Clinical Development of HER3-targeting Monoclonal Antibodies: Perils and Progress

Publication date: Available online 18 June 2018
Source:Cancer Treatment Reviews
Author(s): Wolfgang Jacob, Ian James, Max Hasmann, Martin Weisser
The human epidermal growth factor receptor (HER) family consists of four transmembrane receptor tyrosine kinases: epidermal growth factor receptor (EGFR), HER2, HER3, and HER4. They are part of a complex signalling network and stimulate intracellular pathways regulating cell growth and differentiation. So far, monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors targeting EGFR and HER2 have been developed and approved. Recently, focus has turned to HER3 as it may play an important role in resistance to EGFR- and HER2-targeting therapies. HER3-targeting agents have been undergoing clinical evaluation for the last 10 years and currently thirteen mAbs are in phase 1 or 2 clinical studies. Single agent activity has proven to be limited, however, the tolerability was favourable. Thus, combinations of HER3-binding mAbs with other HER-targeting therapies or chemotherapies have been pursued in various solid tumor entities. Data indicate that the HER3-binding ligand heregulin may serve as a response prediction marker for HER3-targeting therapy. Within this review the current status of clinical development of HER3-targeting compounds is described.



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Clinical benefit of controversial first line systemic therapies for advanced stage ovarian cancer – ESMO-MCBS scores

Publication date: Available online 18 June 2018
Source:Cancer Treatment Reviews
Author(s): KE Broekman, M Jalving, H van Tinteren, C Sessa, AKL Reyners
BackgroundThe magnitude of clinical benefit scale (MCBS) was introduced by the European Society of Medical Oncology (ESMO) to quantify the clinical benefit of therapeutic regimens and to prioritise therapies. It distinguishes curative from palliative treatments and ranks their benefit based on overall survival (OS), progression free survival (PFS), quality of life (QoL) and toxicity. Objective of this study on the first line treatment of ovarian cancer was to evaluate the evidence for the current standard of care using the ESMO-MCBSv1.1 with an emphasis on controversial therapeutic options: intraperitoneal chemotherapy, dose-dense paclitaxel and bevacizumab.MethodsPhase III trials, published since 1992, investigating first line systemic treatment of Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage IIB-IV epithelial ovarian cancer were included. Since most studies included patients with FIGO stage IV disease or incomplete debulking, all treatments were judged to be palliative. Treatments were graded 5 to 1 on the ESMO-MCBSv1.1, where grades 5 and 4 represent a high level of clinical benefit.Results55 studies met the inclusion criteria. ESMO-MCBS scores were calculated for eleven studies that showed a statistically significant benefit of the experimental treatment. Intraperitoneal (ip) cisplatin scored a 4 and 3, but two other studies were negative and therefore not scored on the ESMO-MCBS. Dose-dense paclitaxel showed substantial clinical benefit in one study (score 4), but three studies were negative. Addition of bevacizumab also scored a 4 in one study subgroup including high-risk patients but a 2 in another trial with a larger study population.ConclusionBased on ESMO-MCBS scores, dose-dense paclitaxel and intraperitoneal chemotherapy cannot be recommended as standard treatment. Bevacizumab should be considered only in the high-risk population. The ESMO-MCBSv1.1. helps to summarise reported studies on controversial treatment regimens, and identifies their weaknesses.



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Locally advanced gastro-oesophageal cancer: recent therapeutic advances and research directions

Publication date: Available online 18 June 2018
Source:Cancer Treatment Reviews
Author(s): Lorenzo Fornaro, Enrico Vasile, Giuseppe Aprile, Thorsten Oliver Goetze, Caterina Vivaldi, Alfredo Falcone, Salah-Eddin Al-Batran
Gastric (GC) and gastro-oesophageal (GOJC) adenocarcinomas are often considered as a single entity, even though differences exist in epidemiology, clinical presentation, molecular biology and treatment options. Locally advanced, resectable disease represents a particularly challenging scenario, as many critical issues need to be addressed. In both GC and GOJC among Western countries, systemic chemotherapy demonstrated the greatest benefit when administered before and after surgery and perioperative chemotherapy has been set as a standard in this setting. Nonetheless, multiple chemotherapy regimens have been tested and direct comparisons have been only recently presented. Adjuvant chemoradiotherapy is an option as well, but several trials have questioned its role when more effective combination regimens are used. With regards to GOJC, preoperative chemoradiotherapy is an alternative to perioperative chemotherapy, as it is associated with higher pathologic responses and a different toxicity profile: however, a definitive comparison with chemotherapy is ongoing. Herein, we review the current options for the treatment of resectable GC and GOJC and the main open questions in the management of these patients, trying to depict an update of the available algorithms for everyday practice. Moreover, we summarize the design and preliminary results of the randomized trials in progress that will hopefully give definitive answers to the most debated issues in the field.



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Medication-related osteonecrosis of the jaw: prevention, diagnosis and management in patients with cancer and bone metastases

Publication date: Available online 18 June 2018
Source:Cancer Treatment Reviews
Author(s): Sven Otto, Christoph Pautke, Tim Van den Wyngaert, Daniela Niepel, Morten Schiødt
Medication-related osteonecrosis of the jaw (MRONJ) is primarily an adverse side effect of denosumab or bisphosphonates (particularly when used at high doses to prevent skeletal-related events [SREs] in patients with cancer and bone metastases) or possibly anti-angiogenic cancer treatment. While the implementation of preventive measures over recent years has reduced the risk of MRONJ in patients with bone metastases due to cancer, it is imperative to balance the risk of MRONJ against the beneficial effects of treatment with denosumab or bisphosphonates on the skeletal health of patients. Despite growing awareness of MRONJ within the medical community, there is a lack of large-scale, prospective clinical studies in this rapidly evolving field. Discussing preventive measures with patients and implementing them, both before and during treatment with bisphosphonates or denosumab, is the best option to reduce the risk of MRONJ. In particular, avoiding bone trauma and preventing and treating dental infections before and during denosumab or bisphosphonate therapy is crucial to minimize the risk of MRONJ. If MRONJ develops, conservative (non-surgical) treatment can provide symptom relief, but achieving mucosal closure remains challenging. When management of symptoms and mucosal healing are the ultimate goals of therapy, or after failure of conservative treatment, a surgical approach may be beneficial. This critical review, based on a best-evidence review of currently available literature, provides clear practical guidelines to help to prevent, manage and treat MRONJ. Overall, a multidisciplinary, pragmatic approach to MRONJ should be adopted, prioritizing patient's quality of life and management of their skeletal malignant disease.



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The poor design of clinical trials of statins in oncology may explain their failure – lessons for drug repurposing

Publication date: Available online 18 June 2018
Source:Cancer Treatment Reviews
Author(s): Marwan I. Abdullah, Elizabeth de Wolf, Mohammed J. Jawad, Alan Richardson
Statins are widely used to treat hypercholesterolaemia. However, by inhibiting the production of mevalonate, they also reduce the production of several isoprenoids that are necessary for the function of small GTPase oncogenes such as Ras. As such, statins offer an attractive way to inhibit an "undruggable" target, suggesting that they may be usefully repurposed to treat cancer. However, despite numerous studies, there is still no consensus whether statins are useful in the oncology arena. Numerous preclinical studies have provided evidence justifying the evaluation of statins in cancer patients. Some retrospective studies of patients taking statins to control cholesterol have identified a reduced risk of cancer mortality. However, prospective clinical studies have mostly not been successful. We believe that this has occurred because many of the prospective clinical trials have been poorly designed. Many of these trials have failed to take into account some or all of the factors identified in preclinical studies that are likely to be necessary for statins to be efficacious. We suggest an improved trial design which takes these factors into account. Importantly, we suggest that the design of clinical trials of drugs which are being considered for repurposing should not assume it is appropriate to use them in the same way as they are used in their original indication. Rather, such trials deserve to be informed by preclinical studies that are comparable to those for any novel drug.



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Economic burden of patients with diffuse large B-cell and follicular lymphoma treated in the USA

Future Oncology, Ahead of Print.


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Immune check-point in cervical cancer

Publication date: Available online 18 June 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): F. De Felice, C. Marchetti, I. Palaia, R. Ostuni, L. Muzii, V. Tombolini, P. Benedetti Panici
Despite different treatment strategies, locally advanced cervical cancer (CC) persists as one of the most incurable cancers among women worldwide. In fact, this setting of patients are at high risk of persistent and recurrent disease. In recent years, researches have investigated immune check-point inhibitors in hopes of determining improved response to therapy with prolongation of survival.We reviewed the published literature and conference proceedings and presented pivotal trials supporting immune check-point inhibitors use in the treatment of CC.



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The changing scenario of 1st line therapy in non-oncogene addicted NSCLCs in the era of immunotherapy

Publication date: Available online 18 June 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): A Russo, T Franchina, GRR Ricciardi, G Toscano, S Schifano, G Lo Certo, A Battaglia, E Pantò, M Scaffidi Fonti, V Adamo
During the last two decades front-line treatment of metastatic Non Small Cell Lung Cancer (NSCLC) has profoundly changed moving from the old "one size fits all" concept to a "histology-based" approach and then, for a small subgroup of patients to a "molecularly-selected" one. The development of immune checkpoint inhibitors and the unprecedented results reported in 2^nd/3^rd line prompted the evaluation of these novel therapeutic agents in chemotherapy-naïve patients either alone or in combination with platinum-based chemotherapy. Several randomized trials are evaluating the impact of immune-checkpoint inhibitors in 1^st line and some of them have yet produced preliminary evidence of efficacy. However, still a long way to go and several questions are still unanswered, including proper patients selection, optimal sequential/combinatorial use of these agents, appropriate treatment duration, and finally the identification of predictive biomarkers. The aim of this paper is to provide a comprehensive overview on the growing role of immune checkpoint inhibitors in the upfront treatment of advanced non-oncogene addicted NSCLC either as single agent or in combination with other agents.



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Application of a carbon nanoparticle suspension for sentinel lymph node mapping in patients with early breast cancer: a retrospective cohort study

Abstract

Background

To stage axillary lymph nodes in women with early-stage breast cancer, sentinel lymph node biopsy (SLNB), rather than axillary lymph node dissection (ALND), has been employed. Moreover, different tracer methods have various advantages and disadvantages. In recent years, carbon nanoparticle suspensions (CNSs) have been used as lymph node tracers during surgeries for thyroid cancer, gastric cancer, and colorectal cancer. The study retrospectively analyzed the feasibility and accuracy of CNS for sentinel lymph node (SLN) mapping in patients with early breast cancer.

Methods

This single-center, retrospective study included breast cancer patients who underwent SLNB from January 1, 2016, to December 31, 2017, in the Department of Breast Cancer, Guangdong General Hospital. All patients received standard SLNB surgery using a CNS tracer.

Results

A total of 332 cases were included in this study. The SLN identification rate was 99.1% (329/332), and the mean number of SLNs was 2.6 (range, 1–6). SLN metastasis was found in 62 (18.8%) cases, of which 90.3% were found to be macrometastases. The sensitivity of SLNB was 95.9% (47/49), with a specificity of 100% (42/42), a positive predictive value of 100% (47/47), a negative predictive value of 95.5% (42/44), and a false-negative rate of 4.1% (2/49).

Conclusion

The identification and predictive values of a CNS tracer for SLNB were satisfactory.

https://ift.tt/2M5nSin

The endosomal protein CEMIP links Wnt signaling to MEK1-ERK1/2 activation in Selumetinib-resistant intestinal organoids

MAPK signaling pathways are constitutively active in colon cancer and also promote acquired resistance to MEK1 inhibition. Here we demonstrate that BRAFV600E-mutated colorectal cancers acquire resistance to MEK1 inhibition by inducing expression of the scaffold protein CEMIP through a beta-catenin- and FRA-1-dependent pathway. CEMIP was found in endosomes and bound MEK1 to sustain ERK1/2 activation in MEK1 inhibitor-resistant BRAFV600E-mutated colorectal cancers. The CEMIP-dependent pathway maintained c-Myc protein levels through ERK1/2 and provided metabolic advantage in resistant cells, potentially by sustaining amino acids synthesis. CEMIP silencing circumvented resistance to MEK1 inhibition, partly, through a decrease of both ERK1/2 signaling and c-Myc. Together, our data identify a cross-talk between Wnt and MAPK signaling cascades, which involves CEMIP. Activation of this pathway promotes survival by potentially regulating levels of specific amino acids via a Myc-associated cascade. Targeting this node may provide a promising avenue for treatment of colon cancers that have acquired resistance to targeted therapies.

https://ift.tt/2lguTkT

Circulating tumor cells undergoing EMT provide a metric for diagnosis and prognosis of patients with hepatocellular carcinoma

To clarify the significance of circulating tumor cells (CTC) undergoing epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) patients, we used an advanced CanPatrol™ CTC-enrichment technique and in situ hybridization (ISH) to enrich and classify CTC from blood samples. 101 of 112 (90.18%) HCC patients were CTC-positive, even with early-stage disease. CTC were also detected in 2 of 12 hepatitis B virus (HBV) patients, both of whom had small HCC tumors detected within 5 months. CTC count ≥16 and mesenchymal-CTC (M-CTC) percentage ≥2% prior to resection were significantly associated with early recurrence, multi-intrahepatic recurrence, and lung metastasis. Postoperative CTC monitoring in 10 patients found that most had an increased CTC count and M-CTC percentage before clinically detectable recurrence nodules appeared. Analysis of HCC with high CTC count and high M-CTC percentage identified 67 differentially expressed cancer-related genes involved in cancer-related biological pathways (e.g. cell adhesion and migration, tumor angiogenesis, and apoptosis). One of the identified genes, BCAT1, was significantly upregulated, and knockdown in Hepg2, Hep3B, and Huh7 cells reduced cell proliferation, migration, and invasion while promoting apoptosis. A concomitant increase in epithelial marker expression (EpCAM and E-cadherin) and reduced mesenchymal marker expression (vimentin and Twist) suggests that BCAT1 may trigger the EMT process. Overall, CTC were highly correlated with HCC characteristics, representing a novel marker for early diagnosis and a prognostic factor for early recurrence. BCAT1 overexpression may induce CTC release by triggering EMT and may be an important biomarker of HCC metastasis.

https://ift.tt/2tdC8xw

Zinc Metallochaperones Reactivate Mutant p53 Using an ON/OFF Switch Mechanism: A New Paradigm in Cancer Therapeutics

Purpose: Zinc metallochaperones (ZMCs) are a new class of anti-cancer drugs that reactivate zinc deficient mutant p53 by raising and buffering intracellular zinc levels sufficiently to restore zinc binding. In vitro pharmacodynamics of ZMCs indicate that p53 mutant activity is ON by 4-6 hours and is OFF by 24. We sought to understand the mechanism of this regulation and to translate these findings pre-clinically. We further sought to innovate the formulation of ZMCs to improve efficacy. Experimental Design: We performed in vitro mechanistic studies to determine the role of cellular zinc homeostatic mechanisms in the transient pharmacodynamics of ZMCs. We conducted pre-clinical pharmacokinetic (PK), pharmacodymanic (PD) and efficacy studies using a genetically engineered murine pancreatic cancer model (KPC) to translate these mechanistic findings and investigate a novel ZMC formulation. Results: In vitro, cellular zinc homeostatic mechanisms that restore zinc to its physiologic levels function as the OFF switch in ZMC pharmacodynamics. In vivo PK studies indicate that ZMCs have a short half life (<30 minutes), which is sufficient to significantly improve survival in mice expressing a zinc deficient allele (p53R172H) while having no effect in mice expressing a non-zinc deficient allele (p53R270H). We synthesized a novel formulation of the drug in complex with zinc and demonstrate this significantly improves survival over ZMC1. Conclusions: Cellular zinc homeostatic mechanisms function as an OFF switch in ZMC pharmacodynamics indicating that a brief period of p53 mutant reactivation is sufficient for on-target efficacy. ZMCs synthesized in complex with zinc are an improved formulation.

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Clinical relevance and suppressive capacity of human MDSC subsets

Purpose: Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of pathologically expanded myeloid cells with immunosuppressive activity. In human disease three major MDSC subpopulations can be defined as monocytic M-MDSC, granulocytic PMN-MDSC and early stage e-MDSC, which lack myeloid lineage markers of the former two subsets. It was the purpose of this study to determine and compare the immunosuppressive capacity and clinical relevance of each of these subsets in patients with solid cancer. Experimental Design: The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in a cohort of 49 patients with advanced head and neck cancer (HNC) and 22 patients with urological cancers. Sorted and purified MDSC subsets were tested in vitro for their T cell suppressive capacity. Frequency of circulating MDSC was correlated with overall survival of HNC patients. Results: A high frequency of PMN-MDSC most strongly correlated with poor overall survival in HNC. T cell suppressive activity was higher in PMN-MDSC compared with M-MDSC and e-MDSC. A subset of CD66b+/CD11b+/CD16+ mature PMN-MDSC displayed high expression and activity of arginase I, and was superior to the other subsets in suppressing proliferation and cytokine production of T cells in both cancer types. High levels of this CD11b+/CD16+ PMN-MDSC, but not other PMN-MDSC subsets, strongly correlated with adverse outcome in HNC. Conclusions: A subset of mature CD11b+/CD16+ PMN-MDSC was identified as the MDSC subset with the strongest immunosuppressive activity and the highest clinical relevance.

https://ift.tt/2JNmJix

Radiomics Signature on Magnetic Resonance Imaging: Association with Disease-Free Survival in Patients with Invasive Breast Cancer

Purpose: To develop a radiomics signature based on preoperative magnetic resonance imaging (MRI) to estimate disease-free survival (DFS) in patients with invasive breast cancer and to establish a radiomics nomogram that incorporates the radiomics signature and MRI and clinicopathological findings. Experimental Design: We identified 294 patients with invasive breast cancer who underwent preoperative MRI. Patients were randomly divided into training (n = 194) and validation (n = 100) sets. A radiomics signature (Rad-score) was generated using an elastic net in the training set, and the cutoff point of the radiomics signature to divide the patients into high- and low-risk groups was determined using receiver operating characteristic curve analysis. Univariate and multivariate Cox proportional hazards model and Kaplan-Meier analysis were used to determine the association of the radiomics signature, MRI findings, and clinicopathological variables with DFS. A radiomics nomogram combining the Rad-score and MRI and clinicopathological findings was constructed to validate the radiomic signatures for individualized DFS estimation. Results: Higher Rad-scores were significantly associated with worse DFS in both the training and validation sets (P = 0.002 and 0.036, respectively). The radiomics nomogram estimated DFS (C-index, 0.76; 95% confidence interval [CI], 0.74-0.77) better than the clinicopathological (C-index, 0.72; 95% CI, 0.70-0.74) or Rad-score-only nomograms (C-index, 0.67; 95% CI, 0.65-0.69). Conclusions: The radiomics signature is an independent biomarker for the estimation of DFS in patients with invasive breast cancer. Combining the radiomics nomogram improved individualized DFS estimation.

https://ift.tt/2M2GdMR

LncRNA-FEZF1-AS1 promotes tumor proliferation and metastasis in colorectal cancer by regulating PKM2 signaling

Purpose: Long non-coding RNAs (lncRNAs) play key roles in human cancers. Here, FEZF1-AS1, a highly overexpressed lncRNA in colorectal cancer (CRC), was identified by lncRNA microarrays. We aimed to explore the roles and possible molecular mechanisms of FEZF1-AS1 in CRC. Experimental Design: LncRNA expression in CRC tissues was measured by lncRNA microarray and qRT-PCR. The functional roles of FEZF1-AS1 in CRC were demonstrated by a series of in vitro and in vivo experiments. RNA pull-down, RNA immunoprecipitation and luciferase analyses were used to demonstrate the potential mechanisms of FEZF1-AS1. Results: We identified a series of differentially expressed lncRNAs in CRC using lncRNA microarrays, and revealed that FEZF1-AS1 is one of the most overexpressed. Further validation in two expanded CRC cohorts confirmed the upregulation of FEZF1-AS1 in CRC, and revealed that increased FEZF1-AS1 expression is associated with poor survival. Functional assays revealed that FEZF1-AS1 promotes CRC cell proliferation and metastasis. Mechanistically, FEZF1-AS1 could bind and increase the stability of the pyruvate kinase 2 (PKM2) protein, resulting in increased cytoplasmic and nuclear PKM2 levels. Increased cytoplasmic PKM2 promoted pyruvate kinase activity and lactate production (aerobic glycolysis), whereas FEZF1-AS1-induced nuclear PKM2 upregulation further activated STAT3 signaling. In addition, PKM2 was upregulated in CRC tissues and correlated with FEZF1-AS1 expression and patient survival. Conclusions: Together, these data provide mechanistic insights into the regulation of FEZF1-AS1 on both STAT3 signaling and glycolysis by binding PKM2 and increasing its stability.

https://ift.tt/2JP7ZQo

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease, Published online: 19 June 2018; doi:10.1038/s41416-018-0141-7

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

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Retrospondyloptosis of the Spine Secondary to Nonaccidental Trauma

Spinal fracture rates from NAT have been reported in

https://ift.tt/2tjKcwS

Retrospective evaluation of fidaxomicin versus oral vancomycin for treatment of Clostridium difficile infections in allogeneic stem cell transplant

Publication date: Available online 18 June 2018
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Laura Prohaska, Zahra Mahmoudjafari, Leyla Shune, Anurag Singh, Tara Lin, Sunil Abhyankar, Siddhartha Ganguly, Dennis Grauer, Joseph McGuirk, Lisa Clough
Objective/backgroundClostridium difficile infection (CDI) is a potential complication during hematopoietic stem cell transplantation (HSCT), and no specific recommendations exist regarding treatment of CDI in allogeneic SCT patients. Use of metronidazole and oral vancomycin has been associated with clinical failure. Fidaxomicin has previously been found noninferior to the use of oral vancomycin for the treatment of CDI, and no studies have compared the use of oral vancomycin with fidaxomicin for the treatment of CDI in allogeneic SCT.MethodsThis retrospective chart review included 96 allogeneic SCT recipients who developed CDI within 100 days following transplantation. Participants were treated with oral vancomycin (n = 52) or fidaxomicin (n = 44). The primary outcome was clinical cure, defined as no need for further retreatment 2 days following completion of initial CDI treatment. Secondary outcomes were global cure, treatment failure, and recurrent disease.ResultsNo differences in clinical cure were observed between patients receiving oral vancomycin or fidaxomicin (75% vs. 75%, p = 1.00). Secondary outcomes were similar between oral vancomycin and fidaxomicin in regards to global cure (66% vs. 67%, p = .508), treatment failure (28% vs. 27%, p = .571), and recurrent disease (7% vs. 5%, p = .747). In a subanalysis of individuals that developed acute graft-versus-host disease following CDI, the difference in mean onset of acute graft-versus-host disease was 21.03 days in the oral vancomycin group versus 32.88 days in the fidaxomicin group (p = .0031).ConclusionThe findings of this study suggest that oral vancomycin and fidaxomicin are comparable options for CDI treatment in allogeneic SCT patients within 100 days following transplant.



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Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

https://ift.tt/2K1fzn6

Sensitization of prostate cancer to radiation therapy: Molecules and pathways to target

Radiation therapy is used to treat cancer by radiation-induced DNA damage. Despite the best efforts to eliminate cancer, some cancer cells survive irradiation, resulting in cancer progression or recurrence. Alteration in DNA damage repair pathways is common in cancers, resulting in modulation of their response to radiation. This article focuses on the recent findings about molecules and pathways that potentially can be targeted to sensitize prostate cancer cells to ionizing radiation, thereby achieving an improved therapeutic outcome.

https://ift.tt/2M1EzLz

Can clinicopathological parameters predict for lymph node metastases in ypT0-2 rectal carcinoma? Results of the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 phase 3 trials

The advent of less radical surgical approaches has generated concern about leaving locoregional lymph node metastases (LNM) unresected that could lead to adverse outcome. We examined the prognostic role of clinicopathological factors for ypN-positivity in patients with ypT0-2 rectal carcinoma treated within the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 randomized phase 3 trials.

https://ift.tt/2t8t2Tt

Prospective evaluation of acute toxicity and patient reported outcomes in anal cancer and plan optimization

Chemoradiotherapy (CRT) is the standard therapy for localized anal cancer (AC), but this treatment is associated with substantial toxicity. However, there is a lack of prospectively collected toxicity and patient reported outcome (PRO) data from larger cohorts.The purpose was to prospectively collect and determine agreement between physician assessed toxicity (CTCAE) and PRO during and after CRT and to compare IMRT, VMAT and proton-based planning in a subgroup of patients.

https://ift.tt/2M490AB

Clenched fist syndrome: a case report

The clenched fist syndrome/psycho-flexed hand, first described in the early 1980s, has not yet entered the major psychiatric textbooks. Curiously, the phenomenon has been illuminated mainly in journals and tex...

https://ift.tt/2tkuCRD

Biosimilars for Cancer Emerge as Patents on Widely Used Biological Drugs Expire

As the patents on some widely used drugs to treat cancer expire in the coming years, biosimilar drugs are being developed for the treatment of patients with cancer. Are biosimilars effective and will they expand treatment options for patients?

https://ift.tt/2t9jyYb

Clinical trials involving positron emission tomography and prostate cancer: an analysis of the ClinicalTrials.gov database

The goal of this study is to evaluate the status and future perspectives of clinical trials on positron emission tomography in prostate cancer for diagnostic or therapeutic as well as for surveillance purposes.

https://ift.tt/2lglmtX

Forthcoming Meetings

Edited by Albert H. Kim and Jennie W. Taylor

https://ift.tt/2ylV9Ub

Precision oncology in the era of radiogenomics: the case of D-2HG as an imaging biomarker for mutant IDH gliomas

See the article by Branzoli and Di Stefano et al pp. 907–916.

https://ift.tt/2lfaaOl

Highlights from the Literature

https://ift.tt/2ym01sw

Correction to: Biomarkers in breast cancer: A consensus statement by the Spanish Society of Medical Oncology and the Spanish Society of Pathology

On page 5 of the article, in the last paragraph of the section "Prognostic genetic platforms: molecular phenotypes and translation to the clinic" a relevant discrepancy between the text and Table 1 could be misunderstood, therefore the paragraph was corrected

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New horizons in breast cancer: the promise of immunotherapy

Abstract

Immunology and immunotherapy of cancer is an expanding field in oncology, with recent great achievements obtained through the new successful approaches implemented to circumvent immune evasion, which is undoubtedly considered a novel hallmark of cancer. Translational research in this topic has revealed targets that can be modulated in the clinical setting with new compounds and strategies. Like most of the tumors, breast cancer is considered a complex and heterogeneous disease in which host immune responses have been also recently demonstrated of critical relevance. T infiltrating lymphocyte measurement is suggested as a powerful new tool necessary to predict early breast cancer evolution, especially for the her2-positive and triple-negative subtypes. Other biomarkers in tissue and peripheral blood are under intense scrutiny to ascertain their eventual role as prognostic and/or predictive factors. This background has fueled the interest in developing clinical research strategies to test activity of modern immunotherapy in breast cancer, which constitutes the main focus of this review.

https://ift.tt/2JVCFPd

MGMT promoter methylation and 1p/19q co-deletion of surgically resected pulmonary carcinoid and large-cell neuroendocrine carcinoma

Abstract

Background

The response to temozolomide (TMZ) treatment in small-cell lung cancer (SCLC) correlated with O(6)-methylguanine -DNA methyltransferase (MGMT) promoter methylation. 1p/19q co-deletion within oligodendroglioma is a responsive predictor for TMZ. Currently, the status of MGMT promoter methylation and 1p/19q co-deletion in pulmonary carcinoid (PC) and large-cell neuroendocrine carcinoma (LCNEC) is not reported.

Methods

Nine PC [two atypical carcinoids (AC), seven typical carcinoids (TC)] and six LCNEC patients were collected retrospectively. The pyrosequencing and fluorescence in situ hybridization were used to detect the MGMT promoter methylation and 1p/19q co-deletion in surgically resected specimens. Kaplan–Meier analysis was used to assess the rate of disease-free survival (DFS).

Results

MGMT promoter methylation was found in two (2/6, 15.3%) LCNEC patients but not in any PC patients. Three (3/6, 50%) 1p and two (2/6, 33.3%) 19q single deletions were found in LCNEC patients. One 1p single deletion was found in AC patients. One (1/7, 14.3%) 1p and two (2/7, 28.6%) 19q single deletions were found in TC patients. After a median follow-up of 38 months, three LCNEC patients developed distant metastasis and one patient died of LCNEC disease. The DFS of PC patients was much longer than LCNEC patients (χ²  = 7.565, P = 0.006).

Conclusions

MGMT promoter methylation and 1p/19q co-deletion might not be the ideal biomarkers for TMZ treatment in TC/AC patients. Thus, the detection of MGMT promoter methylation and whether it can be used as a medication for TMZ in LCNEC patients necessitates investigation. Furthermore, 1p deletion could be a negative prognostic factor for LCNEC patients.

https://ift.tt/2JVFRqu

Letter to the editor: is HIF-1α a viable prognostic indicator in OSCC? A critical review of a meta-analysis study

Abstract

The study performed by Zhou et al. (World J Surg Oncol 15:104, 2017) titled "Clinical and prognostic significance of HIF-1α overexpression in oral squamous cell carcinoma: a meta-analysis" attempts to highlight hypoxia-inducible factor-1 alpha as a possible prognostic marker in oral squamous cell carcinoma (OSCC). We would like to underline a few points which may affect such a conclusion. The correlations between HIF-1α expression and tumour size as well as tumour stage are debatable. Further, the subgroup analysis incorporating Australia and Europe into a single subgroup limits the viability of the prognostic analysis of HIF-1α. We also suggest future studies in the same research area to analyse head and neck squamous cell carcinoma instead of OSCC, to ameliorate the limitations encountered by Zhou et al., due to the scarcity of relevant clinical data and a low number of studies about OSCC.

https://ift.tt/2JLuJAG

Androgen Receptor and Ki67 Expression and Survival Outcomes in Non-small Cell Lung Cancer

Abstract

Lung cancer is the most common cause of cancer-related deaths worldwide with non-small cell lung cancer (NSCLC) making up most of these cases. Males have poorer overall survival compared to women following a lung cancer diagnosis. Many studies have focused on the effects of estrogen to explain higher survival rates among women, but few have looked at the effects of androgens. We describe the expression of the androgen receptor (AR) and Ki67 in lung cancer specimens in the Manitoba Tumor Bank (MTB) and correlate these factors with patient outcome. Using the MTB, we performed immunohistochemistry on lung cancer tissue to determine expression of the AR and Ki67. These were then correlated with patient outcome. Of the 136 cases, 55% were female and 55% were adenocarcinoma. AR expression was not independently associated with outcome. Ki67 was associated with a significantly higher hazard ratio for death and recurrence (HR 2.19, 95% CI 1.30–3.70; HR 1.92, 95% CI 1.07–3.46, respectively). AR expression modified the effect of Ki67 on outcome, such that when both were expressed, there was no association with recurrence or survival (HR 2.39, 95% CI 1.31–4.36 for AR− Ki67+ vs HR 1.54, 95% CI 0.44–5.37 for AR+ Ki67+). Ki67 was associated with poorer outcomes alone. AR status alone was not associated with outcome. Although the mechanism remains unclear, AR status seems to negate the association of a high Ki67 and poor outcome.

https://ift.tt/2JXt7Qn

Different menopausal hormone regimens and risk of breast cancer

ABSTRACT

Background

There are considerable knowledge gaps concerning different estrogen and progestin formulations, regimens, and modes of administration of menopausal hormone therapy and the risk of breast cancer. Our objective was to assess the different treatment options for menopausal hormone therapy and the risk of breast cancer.

Patients and methods

This Swedish prospective nationwide cohort study included all women who received ≥1 hormone therapy prescription during the study period 2005–2012 (290,186 ever–users), group–level matched (1:3) to 870,165 never–users; respectively 6,376 (2.2%) and 18,754 (2.2%) developed breast cancer. Hormone therapy, ascertained from the Swedish Prescribed Drug Register, was subdivided by estrogen and progestogen formulation types, regimens (continuous vs. sequential) and modes of administration (oral vs. transdermal). The risk of invasive breast cancer was presented as adjusted odds ratios and 95% confidence intervals.

Results

Current use of estrogen-only therapy was associated with a slight excess breast cancer risk (odds ratio=1.08 (1.02–1.14)). The risk for current estrogen plus progestogen therapy was higher (odds ratio=1.77 (1.69–1.85)) and increased with higher age at initiation (odds ratio=3.59 (3.30–3.91) in women 70+ years). In contrast, past use was associated with reduced breast cancer risk. Current continuous estrogen/progestin use was associated with higher risk (odds ratio=2.18 (1.99–2.40) for progesterone-derived; odds ratio=2.66 (2.49–2.84) for testosterone-derived) than sequential use (odds ratio=1.37 (0.97–1.92)) for progesterone-derived; odds ratio=1.12 (0.96–1.30) for testosterone-derived). The odds ratio for current use was 1.12 (1.04–1.20) for estradiol, 0.76 (0.69–0.84) for estriol, 4.47 (2.67–7.48) for conjugated estrogens, and 1.68 (1.51–1.87) for tibolone. Oral and cutaneous hormone therapy showed similar associations.

Conclusion

Different hormone therapy regimens have profoundly different effects on breast cancer risk. Because of registry limitations some confounders could not be assessed. This knowledge may guide clinical decision-making when hormone therapy is considered.

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Breast cancer brain metastases show increased levels of genomic aberration based homologous recombination deficiency scores relative to their corresponding primary tumors

Abstract

Background

Based on its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Therefore, identification of tumor types with increased HRD is important for the optimal use of this class of therapeutic agents. HRD levels can be estimated using various mutational signatures from next generation sequencing data and we used this approach to determine whether breast cancer brain metastases show altered levels of HRD scores relative to their corresponding primary tumor.

Patients and methods

We used a previously published next generation sequencing dataset of twenty-one matched primary breast cancer/brain metastasis pairs to derive the various mutational signatures/HRD scores strongly associated with HRD. We also performed the myChoice HRD analysis on an independent cohort of seventeen breast cancer patients with matched primary/brain metastasis pairs.

Results

All of the mutational signatures indicative of HRD showed a significant increase in the brain metastases relative to their matched primary tumor in the previously published whole exome sequencing dataset. In the independent validation cohort the myChoice HRD assay showed an increased level in 87.5% of the brain metastases relative to the primary tumor, with 56% of brain metastases being HRD positive according to the myChoice criteria.

Conclusions

The consistent observation that brain metastases of breast cancer tend to have higher HRD measures may raise the possibility that brain metastases may be more sensitive to PARP inhibitor treatment. This observation warrants further investigation to assess whether this increase is common to other metastatic sites as well, and whether clinical trials should adjust their strategy in the application of HRD measures for the prioritization of patients for PARP inhibitor therapy.

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Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Ann Oncol 2017; 28: iv119–iv142 (doi:10.1093/annonc/mdx225)

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Evaluation of the HOXA11 level in patients with lung squamous cancer and insights into potential molecular pathways via bioinformatics analysis

Abstract

Background

This study was carried out to discover the underlying role that HOXA11 plays in lung squamous cancer (LUSC) and uncover the potential corresponding molecular mechanisms and functions of HOXA11-related genes.

Methods

Twenty-three clinical paired LUSC and non-LUSC samples were utilized to examine the level of HOXA11 using quantitative real-time polymerase chain reaction (qRT-PCR). The clinical significance of HOXA11 was systematically analyzed based on 475 LUSC and 18 non-cancerous adjacent tissues from The Cancer Genome Atlas (TCGA) database. A total of 102 LUSC tissues and 121 non-cancerous tissues were available from Oncomine to explore the expressing profiles of HOXA11 in LUSC. A meta-analysis was carried out to further assess the differential expression of HOXA11 in LUSC, including in-house qRT-PCR data, expressing data extracted from TCGA and Oncomine databases. Moreover, the enrichment analysis and potential pathway annotations of HOXA11 in LUSC were accomplished via Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The expression of hub genes and according correlations with HOXA11 were assessed to further explore the biological role of HOXA11 in LUSC.

Results

HOXA11 expression in LUSC had a tendency to be upregulated in comparison to adjacent non-cancerous tissues by qRT-PCR. TCGA data displayed that HOXA11 was remarkably over-expressed in LUSC compared with that in non-LUSC samples, and the area under curves (AUC) was 0.955 (P < 0.001). A total of 1523 co-expressed genes were sifted for further analysis. The most significant term enriched in the KEGG pathway was focal adhesion. Among the six hub genes of HOXA11, including PARVA, ILK, COL4A1, COL4A2, ITGB1, and ITGA5, five (with the exception of COL4A1) were significantly decreased compared with the normal lung tissues. Moreover, the expression of ILK was negatively related to HOXA11 (r = − 0.141, P = 0.002).

Conclusion

High HOXA11 expression may lead to carcinogenesis and the development of LUSC. Furthermore, co-expressed genes might affect the prognosis of LUSC.

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An Enlarging Metastatic Calcified Liver Lesion of an Occult Melanoma

Calcified liver lesions are caused by a wide variety of factors. The most common lesions are inflammatory liver lesions followed by benign and malignant neoplasms. Hemangioma, one of the most common benign hepatic neoplasm in adults, often contains calcifications, in up to 20% of cases secondary to fibrosis and thrombosis of blood vessels. These calcifications are typically large, coarse, and located in the center of the lesions. Liver metastases, the most common malignant lesions found in the noncirrhotic liver, may contain areas of calcification. Radiologists should be aware of morphologic imaging features of calcified liver lesions to help differentiate benign from malignant lesions. Liver biopsy should be offered when the diagnosis is doubtful.
Case Rep Oncol 2018;11:388–391

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Successful Treatment of a Large Superficial Bladder Cancer with Neoadjuvant Arterial Infusion Chemotherapy: A Case Report

We present a case in which neoadjuvant arterial infusion chemotherapy was effective in treating a large superficial bladder cancer. A 50-year-old male was admitted to the Kanazawa Medical Center with the complaint of dizziness. The patient exhibited severe anemia, and his computer tomography showed a large bladder tumor. Cystoscopy revealed a large papillary tumor. Magnetic resonance imaging showed no muscle invasion and no metastasis. To avoid a prolonged operation time and excessive blood loss, we performed neoadjuvant arterial infusion chemotherapy for tumor volume reduction before transurethral resection of the bladder tumor (TUR-BT). The arterial infusion chemotherapy was performed twice, and the tumor size gradually reduced from 275 to 28 cm³. After neoadjuvant chemotherapy, TUR-BT was safely performed without blood transfusion. The tumor was staged as T1 with G1. This is the first report demonstrating that neoadjuvant arterial infusion chemotherapy is effective in treating large superficial bladder cancer and is a possible strategy for bladder preservation.
Case Rep Oncol 2018;11:383–387

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18 F-fluoromisonidazole predicts evofosfamide uptake in pancreatic tumor model

Abstract

Background

Quantitative imaging can facilitate patient stratification in clinical trials. The hypoxia-activated prodrug evofosfamide recently failed a phase III trial in pancreatic cancer. However, the study did not attempt to select for patients with hypoxic tumors. We tested the ability of ¹⁸F-fluoromisonidazole to predict evofosfamide uptake in an orthotopic xenograft model (BxPC3).

Methods

Two forms of evofosfamide were used: (1) labeled on the active moiety (³H) and (2) on the hypoxia targeting nitroimidazole group (¹⁴C). Tumor uptake of evofosfamide and ¹⁸F-fluoromisonidazole was counted ex vivo. Autoradiography of ¹⁴C and ¹⁸F coupled with pimonidazole immunohistochemistry revealed the spatial distributions of prodrug, radiotracer, and hypoxia.

Results

There was significant individual variation in ¹⁸F-fluoromisonidazole uptake, and a significant correlation between normalized ¹⁸F-fluoromisonidazole and both ³H-labeled and ¹⁴C-labeled evofosfamide. ¹⁸F-fluoromisonidazole and ¹⁴C-evofosfamide both localized in hypoxic regions as identified by pimonidazole.

Conclusion

¹⁸F-fluoromisonidazole predicts evofosfamide uptake in a preclinical pancreatic tumor model.

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MALAT1 silencing suppresses prostate cancer progression by upregulating miR-1 and downregulating KRAS

https://ift.tt/2MBtvpq

The association of pretreatment serum albumin with outcomes in bladder cancer: a meta-analysis

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STAT3 induces colorectal carcinoma progression through a novel miR-572-MOAP-1 pathway

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Downregulation of ribophorin II suppresses tumor growth, migration, and invasion of nasopharyngeal carcinoma

https://ift.tt/2JVQxWg

Generalizability of clinical trials of advanced melanoma in the real-world, population-based setting

Abstract

Results from novel therapeutics trials are not always generalizable to real-world patients. We aimed to determine the pattern in which trial findings are applied in a population-based setting of melanoma patients and consequent treatment outcomes. Patients with unresectable disease during 2011–2014 and referred to cancer centers in a large Canadian province were retrospectively reviewed. Based on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipilimumab (Ipi), we classified patients into trial-eligible and ineligible and those treated and untreated with these agents. We identified 290 patients with known BRAF status for the Vem analysis and 212 patients previously treated with first-line agents for the Ipi analysis. For the Vem cohort, a total of 49 patients were considered trial-eligible, of whom 36 (73%) received treatment. For the Ipi cohort, there were 119 trial-eligible cases of whom 43 (36%) received therapy. Factors other than eligibility criteria most frequently associated with non-treatment in these cohorts included concerns regarding treatment harm and patient preferences. In multivariable analysis, overall survival was improved in Vem cohort patients considered trial-eligible and treated compared to those who were ineligible. Within the Ipi cohort, survival was improved in trial-eligible patients regardless of whether they received Ipi compared to ineligible patients. Real-world uptake of new melanoma treatments was suboptimal, and non-use in trial-eligible patients was frequent. Future clinical trials that are more pragmatically designed to include participants who better reflect the real-world population may facilitate increased uptake of novel therapeutics into routine clinical practice.

https://ift.tt/2K3iZc3

Clinical outcomes of African American patients with advanced or metastatic non-small cell lung cancer on Nivolumab in a single community-based cancer center

Abstract

African Americans (AA) have the highest incidence and mortality rates with lung cancer. They are diagnosed at an earlier age with more advanced disease. Programmed cell death protein-1 inhibitor, Nivolumab, was approved as a second-line agent after failure of platinum-based therapy for advanced or metastatic non-small cell lung cancer (NSCLC). The original studies leading to the approval of Nivolumab had insufficient AA patients, thus there is still inadequate knowledge on treatment outcomes among AA patients. Our primary study endpoints were to determine the median overall survival, 1-year overall survival rate, median progression-free survival, and 1-year progression-free survival rate of patients with advanced or metastatic non-small cell lung cancer on Nivolumab. Our secondary study endpoints were to determine the overall tumor response rate, median time to response, median duration of response, and incidence of treatment-related adverse events of grade 3 or 4. In this retrospective study, we reviewed the charts of 38 patients, 29 of which were AA, with advanced or metastatic NSCLC who received Nivolumab from March 1, 2015 until November 30, 2017 from a single community-based cancer center and compared our results with historical data. Adenocarcinoma was the most common histology (71%) among all patients. Seven (18%) continued to use Nivolumab while 21 (55%) discontinued the treatment mainly due to progression of the disease. The median overall survival was 21.4 months (95% CI 13.5–27.4) and 17.6 months (95% CI 11.5–27.6) for all the patients and AA, respectively. Both have statistically significant difference (P < 0.001) compared to the historical studies of Borghaei et al. and Brahmer et al. At 1 year, the overall survival rate was 73% (95% CI 50–86) and 66% (95% CI 40–82) for all patients and AA, respectively. The median progression-free survival was also statistically significant (P < 0.001) between all the patients 6.3 months (95% CI 2.8–8), AA 6.0 months (95% CI 2.3–8.0), and the said historical studies. The 1-year progression-free survival rate was 23% (95% CI 10–39) and 28% (95% CI 12–47) for all patients and AA, respectively. Overall tumor response rate which includes complete and partial responses was 21% (95% CI 10–37) and 24% (95% CI 10–43) for all patients and AA, respectively. The median time to response was 3 and 2.8 months for all patients and AA, respectively. The median duration of response was 3.8 and 4.0 months for all patients and AA, respectively. Treatment-related adverse events of grade 3 or 4 were reported in 8 and 10% in all patients and AA, respectively, similar to the rates previously shown. AA patients with advanced or metastatic NSCLC on Nivolumab had increased overall survival and progression-free survival with similar grade 3 or 4 treatment-related adverse events. Providing adequate access to immunotherapy is indispensable to maximize survival benefit for AA patients.

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