improvement Amendment. This assay covers the entire coding regions of 215 genes and the rearrangement of 17 frequently rearranged genes with clinical relevance in human cancers. The principal indications for the assay were cancers of unknown primary site, rare tumors, and any solid tumors that were refractory to standard chemotherapy. A total of 85 patients underwent testing with multiplex gene assay between April 2015 and July 2016. The most common solid tumor types tested were pancreatic (n = 19; 22.4%), followed by biliary tract (n = 14; 16.5%), and tumors of unknown primary site (n = 13; 15.3%). Samples from 80 patients (94.1%) were successfully sequenced. The median turnaround time was 40 days (range, 18–70 days). Potentially actionable mutations were identified in 69 of 80 patients (86.3%) and were most commonly found in TP53 (46.3%), KRAS (23.8%), APC (18.8%), STK11 (7.5%), and ATR (7.5%). Nine patients (13.0%) received a subsequent therapy based on the NGS assay results. Implementation of clinical sequencing using an NGS-based multiplex gene assay was feasible in the clinical setting and identified potentially actionable mutations in more than 80% of patients. Current challenges are to incorporate this genomic information into better therapeutic decision making.

This article is protected by copyright. All rights reserved.

http://ift.tt/2peSALC

Roles of the PDZ-binding motif of HPV 16 E6 protein in oncogenic transformation of human cervical keratinocytes

Abstract

The high-risk human papillomavirus E6 proteins have been shown to interact with and lead degradation of PDZ-domain-containing proteins through its carboxy-terminal motif. This PDZ-binding motif plays important roles in transformation of cultured cells and carcinogenesis of E6-transgenic mice. However, its biological effects on the natural host cells have not been elucidated. We have examined its roles in an in vitro carcinogenesis model for cervical cancer, in which E6 and E7 together with activated HRAS (HRAS^G12V) can induce tumorigenic transformation of normal human cervical keratinocytes. In this model, E6Δ151 mutant, which is defective in binding to PDZ domains, almost lost tumorigenic ability, whereas E6SAT mutant which is defective in p53 degradation showed activity close to wild-type E6. Interestingly, we found decreased expression of PAR3 in E6-expressing cells independently of E6AP, which has not been previously recognized. Therefore, we knocked down several PDZ-domain containing proteins including PAR3 in human cervical keratinocytes expressing E7, HRAS^G12V and E6Δ151 to examine whether depletion of these proteins can restore the tumorigenic ability. Single knockdown of SCRIB, MAGI1 or PAR3 significantly but partially restored the tumorigenic ability. The combinatorial knockdown of SCRIB and MAGI1 cooperatively restored the tumorigenic ability, and additional depletion of PAR3 further enhanced the tumorigenic ability surpassing that induced by wild-type E6. These data highlight the importance of the carboxy-terminal motif of the E6 protein and downregulation of PAR3 in tumorigenic transformation of human cervical keratinocytes.

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Radical hypo-fractionated radiotherapy with volumetric modulated arc therapy in lung cancer

Abstract

Background

This study aimed to analyse the feasibility and acute toxicity of radical hypo-fractionated radiotherapy (RT) for elderly patients with non-small-cell lung cancer (NSCLC).

Patients and methods

We conducted a retrospective evaluation of treatment with volumetric modulated arc therapy (VMAT) of elderly patients affected by stage III inoperable NSCLC. The dose prescription was 56 Gy in 20 fractions, 55 Gy in 22 fractions, or 50 Gy in 20 fractions. Target volume included only the primary lesion and the infiltrated lymph nodes. The primary end point was acute and late toxicity, while secondary end points were progression-free survival (PFS), and overall survival (OS).

Results

In all, 41 patients were included in this analysis. The mean age of the patients was 78.6 years, and 22 patients had staged IIIA while 19 patients had stage IIIB disease. All but one patient had pathological nodal involvement; 15 patients received chemotherapy before RT. Acute grade 1–2 toxicity was recorded in 25 (61%) patients. Late toxicity was recorded in 13 (32%) patients. No cases of G3 or G4 toxicity were recorded. Complete response was obtained in two (5%) patients, 26 (63%) showed a partial response, and two (5%) experience disease progression. At a mean follow-up of 9.9 months (range, 1.1–25.4), 17 patients had died from disease progression, one died from other causes, and 23 were alive. Median OS was 13.7 ± 1.5 months (95% CI: 10.7–16.7), OS at 12 and 18 months was 51.3 ± 9.5% and 35.1 ± 10.1%, respectively. Median PFS was 13.7 ± 2.3 months (95% CI: 9.1–18.2), and PFS at 12 and 18 months was 50.1 ± 9.9% and 38.9 ± 10.4%, respectively.

Conclusion

Radical hypo-fractionated VMAT is a promising treatment for locally advanced NSCLC in the elderly. The use of hypo-fractionated radiotherapy for lung cancer in older patients can be considered a valuable approach, particularly for patients with poor performance status or refusing other treatment approaches.

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The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series

Abstract

Melanomas in Chinese patients show relatively higher rates of acral and mucosal types than in other populations. However, the efficacy of checkpoint inhibitor therapies against these melanoma subtypes is not well defined. We analyzed 52 patients treated with ipilimumab, pembrolizumab, or a combination of both to evaluate the efficacy and safety of checkpoint inhibitors in Chinese patients with advanced melanoma, particularly those with acral and mucosal types. The objective response rates (ORRs) were 0, 25, and 20% for ipilimumab, pembrolizumab, and pembrolizumab plus ipilimumab, respectively. Pembrolizumab contained therapy was as effective in acral and mucosal melanoma patients (ORR 26.7 and 20%, respectively) as in non-acral cutaneous melanoma patients (ORR 26.7%). Baseline lactate dehydrogenase levels and relative lymphocyte counts were independent prognostic factors for PFS and OS. The incidences of grade 3–4 adverse events were 14% in the two monotherapy groups and 30% in the combined therapy group. The most frequent adverse events were elevation of aminotransferase, skin toxicity, thyroid dysfunction, pyrexia, and fatigue. Treatment-related rash or vitiligo was associated with a better prognosis. In summary, pembrolizumab-based therapy resulted in meaningful efficacy and good tolerability in Chinese patients with melanoma, including those with acral and mucosal types.

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Triple-modality treatment in patients with advanced stage tonsil cancer

BACKGROUND

Concurrent chemoradiation (CCRT) and upfront surgery followed by adjuvant therapy both are recommended treatment options for patients with advanced stage squamous cell carcinoma (SCC) of the tonsil. To the authors' knowledge, the question of whether surgical-based treatments can achieve better survival compared with CCRT has never been compared in a clinical trial. The authors analyzed the National Cancer Data Base to measure the impact of different treatment modalities on overall survival (OS).

METHODS

All patients aged ≤70 years diagnosed with clinical stage III to IVB (excluding T4B) SCC of the tonsil from 1998 through 2011 were selected. Analysis was limited to patients receiving CCRT, surgery plus CCRT, or surgery followed by adjuvant radiotherapy (RT). OS was compared using the Kaplan-Meier method and log-rank test. Univariable and multivariable hazards analyses were performed to identify factors significant for survival. Propensity score matching was performed.

RESULTS

There were 16,891 patients who met the inclusion criteria. The most common treatment was CCRT (8123 patients; 48.1%), followed by surgery plus CCRT (5249; 31.1%) and surgery plus RT (3519 patients; 20.8%). Patients treated with surgery plus CCRT were found to have the highest 3-year OS rate (88.5%) followed by those treated with surgery plus RT (84%) and CCRT (74.2%) (P<.0001). In a propensity score-matched subpopulation of 4962 patients, the 3-year OS rate was 90.2% for those treated with surgery plus CCRT, 84.9% for those treated with surgery plus RT, and 82.1% for those treated with definitive CCRT (P<.0001).

CONCLUSIONS

Patients with advanced stage SCC of the tonsil who underwent surgery followed by CCRT had the greatest OS. Patients undergoing upfront surgery may avoid chemotherapy without jeopardizing survival. Triple-modality therapy may provide a survival benefit for a subset of patients with advanced stage tonsil cancer. Cancer 2017. © 2017 American Cancer Society.

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Breast cancer stage variation and survival in association with insurance status and sociodemographic factors in US women 18 to 64 years old

BACKGROUND

Few population-based studies have examined the association between health insurance status and breast cancer stage at diagnosis and survival. The degree to which sociodemographic characteristics explain this association is also unclear. This study examined associations between insurance status and sociodemographic characteristics and stage at diagnosis and survival.

METHODS

Using the Surveillance, Epidemiology, and End Results 18 registries database, we identified 52,048 women aged 18 to 64 years who were diagnosed with breast cancer in 2007 and 2008. Associations between insurance status and sociodemographic variables and stage at diagnosis and survival were examined with logistic and Cox proportional hazards regression models to calculate adjusted odds ratios (ORs), hazard ratios (HRs), and associated confidence intervals (CIs).

RESULTS

The odds of a later stage breast cancer diagnosis were increased in women with Medicaid (OR, 2.36; 95% CI, 2.19-2.55) and no insurance (OR, 2.64; 95% CI, 2.29-3.04) versus private insurance, in women who had reported black race (OR, 1.18; 95% CI, 1.09-1.28) versus white race, in women who were unmarried (OR, 1.25; 95% CI, 1.18-1.33) versus married at diagnosis, and in women who were 18 to 39 years old (OR, 1.29; 95% CI, 1.18-1.41) versus 40 to 64 years old at diagnosis. The hazard of breast cancer death was increased in association with Medicaid (HR, 1.40; 95% CI, 1.30-1.51) and no insurance (HR, 1.61; 95% CI, 1.41-1.84) versus private insurance, with reported black race (HR, 1.39; 95% CI, 1.29-1.50) versus reported white race, and with being unmarried (HR, 1.19; 95% CI, 1.12-1.27) versus being married.

CONCLUSIONS

Insurance status at diagnosis and sociodemographic factors are associated with breast cancer mortality. Factors underlying these associations warrant further study. Cancer 2017. © 2017 American Cancer Society.

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Immunotherapy with single agent nivolumab for advanced leiomyosarcoma of the uterus: Results of a phase 2 study

BACKGROUND

Immunotherapy has changed the therapeutic landscape in oncology. Advanced uterine leiomyosarcoma (ULMS) remains an incurable disease in most cases, and despite new drug approvals, improvements in overall survival have been modest at best. The goal of this study was to evaluate programmed-death 1 (PD-1) inhibition with nivolumab in this patient population.

METHODS

This single-center phase 2 trial completed enrollment between May and October 2015. Patients received 3 mg/kg of intravenous nivolumab on day 1 of each 2-week cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. We assessed PD-1, PD-ligand 1 (PD-L1), and PD-2 expression in archival tumor samples and variations in immune-phenotyping of circulating immune cells during treatment.

RESULTS

Twelve patients were enrolled in the first stage of the 2-stage design. A median of 5 (range, 2-6) 2-week cycles of nivolumab were administered. Of the 12 patients, none responded to treatment. The overall median progression-free survival was 1.8 months (95% confidence interval, 0.8-unknown). The study did not open the second stage due to lack of benefit as defined by the statistical plan. Archival samples were available for 83% of patients. PD-1 (>3% of cells), PD-L1, and PD-L2 (>5% and >10% of tumor cells, respectively) expression were observed in 20%, 20%, and 90% of samples, respectively. No significant differences were observed between pre- and posttreatment cell phenotypes.

CONCLUSION

Single-agent nivolumab did not demonstrate a benefit in this cohort of previously treated advanced ULMS patients. Further biomarker-driven approaches and studies evaluating combined immune checkpoint-modulators should be considered. Cancer 2017. © 2017 American Cancer Society.

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Improved outcomes after successful implementation of a pediatric early warning system (PEWS) in a resource-limited pediatric oncology hospital

BACKGROUND

Hospitalized pediatric oncology patients are at high risk of clinical decline and mortality, particularly in resource-limited settings. Pediatric early warning systems (PEWS) aid in the early identification of clinical deterioration; however, there are limited data regarding their feasibility or impact in low-resource settings. This study describes the successful implementation of PEWS at the Unidad Nacional de Oncología Pediátrica (UNOP), a pediatric oncology hospital in Guatemala, resulting in improved inpatient outcomes.

METHODS

A modified PEWS was implemented at UNOP with systems to track errors, transfers to a higher level of care, and high scores. A retrospective cohort study was used to evaluate clinical deterioration events in the year before and after PEWS implementation.

RESULTS

After PEWS implementation at UNOP, there was 100% compliance with PEWS documentation and an error rate of <10%. Implementation resulted in 5 high PEWS per week, with 30% of patients transferring to a higher level of care. Among patients requiring transfer to the pediatric intensive care unit (PICU), 93% had an abnormal PEWS before transfer. The rate of clinical deterioration events decreased after PEWS implementation (9.3 vs 6.5 per 1000-hospitalpatient-days, p = .003). Despite an 18% increase in total hospital patient-days, PICU utilization for inpatient transfers decreased from 1376 to 1088 PICU patient-days per year (21% decrease; P<.001).

CONCLUSIONS

This study describes the successful implementation of PEWS in a pediatric oncology hospital in Guatemala, resulting in decreased inpatient clinical deterioration events and PICU utilization. This work demonstrates that PEWS is a feasible and effective quality improvement measure to improve hospital care for children with cancer in hospitals with limited resources. Cancer 2017. © 2017 American Cancer Society.

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Regulations and policies regarding e-cigarettes

Electronic cigarettes (e-cigarettes) are a growing public health concern because of a dramatic increase in use by adolescents and the uncertainty of potential health impacts. These health concerns and lack of an established federal regulatory scheme have led many local and state governments to address the regulatory void for e-cigarettes by incorporating them into the statutory definition of tobacco or by passing laws specific to the use of e-cigarettes. In August 2016, the US Food and Drug Administration issued a final rule deeming e-cigarettes within their authority; providing uniform requirements like premarket approval applications, Harmful and Potentially Harmful Constituents reporting, and warning labels; and establishing 18 years as a minimum age of purchase. Although the impact on the public's health remains uncertain, regulations and laws governing e-cigarettes continue to develop. This review highlights the available data regarding safety and public health impacts of e-cigarettes and details the status of US regulations and policies affecting their sale and use. Cancer 2017. © 2017 American Cancer Society.

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Lay health educators and print materials for the promotion of colorectal cancer screening among Korean Americans: A randomized comparative effectiveness study

BACKGROUND

Colorectal cancer (CRC) is the second most commonly diagnosed cancer among Korean American men and women. Although CRC screening is effective in reducing the burden of this disease, studies have shown that Korean Americans have low screening rates.

METHODS

The authors conducted a 2-arm cluster randomized controlled trial comparing a brochure (print) with a brochure and lay health educator (LHE) outreach (print + LHE) in increasing CRC screening rates among Korean American individuals. Self-administered written surveys at baseline and at 6 months assessed knowledge of CRC and its screening, ever screening, and being up to date with screening.

RESULTS

A total of 28 LHEs recruited 348 participants aged 50 to 75 years from their social networks. Significant percentages of participants reported not having health insurance (29.3%) or a usual source of care (35.6%). At 6 months postintervention, the print + LHE participants had a greater increase in knowledge compared with those in the print arm (P = .0013). In multivariable analyses, both groups had significant increases in ever screening (print plus LHE: odds ratio [OR], 1.60 [95% confidence interval (95% CI), 1.26-2.03] and print: OR, 1.42 [95% CI, 1.10-1.82]) and being up to date with screening (print plus LHE: OR, 1.63 [95% CI, 1.23-2.16] and print: OR, 1.40 [95% CI, 1.04-1.89]). However, these increases did not differ significantly between the study arms. Having insurance and having seen a provider within the past year were found to be positively associated with screening.

CONCLUSIONS

Compared with a brochure, LHE outreach yielded greater increases in knowledge but resulted in similar increases in CRC screening in a Korean American population with barriers to health care access. More work is needed to appropriately address logistical and system barriers in this community. Cancer 2017. © 2017 American Cancer Society.

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Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors

BACKGROUND

Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose-escalation study, the authors investigated IMGN853 in patients with FRα-positive solid tumors.

METHODS

Patients received IMGN853 on day 1 of a 21-day cycle (once every 3 weeks dosing), with cycles repeated until patients experienced dose-limiting toxicity or progression. Dose escalation commenced in single-patient cohorts for the first 4 planned dose levels and then followed a standard 3 + 3 scheme. The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Secondary objectives were to determine safety and tolerability, to characterize the pharmacokinetic profile, and to describe preliminary clinical activity.

RESULTS

In total, 44 patients received treatment at doses escalating from 0.15 to 7.0 mg/kg. No meaningful drug accumulation was observed with the dosing regimen of once every 3 weeks. The most common treatment-related adverse events were fatigue, blurred vision, and diarrhea, the majority of which were grade 1 or 2. The dose-limiting toxicities observed were grade 3 hypophosphatemia (5.0 mg/kg) and grade 3 punctate keratitis (7.0 mg/kg). Two patients, both of whom were individuals with epithelial ovarian cancer, achieved confirmed tumor responses according to Response Evaluation Criteria in Solid Tumors 1.1, and each was a partial response.

CONCLUSIONS

IMGN853 demonstrated a manageable safety profile and encouraging preliminary clinical activity, particularly in patients with ovarian cancer. The results establish a recommended phase 2 dosing of 6.0 mg/kg (based on adjusted ideal body weight) once every 3 weeks. Cancer 2017. © 2017 American Cancer Society.

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An alert to Latin America: Current human papillomavirus vaccination trends highlight key barriers to successful implementation

Human papillomavirus vaccine programs run the risk of repeating the problems associated with Papanicolaou testing programs in low-income and middle-income countries: an efficient, life-saving tool that unfortunately is underused for cancer prevention. There is a great need for vigilance in the ongoing implementation of the human papillomavirus vaccine in Latin America.

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Triple-modality treatment in patients with advanced stage tonsil cancer

BACKGROUND

Concurrent chemoradiation (CCRT) and upfront surgery followed by adjuvant therapy both are recommended treatment options for patients with advanced stage squamous cell carcinoma (SCC) of the tonsil. To the authors' knowledge, the question of whether surgical-based treatments can achieve better survival compared with CCRT has never been compared in a clinical trial. The authors analyzed the National Cancer Data Base to measure the impact of different treatment modalities on overall survival (OS).

METHODS

All patients aged ≤70 years diagnosed with clinical stage III to IVB (excluding T4B) SCC of the tonsil from 1998 through 2011 were selected. Analysis was limited to patients receiving CCRT, surgery plus CCRT, or surgery followed by adjuvant radiotherapy (RT). OS was compared using the Kaplan-Meier method and log-rank test. Univariable and multivariable hazards analyses were performed to identify factors significant for survival. Propensity score matching was performed.

RESULTS

There were 16,891 patients who met the inclusion criteria. The most common treatment was CCRT (8123 patients; 48.1%), followed by surgery plus CCRT (5249; 31.1%) and surgery plus RT (3519 patients; 20.8%). Patients treated with surgery plus CCRT were found to have the highest 3-year OS rate (88.5%) followed by those treated with surgery plus RT (84%) and CCRT (74.2%) (P<.0001). In a propensity score-matched subpopulation of 4962 patients, the 3-year OS rate was 90.2% for those treated with surgery plus CCRT, 84.9% for those treated with surgery plus RT, and 82.1% for those treated with definitive CCRT (P<.0001).

CONCLUSIONS

Patients with advanced stage SCC of the tonsil who underwent surgery followed by CCRT had the greatest OS. Patients undergoing upfront surgery may avoid chemotherapy without jeopardizing survival. Triple-modality therapy may provide a survival benefit for a subset of patients with advanced stage tonsil cancer. Cancer 2017. © 2017 American Cancer Society.

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Breast cancer stage variation and survival in association with insurance status and sociodemographic factors in US women 18 to 64 years old

BACKGROUND

Few population-based studies have examined the association between health insurance status and breast cancer stage at diagnosis and survival. The degree to which sociodemographic characteristics explain this association is also unclear. This study examined associations between insurance status and sociodemographic characteristics and stage at diagnosis and survival.

METHODS

Using the Surveillance, Epidemiology, and End Results 18 registries database, we identified 52,048 women aged 18 to 64 years who were diagnosed with breast cancer in 2007 and 2008. Associations between insurance status and sociodemographic variables and stage at diagnosis and survival were examined with logistic and Cox proportional hazards regression models to calculate adjusted odds ratios (ORs), hazard ratios (HRs), and associated confidence intervals (CIs).

RESULTS

The odds of a later stage breast cancer diagnosis were increased in women with Medicaid (OR, 2.36; 95% CI, 2.19-2.55) and no insurance (OR, 2.64; 95% CI, 2.29-3.04) versus private insurance, in women who had reported black race (OR, 1.18; 95% CI, 1.09-1.28) versus white race, in women who were unmarried (OR, 1.25; 95% CI, 1.18-1.33) versus married at diagnosis, and in women who were 18 to 39 years old (OR, 1.29; 95% CI, 1.18-1.41) versus 40 to 64 years old at diagnosis. The hazard of breast cancer death was increased in association with Medicaid (HR, 1.40; 95% CI, 1.30-1.51) and no insurance (HR, 1.61; 95% CI, 1.41-1.84) versus private insurance, with reported black race (HR, 1.39; 95% CI, 1.29-1.50) versus reported white race, and with being unmarried (HR, 1.19; 95% CI, 1.12-1.27) versus being married.

CONCLUSIONS

Insurance status at diagnosis and sociodemographic factors are associated with breast cancer mortality. Factors underlying these associations warrant further study. Cancer 2017. © 2017 American Cancer Society.

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Immunotherapy with single agent nivolumab for advanced leiomyosarcoma of the uterus: Results of a phase 2 study

BACKGROUND

Immunotherapy has changed the therapeutic landscape in oncology. Advanced uterine leiomyosarcoma (ULMS) remains an incurable disease in most cases, and despite new drug approvals, improvements in overall survival have been modest at best. The goal of this study was to evaluate programmed-death 1 (PD-1) inhibition with nivolumab in this patient population.

METHODS

This single-center phase 2 trial completed enrollment between May and October 2015. Patients received 3 mg/kg of intravenous nivolumab on day 1 of each 2-week cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. We assessed PD-1, PD-ligand 1 (PD-L1), and PD-2 expression in archival tumor samples and variations in immune-phenotyping of circulating immune cells during treatment.

RESULTS

Twelve patients were enrolled in the first stage of the 2-stage design. A median of 5 (range, 2-6) 2-week cycles of nivolumab were administered. Of the 12 patients, none responded to treatment. The overall median progression-free survival was 1.8 months (95% confidence interval, 0.8-unknown). The study did not open the second stage due to lack of benefit as defined by the statistical plan. Archival samples were available for 83% of patients. PD-1 (>3% of cells), PD-L1, and PD-L2 (>5% and >10% of tumor cells, respectively) expression were observed in 20%, 20%, and 90% of samples, respectively. No significant differences were observed between pre- and posttreatment cell phenotypes.

CONCLUSION

Single-agent nivolumab did not demonstrate a benefit in this cohort of previously treated advanced ULMS patients. Further biomarker-driven approaches and studies evaluating combined immune checkpoint-modulators should be considered. Cancer 2017. © 2017 American Cancer Society.

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Improved outcomes after successful implementation of a pediatric early warning system (PEWS) in a resource-limited pediatric oncology hospital

BACKGROUND

Hospitalized pediatric oncology patients are at high risk of clinical decline and mortality, particularly in resource-limited settings. Pediatric early warning systems (PEWS) aid in the early identification of clinical deterioration; however, there are limited data regarding their feasibility or impact in low-resource settings. This study describes the successful implementation of PEWS at the Unidad Nacional de Oncología Pediátrica (UNOP), a pediatric oncology hospital in Guatemala, resulting in improved inpatient outcomes.

METHODS

A modified PEWS was implemented at UNOP with systems to track errors, transfers to a higher level of care, and high scores. A retrospective cohort study was used to evaluate clinical deterioration events in the year before and after PEWS implementation.

RESULTS

After PEWS implementation at UNOP, there was 100% compliance with PEWS documentation and an error rate of <10%. Implementation resulted in 5 high PEWS per week, with 30% of patients transferring to a higher level of care. Among patients requiring transfer to the pediatric intensive care unit (PICU), 93% had an abnormal PEWS before transfer. The rate of clinical deterioration events decreased after PEWS implementation (9.3 vs 6.5 per 1000-hospitalpatient-days, p = .003). Despite an 18% increase in total hospital patient-days, PICU utilization for inpatient transfers decreased from 1376 to 1088 PICU patient-days per year (21% decrease; P<.001).

CONCLUSIONS

This study describes the successful implementation of PEWS in a pediatric oncology hospital in Guatemala, resulting in decreased inpatient clinical deterioration events and PICU utilization. This work demonstrates that PEWS is a feasible and effective quality improvement measure to improve hospital care for children with cancer in hospitals with limited resources. Cancer 2017. © 2017 American Cancer Society.

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