Cancer by Sfakianakis Alexandros: 08/22/17

Τρίτη 22 Αυγούστου 2017

The Evolving Role of Tumor Treating Fields in Managing Glioblastoma: Guide for Oncologists.

Glioblastoma (GBM) is a devastating brain tumor with poor prognosis despite advances in surgery, radiation, and chemotherapy. Survival of patients with glioblastoma remains poor, with only 1 in 4 patients alive at 2 years, and a 5-year survival rate of about 5%. Recurrence is nearly universal and, after recurrence, prognosis is poor with very short progression-free survival and overall survival (OS). Various salvage chemotherapy strategies have been applied with limited success. Tumor Treating Fields (TTFields) are a novel treatment modality approved for treatment of either newly diagnosed or recurrent GBM. TTFields therapy involves a medical device and transducer arrays to provide targeted delivery of low intensity, intermediate frequency, alternating electric fields to produce antimitotic effects selective for rapidly dividing tumor cells with limited toxicity. In the phase 3 EF-14 trial, TTFields plus temozolomide provided significantly longer progression-free survival and OS compared with temozolomide alone in patients with newly diagnosed GBM after initial chemoradiotherapy. The addition of TTFields to standard therapy improved median OS from 15.6 to 20.5 months (P=0.04). In the phase 3 EF-11 trial, for recurrent GBM, TTFields provided comparable efficacy as investigator's choice systemic therapy, with improved patient-reported quality of life and a lower incidence of serious adverse events. Primary toxicity associated with TTFields is skin irritation generally managed with array relocation and topical treatments including antibiotics and steroids. TTFields therapy has demonstrated proven efficacy in management of GBM, including improvement in OS for patients with newly diagnosed GBM, and is under current investigation in other brain and extracranial tumors. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Effects of Autologous Cytokine-Induced Killer Cells Infusion in Colorectal Cancer Patients: A Prospective Study

Cancer Biotherapy & Radiopharmaceuticals Aug 2017, Vol. 32, No. 6: 221-226.

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In Vivo and In Vitro Effects of ATM/ATR Signaling Pathway on Proliferation, Apoptosis, and Radiosensitivity of Nasopharyngeal Carcinoma Cells

Cancer Biotherapy & Radiopharmaceuticals Aug 2017, Vol. 32, No. 6: 193-203.

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Clinical Effects of CpG-Based Treatment on the Efficacy of Hepatocellular Carcinoma by Skewing Polarization Toward M1 Macrophage from M2

Cancer Biotherapy & Radiopharmaceuticals Aug 2017, Vol. 32, No. 6: 215-219.

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Selected Literature Watch

Cancer Biotherapy & Radiopharmaceuticals Aug 2017, Vol. 32, No. 6: 227-228.

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Cytoreductive nephrectomy for metastatic renal cell carcinoma: inequities in access exist despite improved survival

Abstract

The use of cytoreductive nephrectomy (CRN) in the targeted therapy era is still debated. We aimed to determine factors associated with reduced use of CRN and determine the effect of CRN on overall survival in patients with metastatic renal cell carcinoma (RCC). All advanced RCC diagnosed between 2001 and 2009 in New South Wales, Australia, were identified from the Central Cancer Registry. Records of treatment and death were electronically linked. Follow-up was to the end of 2011. Multivariable logistic regression analysis was used to determine factors associated with the receipt of CRN. Cox proportional hazards model was used to determine factors associated with survival. A total of 1062 patients were identified with metastatic RCC of whom 289 (27%) received CRN. There was no difference in the use of CRN over the time period of the study. Females (OR 0.68 (95% CI: 0.48–0.96)), unmarried individuals (OR 0.68 (95% CI: 0.48–0.96)), treatment in a nonteaching hospital (OR 0.26 (95% CI: 0.18–0.36)) and individuals without private insurance (OR 0.29 (95% CI: 0.20–0.41)) all had reduced likelihood of receiving CRN. On multivariable analysis, not receiving CRN resulted in a 90% increase in death (HR 1.90 (95% CI: 1.61–2.25)). In addition, increasing age (P < 0.001), increasing Charlson comorbidity status (P = 0.002) and female gender also had a significant independent association with death. Despite a strong association with improved survival, individuals who are elderly, female, have treatment in a nonteaching facility or have no private insurance have a reduced likelihood of receiving CRN.

Cytoreductive nephrectomy is commonly used in conjunction with systemic therapy to treat advanced renal cell carcinoma. Despite a strong association with improved survival, individuals who are elderly, female, have treatment in a nonteaching facility or do not have private insurance have a reduced likelihood of receiving this surgery.

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The colorectal cancer immune microenvironment and approach to immunotherapies

Future Oncology, Ahead of Print.

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The evolutionary nature of the cancer immunotherapy revolution

Future Oncology, Ahead of Print.

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Should we be combining local tumor therapies with immunotherapies as standard?

Future Oncology, Ahead of Print.

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Docetaxel or abiraterone in addition to androgen deprivation therapy in metastatic castration-sensitive prostate cancer

Future Oncology, Ahead of Print.

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How and when adjuvant treatment should be intensified in stage III colorectal cancers?

Future Oncology, Ahead of Print.

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Long noncoding RNA ZEB1-AS1 epigenetically regulates the expressions of ZEB1 and downstream molecules in prostate cancer

Abstract

Background

Emerging studies show that long noncoding RNAs (lncRNAs) play important roles in carcinogenesis and cancer progression. The lncRNA ZEB1 antisense 1 (ZEB1-AS1) derives from the promoter region of ZEB1 and we still know little about its expressions, roles and mechanisms.

Methods

RACE was used to obtain the sequence of ZEB1-AS1. RNA interference was used to decrease ZEB1-AS1 expression. Adenovirus expression vector was used to increase ZEB1-AS1 expression. CHIP and RIP were used to detect the epigenetic mechanisms by which ZEB1-AS1 regulated ZEB1. CCK8 assay, wound healing assay and transwell assay were used to measure proliferation and migration of prostate cancer cells.

Results

In this study, in prostate cancer cells, we found that RNAi-mediated downregulation of ZEB1-AS1 induced significant ZEB1 inhibition while artificial overexpression of ZEB1-AS1 rescued ZEB1 expression, which means that ZEB1-AS1 promotes ZEB1 expression. Also, ZEB1-AS1 indirectly inhibited miR200c, the well-known target of ZEB1, and upregulated miR200c's target BMI1. Mechanistically, ZEB1-AS1 bound and recruited histone methyltransferase MLL1 to the promoter region of ZEB1, induced H3K4me3 modification therein, and activated ZEB1 transcription. Biologically, ZEB1-AS1 promoted proliferation and migration of prostate cancer cells.

Conclusions

Collectively, ZEB1-AS1 functions as an oncogene in prostate cancer via epigenetically activating ZEB1 and indirectly regulating downstream molecules of ZEB1.

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Deletion of 11q in neuroblastomas drives sensitivity to PARP inhibition

Purpose: Despite advances in multimodal therapy, neuroblastomas with hemizygous deletion in chromosome 11q (20-30%) undergo consecutive recurrences with poor outcome. We hypothesized that patients with 11q loss may share a druggable molecular target(s) that can be exploited for a precision medicine strategy to improve treatment outcome. Experimental Design: SNP arrays were combined with next generation sequencing (NGS) to precisely define the deleted region in 17 primary 11q-loss neuroblastomas and identify allelic variants in genes relevant for neuroblastoma aetiology. We assessed PARP inhibitor olaparib in combination with other chemotherapy medications using both in vitro and in vivo models. Results: We detected that ATM haploinsufficiency and ATM allelic variants are common genetic hallmarks of 11q-loss neuroblastomas. Based on the distinct DNA repair pathways triggered by ATM and PARP, we postulated that 11q-loss may define a subgroup of neuroblastomas with higher sensitivity to PARP inhibitors. Noteworthy, concomitant treatment with olaparib and DNA alkylating agent temozolomide potently inhibited growth of cell lines harboring 11q-loss. This drug synergism was less potent when temozolomide was exchanged for cisplatin or irinotecan. Intact 11q cells concomitantly treated with ATM inhibitor displayed growth arrest and enhanced apoptosis, revealing a role for ATM in the mechanism that mediates sensitivity to temozolomide-olaparib. Interestingly, functional TP53 is required for efficacy of this treatment. In an in vivo model, co-administration of temozolomide-olaparib resulted in sustained xenograft regression. Conclusions: Our findings reveal a potent synergism between temozolomide and olaparib in treatment of neuroblastomas with 11q loss and provide a rationale for further clinical investigation.

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Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma indicate the potential for CDK4/6 Inhibitors in Targeted Therapy

Purpose: Effective therapies for the majority of metastatic acral melanoma (AM) patients has not been established. Thus, we investigated genetic aberrations of CDK4 pathway in AM and evaluate the efficacy of CDK4/6 inhibitors in targeted therapy of AM. Experimental Design: A total of 514 primary AM samples were examined for the copy number variations (CNVs) of CDK4 pathway-related genes, including Cdk4, Ccnd1 and P16INK4a, by QuantiGenePlex DNA Assay. The sensitivity of established AM cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated. Results: Among the 514 samples, 203 cases, 137 cases and 310 cases respectively showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%) and p16INK4a loss (60.3%). The overall frequency of AMs that contain at least one aberration in Cdk4, Ccnd1 and P16INK4a was 82.7%. The median overall survival time for AM patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations P = .005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of AM cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss and Ccnd1 gain plus P16INK4a loss. Conclusions: Genetic aberration of CDK4 pathway is a frequent event in AM. AM cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in AM patients.

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Motor impairment and compensation in a hemiparkinsonian rat model: correlation between dopamine depletion severity, cerebral metabolism and gait patterns

Abstract

Background

In Parkinson's disease (PD), cerebral dopamine depletion is associated with PD subtype-specific metabolic patterns of hypo- and hypermetabolism. It has been hypothesised that hypometabolism reflects impairment, while hypermetabolism may indicate compensatory activity. In order to associate metabolic patterns with pathophysiological and compensatory mechanisms, we combined resting state [¹⁸F]FDG-PET (to demonstrate brain metabolism in awake animals), [¹⁸F]FDOPA-PET (dopamine depletion severity) and gait analysis in a unilateral 6-hydroxydopamine rat model.

Results

We found unilateral nigro-striatal dopaminergic loss to decrease swing speed of the contralesional forelimb and stride length of all paws in association with depletion severity. Depletion severity was found to correlate with compensatory changes such as increased stance time of the other three paws and diagonal weight shift to the ipsilesional hind paw. [¹⁸F]FDG-PET revealed ipsilesional hypo- and contralesional hypermetabolism; metabolic deactivation of the ipsilesional network needed for sensorimotor integration (hippocampus/retrosplenial cortex/lateral posterior thalamus) was solely associated with bradykinesia, but hypometabolism of the ipsilesional rostral forelimb area was related to both pathological and compensatory gait changes. Mixed effects were also found for hypermetabolism of the contralesional midbrain locomotor region, while contralesional striatal hyperactivation was linked to motor impairments rather than compensation.

Conclusions

Our results indicate that ipsilesional hypo- and contralesional hypermetabolism contribute to both motor impairment and compensation. This is the first time when energy metabolism, dopamine depletion and gait analysis were combined in a hemiparkinsonian model. By experimentally increasing or decreasing compensational brain activity, its potential and limits can be further investigated.

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Combined targeting of Arf1 and Ras potentiates anticancer activity for prostate cancer therapeutics

Abstract

Background

Although major improvements have been made in surgical management, chemotherapeutic, and radiotherapeutic of prostate cancer, many prostate cancers remain refractory to treatment with standard agents. Therefore, the identification of new molecular targets in cancer progression and development of novel therapeutic strategies to target them are very necessary for achieving better survival for patients with prostate cancer. Activation of small GTPases such as Ras and Arf1 is a critical component of the signaling pathways for most of the receptors shown to be upregulated in advanced prostate cancer.

Methods

The drug effects on cell proliferation were measured by CellTiter 96® AQueous One Solution Cell Proliferation Assay. The drug effects on cell migration and invasion were determined by Radius™ 24-well and Matrigel-coated Boyden chambers. The drug effects on apoptosis were assessed by FITC Annexin V Apoptosis Detection Kit with 7-AAD and Western blot with antibodies against cleaved PARP and Caspase 3. A NOD/SCID mouse model generated by subcutaneous injection was used to assess the in vivo drug efficacy in tumor growth. ERK activation and tumor cell proliferation in xenografts were examined by immunohistochemistry.

Results

We show that Exo2, a small-molecule inhibitor that reduces Arf1 activation, effectively suppresses prostate cancer cell proliferation by blocking ERK1/2 activation. Exo2 also has other effects, inhibiting migration and invasion of PCa cells and inducing apoptosis. The Ras inhibitor salirasib augments Exo2-induced cytotoxicity in prostate cancer cells partially by enhancing the suppression of ERK1/2 phosphorylation. In a xenograft mouse model of prostate cancer, Exo2 reduces prostate tumor burden and inhibits ERK1/2 activation at a dose of 20 mg/kg. Synergistic treatment of salirasib and Exo2 exhibits a superior inhibitory effect on prostate tumor growth compared with either drug alone, which may be attributed to the more efficient inhibition of ERK1/2 phosphorylation.

Conclusion

This study suggests that simultaneous blockade of Arf1 and Ras activation in prostate cancer cells is a potential targeted therapeutic strategy for preventing prostate cancer development.

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Characterization of in vivo resistance to osimertinib and JNJ-61186372, an EGFR/Met bi-specific antibody, reveals unique and consensus mechanisms of resistance

Approximately 10% of non-small cell lung cancer (NSCLC) patients in the U.S. and 40% of NSCLC patients in Asia have activating EGFR mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be co-targeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival. Mass spectrometry-based quantitative proteomics was used to profile in vivo signaling changes in 41 therapy resistant tumors from four xenograft NSCLC models. We identified unique and tumor-specific tyrosine phosphorylation rewiring in tumors resistant to treatment with the irreversible third generation EGFR-inhibitor, osimertinib, or the novel dual-targeting EGFR/Met antibody, JNJ-61186372. Tumor-specific increases in tyrosine-phosphorylated peptides from EGFR family members, Shc1 and Gab1 or Src family kinase substrates were observed, underscoring a differential ability of tumors to uniquely escape EGFR inhibition. Although most resistant tumors within each treatment group displayed a marked inhibition of EGFR as well as Src family kinase (SFK) signaling, the combination of EGFR inhibition (osimertinib) and SFK inhibition (saracatinib or dasatinib) led to further decrease in cell growth in vitro. This result suggests that residual SFK signaling mediates therapeutic resistance and that elimination of this signal through combination therapy may delay onset of resistance. Overall, analysis of individual resistant tumors captured unique in vivo signaling rewiring that would have been masked by analysis of in vitro cell population averages.

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Targeting TAO kinases using a new inhibitor compound delays mitosis and induces mitotic cell death in centrosome amplified breast cancer cells.

Thousand-and-one amino acid kinases (TAOKs) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC₅₀ values of 11-15 nM, is ATP-competitive and targets these kinases selectively. TAOK inhibition or depletion in centrosome amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death and inhibits cell growth. In contrast, non-tumorigenic and dividing bipolar MCF-10A breast cells appear less dependent on TAOK activity and can complete mitosis and proliferate in the presence of the TAOK inhibitor. We demonstrate that TAOK1 and TAOK2 localize to the cytoplasm and centrosomes respectively during mitosis. Live cell imaging shows that the TAOK inhibitor prolongs the duration of mitosis in SKBR3 cells, increases mitotic cell death and reduces the percentages of cells exiting mitosis, whereas MCF-10A cells continue to divide and proliferate. Over 80% of breast cancer tissues display supernumerary centrosomes and tumor cells frequently cluster extra centrosomes to avoid multipolar mitoses and associated cell death. Consequently, drugs that stimulate centrosome declustering and induce multipolarity are likely to target dividing centrosome amplified cancer cells preferentially, whilst sparing normal bipolar cells. Our results demonstrate that TAOK inhibition can enhance centrosome declustering and mitotic catastrophe in cancer cells and these proteins may therefore offer novel therapeutic targets suitable for drug inhibition and the potential treatment of breast cancers, where supernumerary centrosomes occur.

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HPMA-Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer

Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAMs) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro, and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+TAMs co-stained with pan macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development.

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Arginine Deprivation Therapy: Putative Strategy to Eradicate Glioblastoma Cells by Radiosensitization

Tumor cells - even if non-auxotrophic - are often highly sensitive to arginine deficiency. We hypothesized that arginine deprivation therapy (ADT) if combined with irradiation could be a new treatment strategy for glioblastoma (GBM) patients since systemic ADT is independent of local penetration and diffusion limitations. A proof-of-principle in vitro study was performed with ADT been mimicked by application of recombinant human arginase or arginine-free diets. <p>ADT inhibited 2-D growth and cell cycle progression, and reduced growth recovery after completion of treatment in four different GBM cell line models. Cells were less susceptible to ADT alone in the presence of citrulline and in a 3-D environment. Migration and 3-D invasion were not unfavourably affected. However, ADT caused a significant radiosensitization which was more pronounced in a GBM cell model with p53 loss of function as compared to its p53- wildtype counterpart. The synergistic effect was independent of basic and induced argininosuccinate synthase (ASS) or argininosuccinate lyase (ASL) protein expression and not abrogated by the presence of citrulline. The radiosensitizing potential was maintained or even more distinguishable in a 3-D environment as verified in p53-knockdown and p53-wildtype U87-MG cells via a 60-day spheroid control probability assay. While the underlying mechanism is still ambiguous, the observation of ADT-induced radiosensitization is of great clinical interest, in particular for patients with GBM showing high radioresistance and/or p53 loss of function.

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Intermediate-term outcome after PSMA-PET guided high-dose radiotherapy of recurrent high-risk prostate cancer patients

Abstract

Background

By the use of PSMA positron emission tomography (PET) detection of prostate cancer lesions with a high sensitivity and specificity combined with a favorable lesion to background contrast is feasible. Therefore, PSMA-PET is increasingly used for planning of radiotherapy treatment; however, any data on intermediate-term outcome is missing so far.

Methods

Patients with high-risk or very high risk prostate cancer, referred for salvage radiotherapy (SRT, n = 22) between 2013 and 2015, underwent PSMA-PET prior to therapy. Irradiation was planned on PET data with boost to macroscopic tumors/metastases. Treatment related toxicity was measured using Common Terminology Criteria for Adverse Events (CTCAE, v4.0).

Result

Findings in PSMA-PET led to treatment modifications in 77% of SRT patients compared to available CT information. One patient did not receive irradiation due to disseminated disease, the other patients received increased boost doses to macroscopic disease and/or inclusion of additional target volumes. Toxicity was low as only 2 patients reported toxicities > grade 1. With a Median follow-up time of 29 in patients that were not lost to follow-up, prolonged PSA responses below baseline were observed in the majority of patients (14 of 20). In hormone-naïve SRT patients (n = 11), radiotherapy led to prolonged PSA decrease in 8/11 patients, however with 3 of these 8 patients receiving repeated PSMA based irradiation of novel lesions during follow-up.

Conclusion

PSMA-PET guided planning of radiotherapy led to change of treatment in the majority of patients. Treatment related toxicity was well tolerated and promising results regarding intermediate-term PSA decrease were observed.

Trial registration

No trial registration was performed due to retrospective evaluation.

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Preoperative intensity-modulated radiotherapy with a simultaneous integrated boost combined with Capecitabine in locally advanced rectal cancer: short-term results of a multicentric study

Human pluripotent stem cell-derived TSC2-haploinsufficient smooth muscle cells recapitulate features of Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here we generated a robust human cell model of LAM by reprogramming TSC2 mutation-bearing fibroblasts from a patient with both Tuberous Sclerosis Complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSCs), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/- mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributed to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM which can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM.

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Caution is required in the implementation of 90-day mortality indicators for radiotherapy in a curative setting: A retrospective population-based analysis of over 16,000 episodes

90-day mortality (90DM) has been proposed as a clinical indicator in radiotherapy delivered in a curative setting. No large scale assessment has been made. Its value in allowing robust comparisons between centres and facilitating service improvement is unknown.

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A randomised controlled trial evaluating the utility of a patient Decision Aid to improve clinical trial (RAVES 08.03) related decision-making

Randomised controlled trials (RCTs) are considered the 'gold-standard' for evaluating medical treatments. However, patients and clinicians report difficulties with informed consent and recruitment. We evaluated the utility of a Decision Aid (DA) in reducing RCT-related decisional conflict, and improving RCT knowledge and recruitment.

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Long-term outcomes of patients with 10 or more colorectal liver metastases

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Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma

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Knowledge or noise? Making sense of General Practitioners’ and Consultant use of 2-week-wait referrals for suspected cancer

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Leukocyte telomere length and renal cell carcinoma survival in two studies

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Hamburg-Glasgow classification: preoperative staging by combination of disseminated tumour load and systemic inflammation in oesophageal carcinoma

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Correlation between circulating mutant DNA and metabolic tumour burden in advanced non-small cell lung cancer patients

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The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

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Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium

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Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models

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The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer

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HMGA1 expression levels are elevated in pancreatic intraepithelial neoplasia cells in the Ptf1a-Cre; LSL-KrasG12D transgenic mouse model of pancreatic cancer

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Platelet releasate promotes breast cancer growth and angiogenesis via VEGF–integrin cooperative signalling

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Nuclear expression of Gli-1 is predictive of pathologic complete response to chemoradiation in trimodality treated oesophageal cancer patients

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A comparative study of germline BRCA1 and BRCA2 mutation screening methods in use in 20 European clinical diagnostic laboratories

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TCTP as a therapeutic target in melanoma treatment

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Disseminated tumour cells with highly aberrant genomes are linked to poor prognosis in operable oesophageal adenocarcinoma

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A combined biomarker panel shows improved sensitivity for the early detection of ovarian cancer allowing the identification of the most aggressive type II tumours

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Lung cancer prognostic index: a risk score to predict overall survival after the diagnosis of non-small-cell lung cancer

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RBM38 is involved in TGF-β-induced epithelial-to-mesenchymal transition by stabilising zonula occludens-1 mRNA in breast cancer

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Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer

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Dynamics of regulatory T cells (Tregs) in patients with oral squamous cell carcinoma

Background and Objectives

The immune dysfunction in oral squamous cell carcinoma (OSCC) patients is one of the major factors for growth and dissemination of tumor affecting disease-free survival.

Methods

The phenotypic and functional characteristics of Regulatory T (T_reg) CD4⁺CD25⁺FoxP3⁺ subsets in OSCC patients were assessed by multicolor flow cytometry and its effector component (TGF-β) by Western blot and qRT-PCR.

Results

An increased (P < 0.05) prevalence of T_reg phenotypes (CD4⁺CD25⁺, CD4⁺FoxP3⁺, CD8⁺FoxP3⁺, CD4⁺CD25⁺FoxP3⁺) was observed in the peripheral circulation of OSCC patients that positively correlated with clinicopathological features. The increased frequency of CD4⁺CD8⁺CD25⁺FoxP3⁺, a unique T cell subset, CTLA-4⁺, GITR⁺, NrP1⁺, HLA-DR⁺, CD127⁺, Tbet⁺, TGF-β⁺, and granzyme B⁺ (GzmB) T_regs also showed a significantly higher prevalence in OSCC patients. Functionally, CD4⁺FoxP3⁺ T_regs showed skewed expression of IL-2, IL-10, and IL-35 in patients as compared with the normal controls. Further, enhanced expression of CCR5 and CCR7 on T_regs with up regulation of their ligands (CCL5, CCL19, and CCL21) in tumor cells indicates efficient recruitment and trafficking of T_regs to the tumor site.

Conclusion

It seems reasonable to assume that modulation of functional dynamics of selective T_reg subsets may be useful in developing immunotherapeutic strategy for OSCC patients.

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Best practices for multidisciplinary integration of a DCIS genomic assay into clinical practice

Most newly diagnosed ductal carcinoma in situ (DCIS) is treated with breast-conserving surgery (BCS) ± radiation therapy (RT). A key challenge is deciding whether or not to include RT with BCS. This decision is often determined by the degree of risk associated with disease recurrence. However, methods for risk assessment have not kept pace with diagnostic advances. The DCIS Score is an independent predictor and quantifier of individualized recurrence risk in patients with DCIS. Although the test is the only available genomic classifier for DCIS, the degree of adoption is varied, and it has not yet been fully accepted as standard practice. Recognizing the importance of individualizing recurrence assessment in patients with DCIS, the authors convened to review relevant clinical data, share best practices, and establish recommendations regarding how the assay should be incorporated into the decision-making process. Based on their clinical experiences, the authors concluded that effective integration of the DCIS Score should involve shared decision-making between surgeons and other specialties (radiation oncologists, pathologists, patient navigators, and physician assistants), with the patient's preference being a primary consideration. This manuscript aims to provide easy-to-use, clear-cut, and practical guidance to help physicians utilize the DCIS Score to improve risk assessment and inform treatment decisions for their patients with DCIS, including how to understand, run, interpret, and communicate the actionable results to patients.

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Chest radiographic features of human metapneumovirus infection in pediatric patients

Abstract

Background

Human metapneumovirus (HMPV) was identified in 2001 and is a common cause of acute respiratory illness in young children. The radiologic characteristics of laboratory-confirmed HMPV acute respiratory illness in young children have not been systematically assessed.

Objective

We systematically evaluated the radiographic characteristics of acute respiratory illness associated with HMPV in a prospective cohort of pediatric patients.

Materials and methods

We included chest radiographs from children <5 years old with acute respiratory illness who were enrolled in the prospective New Vaccine Surveillance Network (NVSN) study from 2003 to 2009 and were diagnosed with HMPV by reverse transcription-polymerase chain reaction (RT-PCR). Of 215 HMPV-positive subjects enrolled at our tertiary care children's hospital, 68 had chest radiographs obtained by the treating clinician that were available for review. Two fellowship-trained pediatric radiologists, independently and then in consensus, retrospectively evaluated these chest radiographs for their radiographic features.

Results

Parahilar opacities were the most commonly observed abnormality, occurring in 87% of children with HMPV. Hyperinflation also occurred frequently (69%). Atelectasis (40%) and consolidation (18%) appeared less frequently. Pleural effusion and pneumothorax were not seen on any radiographs.

Conclusion

The clinical presentations of HMPV include bronchiolitis, croup and pneumonia. Dominant chest radiographic abnormalities include parahilar opacities and hyperinflation, with occasional consolidation. Recognition of the imaging patterns seen with common viral illnesses like respiratory syncytial virus (RSV) and HMPV might facilitate diagnosis and limit unnecessary antibiotic treatment.

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Metabolic profiling of triple-negative breast cancer cells reveals metabolic vulnerabilities

Abstract

Background

Among breast cancers, the triple-negative breast cancer (TNBC) subtype has the worst prognosis with no approved targeted therapies and only standard chemotherapy as the backbone of systemic therapy. Unique metabolic changes in cancer progression provide innovative therapeutic opportunities. The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), and MET receptor are highly expressed in TNBC, making both promising therapeutic targets. RTK signaling profoundly alters cellular metabolism by increasing glucose consumption and subsequently diverting glucose carbon sources into metabolic pathways necessary to support the tumorigenesis. Therefore, detailed metabolic profiles of TNBC subtypes and their response to tyrosine kinase inhibitors may identify therapeutic sensitivities.

Methods

We quantified the metabolic profiles of TNBC cell lines representing multiple TNBC subtypes using gas chromatography mass spectrometry. In addition, we subjected MDA-MB-231, MDA-MB-468, Hs578T, and HCC70 cell lines to metabolic flux analysis of basal and maximal glycolytic and mitochondrial oxidative rates. Metabolic pool size and flux measurements were performed in the presence and absence of the MET inhibitor, INC280/capmatinib, and the EGFR inhibitor, erlotinib. Further, the sensitivities of these cells to modulators of core metabolic pathways were determined. In addition, we annotated a rate-limiting metabolic enzymes library and performed a siRNA screen in combination with MET or EGFR inhibitors to validate synergistic effects.

Results

TNBC cell line models displayed significant metabolic heterogeneity with respect to basal and maximal metabolic rates and responses to RTK and metabolic pathway inhibitors. Comprehensive systems biology analysis of metabolic perturbations, combined siRNA and tyrosine kinase inhibitor screens identified a core set of TCA cycle and fatty acid pathways whose perturbation sensitizes TNBC cells to small molecule targeting of receptor tyrosine kinases.

Conclusions

Similar to the genomic heterogeneity observed in TNBC, our results reveal metabolic heterogeneity among TNBC subtypes and demonstrate that understanding metabolic profiles and drug responses may prove valuable in targeting TNBC subtypes and identifying therapeutic susceptibilities in TNBC patients. Perturbation of metabolic pathways sensitizes TNBC to inhibition of receptor tyrosine kinases. Such metabolic vulnerabilities offer promise for effective therapeutic targeting for TNBC patients.

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AYA-Myeloma: Real-World, Single-Center Experience Over Last 5 Years

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.

http://ift.tt/2vbXco5

Dynamics of regulatory T cells (Tregs) in patients with oral squamous cell carcinoma

Background and Objectives

The immune dysfunction in oral squamous cell carcinoma (OSCC) patients is one of the major factors for growth and dissemination of tumor affecting disease-free survival.

Methods

Results

Conclusion

It seems reasonable to assume that modulation of functional dynamics of selective T_reg subsets may be useful in developing immunotherapeutic strategy for OSCC patients.

http://ift.tt/2wlianY

http://ift.tt/2xqo9VC

A study of 853 high grade osteosarcomas from a single institution—Are outcomes in Indian patients different?

Aims

To review outcomes of 853 patients of primary high grade osteosarcoma operated with curative intent between January 2006 to December 2013.

Methods

Results

Conclusions

http://ift.tt/2wvPYj2

Comparison of risk factors and complications in patients by stratified mastectomy weight: An institutional review of 1041 consecutive cases

Background and Objectives

This study aims to investigate the specific complication rates, reconstructive differences, and delineate the pertinent independent risk factors in patients with different mastectomy weights.

Methods

Results

Conclusion

http://ift.tt/2xq64Hc

Können 12- statt 4‑wöchentliche Zoledronsäuregaben skelettale Ereignisse bei Patienten mit Knochenmetastasen reduzieren?

http://ift.tt/2vlU48f

New chemotherapies in breast cancer

Summary

In the era of targeted therapies and immunotherapy for cancer, the focus in breast cancer (BC) research has shifted away from classical chemotherapy. Many BC patients, however, still need chemotherapy and thus benefit from the development of new chemotherapeutic agents or regimens. In the past decade, the approval of eribulin and trastuzumab emtansine (T-DM1) have been important advances in this regard. Improved ways of delivery of paclitaxel, anthracyclines, and vinorelbine have also had a considerable clinical impact. Finally, optimizing the use of well-known drugs, such as carboplatin, capecitabine, or adjuvant chemoimmunotherapy in low-risk early BC, has brought about progress in the field of chemo(immuno)therapy.

http://ift.tt/2vVMnJw

Survival outcomes of hepatectomy for stage B Hepatocellular carcinoma in the BCLC classification

Abstract

Background

Because hepatectomy is not recommended in patients with stage B hepatocellular carcinoma (HCC) of the Barcelona Clinic Liver Cancer (BCLC) staging, we evaluated the survival outcomes of hepatectomy for stage B in the BCLC system.

Methods

Data were collected from 297 consecutive adult stage B patients who underwent curative hepatectomy for HCC between 1996 and 2014 in Hokkaido University Hospital. Overall survival (OS), disease-free survival (DFS), and risk factors were analyzed using the Kaplan–Meier method. Independent prognostic factors were evaluated using a Cox proportional hazards regression model. AP-factor (alpha-fetoprotein [AFP] × protein induced by vitamin K absence or antagonism factor II [PIVKA-II]) was categorized according to the serum concentrations of AFP and PIVKA-II: AP1 (AFP < 200 ng/ml and PIVKA-II < 100 mAU/ml), AP2 (AFP × PIVKA-II < 10⁵), and AP3 (AFP × PIVKA-II ≥ 10⁵).

Results

There were 130 deaths among our 297 stage B patients (43.8%). The causes of death in these cases were HCC recurrence (n = 106; 81.5%), liver failure (n = 7; 5.4%), and other causes (n = 17; 16.1%). The operative mortality rate was 0.34% (1/297). The 5-year OS and DFS rates for the stage B cases were 54.3 and 21.9%, respectively. By multivariate analysis, tumor number and AP-factor were risk factors for both survival and recurrence that were tumor related and could be evaluated preoperatively. The study patients with stage B HCC were classified into three groups by tumor number (B1, 1; B23, 2 or 3; B4over: ≥4) and into three groups stratified by AP-factor (AP1, AP2, and AP3). The 5-year OS rates of B1, B23, and B4over were 63.6, 52.3, and 29.0%. The 5-year OS rates of AP1, AP2, and AP3 were 67.6, 65.2, and 39.1%. Stratified by the 5-year OS rate, stage B HCC patients were classified into three subgroups (A-C).The 5-year OS rates of groups A (B1 or B23 and AP-1 or AP-2), B (B1 or B23 and AP-3, or B4over and AP-1 or AP-2), and C (B4over and AP-3) were 69.5, 43.7, and 21.3%.

Conclusion

Stage B HCC patients with a tumor number ≤ 3 and/or AP-factor < 1 × 10⁵ show acceptable 5-year OS rates and could be treated by hepatectomy.

http://ift.tt/2vbw5sY

Können 12- statt 4‑wöchentliche Zoledronsäuregaben skelettale Ereignisse bei Patienten mit Knochenmetastasen reduzieren?

http://ift.tt/2vlU48f

The role of phospholipase Cγ1 in breast cancer and its clinical significance

Future Oncology, Ahead of Print.

http://ift.tt/2v2GkUH

PD-1/PD-L1 biology and immunotherapy in HPV-positive oral cancers

Future Oncology, Ahead of Print.

http://ift.tt/2vlOYJ9

The new smNLR score is a useful and cost-effective prognostic factor in lung cancer patients with MPE. Although further studies are required to generalize our results, this information will benefit clinicians and patients in determining the most appropriate therapy for patients with MPE.

http://ift.tt/2vbkV7x

Cancer associated faecal microbial markers in colorectal cancer detection

Abstract

Colorectal cancer (CRC) is the second most common cause of cancer death in the western world. An effective screening program leading to early detection of disease would severely reduce the mortality of CRC. Alterations in the gut microbiota has been linked to CRC, but the potential of microbial markers for use in CRC screening has been largely unstudied.

We used a nested case-control study of 238 study subjects to explore the use of microbial markers for clbA+ bacteria harbouring the pks pathogenicity island, afa-C+ diffusely adherent Escherichia coli harbouring the afa-1 operon, and Fusobacterium nucleatum in stool as potential screening markers for CRC. We found that individual markers for clbA+ bacteria and Fusobacterium nucleatum were more abundant in stool of patients with CRC, and could predict cancer with a relatively high specificity (81.5% and 76.9%, respectively) and with a sensitivity of 56.4% and 69.2%, respectively. In a combined test of clbA+ bacteria and Fusobacterium nucleatum, CRC was detected with a specificity of 63.1% and a sensitivity of 84.6%.

Introduction: The use of immune checkpoint inhibitors (ICIs) in combination therapy is an emerging trend in tumor immunology. However, the value of combination immunotherapy remains controversial, because of the toxic effects induced by combination. The added benefit of each additional drug has not been assessed against the added toxicity.

Methods and materials: We searched for clinical trials that evaluated ICI monotherapies and combination therapies in lung cancer and melanoma patients. The overall response rate (ORR), grade 3/4 treatment-related adverse event rate, overall survival (OS), and progression-free survival (PFS) were extracted from the most recently published studies to determine the relative risk (RR), hazard ratios (HRs), and 95% confidence intervals (CIs).

Results: Seven randomized controlled trials and one open-label study were identified (n = 3,097). Treatments included combinations of several ICIs, a combination of an ICI and dacarbazine, two combinations of an ICI, paclitaxel, and carboplatin, and a combination of an ICI and gp100 vaccine. Higher ORR (RR: 1.51, 95% CI: 1.03–2.20, p = 0.034), OS (HR: 0.86, 95% CI: 0.78–0.95, p = 0.000), and PFS (HR: 0.93, 95% CI: 0.72–1.14, p = 0.000) values were observed in combination therapy than in monotherapy. In addition, the toxicity of combination ICI immunotherapy was higher (RR: 1.50, 95% CI: 1.03–2.19, p = 0.036) than that of monotherapy.

Conclusion: This meta-analysis showed that the addition of nivolumab to ipilimumab better benefits PFS and ORR. Adding sargramostim was associated with better OS and safety. The efficacy and safety of a nivolumab-ipilimumab-sargramostim combination should be investigated further. This article is protected by copyright. All rights reserved.

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Preoperative intensity-modulated radiotherapy with a simultaneous integrated boost combined with Capecitabine in locally advanced rectal cancer: short-term results of a multicentric study

Abstract

Background

Preoperative radiotherapy (RT) in combination with fluoropyrimidine-based chemotherapy (CT) is the standard of care in patients with locally advanced, T3-T4 N0–2, rectal cancer (LARC). Given the correlation between RT dose-tumor response and the prognostic role of the tumor regression grade (TRG), treatment intensification represents an area of active investigation. The aim of the study was to analyze the role of RT dose-intensification in the preoperative treatment of LARC in terms of feasibility, efficacy and toxicity.

Methods

We retrospectively analyzed patients with LARC treated with intensity-modulated radiotherapy (IMRT) and simultaneous integrated boost (SIB) at five Italian radiation oncology centers. Concurrent Capecitabine was administered. Treatment response was evaluated in terms of disease down-staging and TRG. Acute toxicity was evaluated according to the CTC-AE 4.0 scale.

Results

A total of 76 patients were identified for this analysis. A dose of 45 Gy was prescribed to the entire mesorectum and pelvic lymph nodes with a median SIB dose of 54 Gy (range 52.5–57.5) to the tumor and corresponding mesorectum. Overall, 74/76 (97.4%) patients completed the planned RT, whereas 64/76 (84.2%) patients completed the prescribed CT. Eight (10.5%) patients developed grade 3–4 acute toxicity. Overall, 72/76 patients underwent surgery. The tumor and nodal down-staging was documented in 51 (70.8%) and 43 (67%) patients, respectively. Twenty (27.8%) patients obtained a pathologic complete response. Surgical morbidity was reported in 13/72 patients (18.1%).

Conclusions

Although retrospective in design, this study indicates that IMRT-SIB with a dose range of 52.5–57.5 Gy (median 54 Gy) and concomitant Capecitabine appears feasible, well tolerated and effective in terms of disease down-staging and pathological complete response. Long-term toxicity and the impact on disease control and patient survival will be evaluated with a longer follow-up time.

Trial registration

http://ift.tt/2g2kWrI

MicroRNA-218 functions as a tumor suppressor in lung cancer by targeting IL-6/STAT3 and negatively correlates with poor prognosis

Abstract

Background

Aberrant expression of microRNAs in different human cancer types has been widely reported. MiR-218 acts as a tumor suppressor in diverse human cancer types impacting regulation of multiple genes in oncogenic pathways. Here, we evaluated the expression and function of miR-218 in human lung cancer and ALDH positive lung cancer cells to understand the potential mechanisms responsible for disease pathology. Also, the association between its host genes and the target genes could be useful towards the better understanding of prognosis in clinical settings.

Methods

Publicly-available data from The Cancer Genome Atlas (TCGA) was mined to compare the levels of miR-218 and its host gene SLIT2/3 between lung cancer tissues and normal lung tissues. Transfection of miR-218 to investigate its function in lung cancer cells was done and in vivo effects were determined using miR-218 expressing lentiviruses. Aldefluor assay and Flow cytometry was used to quantify and enrich ALDH positive lung cancer cells. Levels of miR-218, IL-6R, JAK3 and phosphorylated STAT3 were compared in ALDH1A1 positive and ALDH1A1 negative cells. Overexpression of miR-218 in ALDH positive cells was carried to test the survival by tumorsphere culture. Finally, utilizing TCGA data we studied the association of target genes of miR-218 with the prognosis of lung cancer.

Results

We observed that the expression of miR-218 was significantly down-regulated in lung cancer tissues compared to normal lung tissues. Overexpression of miR-218 decreased cell proliferation, invasion, colony formation, and tumor sphere formation in vitro and repressed tumor growth in vivo. We further found that miR-218 negatively regulated IL-6 receptor and JAK3 gene expression by directly targeting the 3′-UTR of their mRNAs. In addition, the levels of both miR-218 host genes and the components of IL-6/STAT3 pathway correlated with prognosis of lung cancer patients.

Conclusions

MiR-218 acts as a tumor suppressor in lung cancer via IL-6/STAT3 signaling pathway regulation.

http://ift.tt/2vW2GpH

Influence of radiation treatment technique on outcome and toxicity in anal cancer

Abstract

Objective

Intensity-modulated radiation therapy (IMRT) has largely supplanted three-dimensional conformal radiation (3D-CRT) for definitive anal cancer treatment due to decreased toxicity and potentially improved outcomes. Convincing data demonstrating its advantages, however, remain limited. We compared outcomes and toxicity with concurrent chemotherapy and IMRT vs 3D-CRT for anal cancer.

Methods

We performed a single-institution retrospective review of patients treated with IMRT or 3D-CRT as part of definitive mitomycin-C/5-fluorouricil-based chemoradiation for anal cancer from January 2003 to December 2012.

Results

One hundred sixty-five patients were included, with 61 and 104 receiving IMRT and 3D-CRT, respectively. Overall, 92.7% had squamous cell carcinoma. The mean initial pelvic dose was 48.3 and 44 Gy for IMRT and 3D-CRT, respectively. Complete response, partial response, and disease progression rates were similar (IMRT 83.6, 8.2, 8.2%; 3D-CRT 85.6, 6.7, 7.7%; p = 0.608, p = 0.728, p = 0.729). There was no significant difference in overall survival (p = 0.971), event-free survival (p = 0.900), or local or distant recurrence rates (p = 0.118, p = 0.373). IMRT caused significantly less acute grade 1–2 incontinence (p = 0.035), grade 3–4 pain (p = 0.033), and fatigue (p = 0.030). IMRT patients had significantly fewer chronic post-treatment toxicities (p = 0.008), outperforming 3D-CRT in six of eight toxicities reviewed. Though total treatment length was comparable (43.6 and 44.5 days), IMRT recipients had fewer (27.9 vs 41.3% of patients, p = 0.89), shorter treatment breaks (mean 2.9 vs 4.1 days, p = 0.229).

Conclusion

This report represents the largest series directly comparing concurrent chemotherapy with IMRT vs 3D-CRT for definitive treatment of anal cancer. IMRT significantly reduced acute and post-treatment toxicities and allowed for safe and effective pelvic dose escalation.

http://ift.tt/2vb00BJ

Psychological distress associated with cancer screening: A systematic review

BACKGROUND

Current national cancer screening recommendations include the potential risk of psychological harm related to screening. However, data on the relation of psychological distress to cancer screening is limited. The authors conducted a systematic review to assess psychological distress associated with cancer screening procedures.

METHODS

Studies that administered measures of psychological distress between 2 weeks before and 1 month after the screening procedure were included.

RESULTS

In total, 22 eligible studies met criteria for review, including 13 observational trials and 9 randomized controlled trials. Eligible studies used a broad range of validated and unvalidated measures. Anxiety was the most commonly assessed construct and was measured using the State Trait Anxiety Inventory. Studies included breast, colorectal, prostate, lung, and cervical screening procedures. Distress was low across procedures, with the exception of colorectal screening. Distress did not vary according to the time at which distress was measured. None of the studies were conducted exclusively with the intention of assessing distress at the time of screening.

CONCLUSIONS

Evidence of low distress during the time of cancer screening suggests that distress might not be a widespread barrier to screening among adults who undergo screening. However, more studies are needed using validated measures of distress to further understand the extent to which screening may elicit psychological distress and impede adherence to national screening recommendations. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2wAVHTZ

Bevacizumab alone or in combination with TRC105 for patients with refractory metastatic renal cell cancer

BACKGROUND

Targeting the vascular endothelial growth factor (VEGF) pathway has improved outcomes in metastatic renal cell carcinoma (RCC); however, resistance inevitably occurs. CD105 (endoglin) is an angiogenic pathway that is strongly upregulated after VEGF inhibition, potentially contributing to resistance. The authors tested whether TRC105, a monoclonal antibody against endoglin, impacted disease control in patients with previously treated RCC who were receiving bevacizumab.

METHODS

Eligible patients with metastatic RCC who had previously received 1 to 4 prior lines of therapy, including VEGF-targeted agents, were randomized 1:1 to receive bevacizumab 10 mg/kg intravenously every 2 weeks (arm A) or the same plus TRC105 10 mg/kg intravenously every 2 weeks (arm B). The primary endpoint was progression-free survival (PFS) at 12 and 24 weeks. Correlative studies included serum transforming growth factor β (TGFβ) and CD105 levels as well as tissue immunostaining for TGFβ receptors.

RESULTS

Fifty-nine patients were enrolled (28 on arm A and 31 on arm B), and 1 patient on each arm had a confirmed partial response. The median PFS for bevacizumab alone was 4.6 months compared with 2.8 for bevacizumab plus TRC105 (P = .09). Grade ≥ 3 toxicities occurred in 16 patients (57%) who received bevacizumab compared with 19 (61%) who received bevacizumab plus TRC105 (P = .9). Baseline serum TGFβ levels below the median (<10.6 ng/mL) were associated with longer median PFS (5.6 vs 2.1 months; P = .014).

CONCLUSIONS

TRC105 failed to improve PFS when added to bevacizumab. TGFβ warrants further study as a biomarker in RCC. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2vb7PqT

An unusual cause of genu valgum and persistent instability

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Abstract

We present the case of a professional adolescent footballer who attended our clinic with ongoing instability symptoms and valgus knee deformity after conservative management of an medial collateral ligament injury. The patient was found to have sustained a contra-coup Salter Harris Type V injury to his lateral distal femur physis resulting in premature growth arrest and deformity. Salter Harris Type V injuries are rare, and often not diagnosed until growth has arrest has occurred due to lack of identifiable features on initial plain radiographs. The patient was successfully treated with opening wedge femoral osteotomy and plication of the medial collateral ligament. This case reinforces the need for awareness of such injuries to avoid delayed diagnosis and describes options for management.

http://ift.tt/2w0pK56

Closed posterior ankle dislocation without associated fractures: a case report

$Plain film X-rays of right ankle showing total posterior dislocation of the ankle joint with no fracture of the medial or lateral malleolus.$

Abstract

Ankle dislocation without associated fractures, also known as pure ankle dislocation is a rare injury. It is usually the result of high energy trauma. It could be a combination of predisposing anatomical factors plus certain ankle position at time of injury that produce this peculiar injury. In most cases it is managed conservatively with urgent reduction, 6–9 weeks of immobilization followed with intense physiotherapy. The outcome after these injuries is generally good where most of the patients in reported cases managed to return to the preinjury level of activity.

http://ift.tt/2vZW7k6

Free flap transfer reconstruction in managing tongue carcinoma during pregnancy

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Abstract

Malignant oral cancers do not commonly occur in pregnant women. But when they do, the presence of a foetus and maternal physiological changes complicate and limit the treatment options. Risk benefit assessment and balancing of them are always important. A 33-year-old woman, who was 25 weeks pregnant, presented with a squamous cell carcinoma on her tongue. She was clinically staged II (T2, N0 and M0). Discussions between the patient, surgical teams and obstetricians agreed to continue her pregnancy while managing the tumour. Hemi-glossectomy and ipsilateral neck dissection was performed. Free antero-lateral thigh flap was transferred to reconstruct the tongue defect, successfully. The patient gave birth to a healthy baby afterward. She is tumour free for 6 years. Free flap reconstruction can be an option, even if the patient is pregnant.

http://ift.tt/2vZEqBr

Making the grade: The newest US Preventive Services Task Force prostate cancer screening recommendation

The US Preventive Services Task Force recently issued a draft guideline supporting individualized decision making for prostate cancer screening. Although the authors believe this guideline appropriately reflects changing evidence regarding the benefits and harms of screening, they raise concerns about achieving decision making, interpreting active surveillance data, and initiating screening for African American men.

http://ift.tt/2x9hEau

Programmed cell death ligand 1 and tumor-infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation

BACKGROUND

The immune profile of sarcomatoid renal cell carcinoma (sRCC), including the programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) status, has not been well characterized.

METHODS

An immunohistochemical digital analysis of PD-L1, PD-1, CD4, and CD8 was performed on nephrectomy specimens from 118 sRCC patients and 92 nonsarcomatoid clear cell renal cell carcinoma (ccRCC) patients. The clinical characteristics of the population were compared between sRCC and ccRCC. Overall survival was estimated, and comparisons were made between PD-L1–positive and PD-L1–negative groups as well as tumor-infiltrating lymphocyte (TIL)–high and TIL-low groups.

RESULTS

The PD-L1 H-score of sRCC (mean, 3.7; range, 0-192.1) was significantly higher than the score of grade 4 ccRCC (P = .001), and 41.3% of sRCC cases showed a PD-L1 H-score ≥ 10. The PD-1–positive cell density was significantly higher in sRCC versus ccRCC within the tumor and at the invasive front. The intratumoral CD8-positive cell density was significantly higher in sRCC versus ccRCC. Forty-one percent in the sarcomatoid component of sRCC and 8% in the epithelioid component of sRCC had an adaptive immune resistance phenotype (PD-L1–positive and TIL-positive), whereas only 1% in ccRCC had the type I phenotype.

CONCLUSIONS

sRCC showed higher PD-L1 expression and higher PD-1– and CD8-positive cell density than grade 4 ccRCC. The results indicate a notable immunosuppressive environment in sRCC. Despite advances in the treatment of advanced-stage renal cell carcinoma, sRCC still has a poor prognosis. This work describes highly immunosuppressive characteristics of sRCC in comparison with an appropriate ccRCC control. The results suggest PD-1/PD-L1 blockade therapy as a potential therapeutic approach for sRCC. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2vV7EmG

Receipt of definitive therapy in elderly patients with unfavorable-risk prostate cancer

BACKGROUND

Conservative management of aggressive prostate cancer in the elderly without definitive therapy has been associated with a 10-year prostate cancer-specific mortality of approximately 50%. The authors examined the prevalence of definitive therapy in elderly patients with intermediate-risk or high-risk disease.

METHODS

411,343 patients who were diagnosed from 2004 through 2012 with intermediate-risk or high-risk prostate cancer were identified in the National Cancer Database. Multivariable logistic regression adjusting for sociodemographic characteristics and comorbidity was used to examine the association between age and receipt of definitive therapy, defined as radical prostatectomy or radiotherapy, and of primary androgen deprivation therapy (ADT) among patients who did not receive definitive therapy.

RESULTS

In total, 87.1% of high-risk patients and 91.9% of intermediate-risk patients received definitive therapy. When stratified by age, 93.7%, 92.1%, 90.8%, 87.6%, 80.9%, and 55.2% of high-risk patients and 96.1%, 94.7%, 93.4%, 89.7%, 82.7%, and 62.8% of intermediate-risk patients ages <60, 60 to 64, 65 to 69, 70 to 74, 75 to 79, and ≥80 years received definitive therapy, respectively. For both high-risk and intermediate-risk patients, increasing age was significantly associated with a decreased likelihood of receiving definitive therapy overall (both P < .001) and a greater likelihood of receiving primary ADT among those who did not receive definitive therapy (both P < .001).

CONCLUSIONS

Background

The Empty Spiracles Homeobox (EMX-) 2 gene has been associated with regulation of growth and differentiation in neuronal development. While recent studies provide evidence that EMX2 regulates tumorigenesis of various solid tumors, its role in colorectal cancer remains unknown. We aimed to assess the prognostic significance of EMX2 expression in stage III colorectal adenocarcinoma.

Methods

Expression levels of EMX2 in human colorectal cancer and adjacent mucosa were assessed by qRT-PCR technology, and results were correlated with clinical and survival data. siRNA-mediated knockdown and adenoviral delivery-mediated overexpression of EMX2 were performed in order to investigate its effects on the migration of colorectal cancer cells in vitro.

Results

Compared to corresponding healthy mucosa, colorectal tumor samples had decreased EMX2 expression levels. Furthermore, EMX2 down-regulation in colorectal cancer tissue was associated with distant metastasis (M1) and impaired overall patient survival. In vitro knockdown of EMX2 resulted in increased tumor cell migration. Conversely, overexpression of EMX2 led to an inhibition of tumor cell migration.

Conclusions

EMX2 is frequently down-regulated in human colorectal cancer, and down-regulation of EMX2 is a prognostic marker for disease-free and overall survival. EMX2 might thus represent a promising therapeutic target in colorectal cancer.

http://ift.tt/2vV69F4

BiClamp® vessel-sealing device for open hepatic resection of malignant and benign liver tumours: a single-institution experience

Abstract

Background

Intraoperative blood loss during hepatectomy worsens prognosis, and various tools have been used to improve perioperative safety and feasibility. We aimed to retrospectively evaluate the feasibility and safety of the BiClamp® device for open liver resection.

Methods

We included 84 patients undergoing liver resection from a single centre, with all patients operated by the same surgical group. All hepatectomies were performed using BiClamp® (Erbe Elektromedizin GmbH, Tubingen, Germany), an electrosurgical device that simultaneously transects liver parenchyma and seals vessels <7 mm in diameter. We collected data on intraoperative blood loss, resection time, and perioperative complications, comparing cirrhotic and non-cirrhotic patients.

Results

The 84 patients enrolled in this study included 56 cirrhotic and 28 non-cirrhotic patients. All patients underwent hepatectomy (30 major and 54 minor hepatectomies) using the BiClamp®, exclusively, and 54 patients required inflow occlusion (Pringle manoeuvre). Overall intraoperative blood loss (mean ± standard deviation) was 523.5 ± 558.6 ml, liver parenchymal transection time was 36.3 ± 16.5 min (range, 13-80 min), and the mean parenchymal transection speed was 3.0 ± 1.9 cm²/min. Twelve patients received perioperative blood transfusion. The cost of BiClamp® for each patient was 800 RMB (approximately 109€). There were no deaths, and the morbidity rate was 25%. The mean (standard deviation) hospital stay was 9.3 (2.3) days. Comparisons between cirrhotic and non-cirrhotic patients revealed no difference in blood loss (491.0 ± 535.7 ml vs 588.8 ± 617.5 ml, P = 0.598), liver parenchymal transection time (34.1 ± 14.8 min vs 40.9 ± 19.2 min, P = 0.208), mean parenchymal transection speed (3.3 ± 2.1 cm²/min vs 2.5 ± 1.3 cm²/min, P = 0.217), and operative morbidity (28.6% vs 14.3%, P = 0.147).

Conclusions

The reusable BiClamp® vessel-sealing device allows for safe and feasible major and minor hepatectomy, even in patients with cirrhotic liver.

Trial registration

This trial was retrospectively registered and the detail information was as followed. Registration number: ChiCTR-ORC-17011873 (Chinese Clinical Trial Registry). Registration Date: 2017-07-05.

http://ift.tt/2x8ZyoM

Gastrointestinal adenocarcinoma metastasizing to the vulva: a case report

Metastatic vulval adenocarcinoma is a rare occurrence with only a few cases reported to date. They can arise from the breast, gastrointestinal system, or endometrium.

http://ift.tt/2wuOg1g

Role of MEK partner-1 in cancer stemness through MEK/ERK pathway in cancerous neural stem cells, expressing EGFRviii

Abstract

Background

Glioma stem cells (GSCs) are a major cause of the frequent relapse observed in glioma, due to their high drug resistance and their differentiation potential. Therefore, understanding the molecular mechanisms governing the 'cancer stemness' of GSCs will be particularly important for improving the prognosis of glioma patients.

Methods

We previously established cancerous neural stem cells (CNSCs) from immortalized human neural stem cells (F3 cells), using the H-Ras oncogene. In this study, we utilized the EGFRviii mutation, which frequently occurs in brain cancers, to establish another CNSC line (F3.EGFRviii), and characterized its stemness under spheroid culture.

Results

The F3.EGFRviii cell line was highly tumorigenic in vitro and showed high ERK1/2 activity as well as expression of a variety of genes associated with cancer stemness, such as SOX2 and NANOG, under spheroid culture conditions. Through meta-analysis, PCR super-array, and subsequent biochemical assays, the induction of MEK partner-1 (MP1, encoded by the LAMTOR3 gene) was shown to play an important role in maintaining ERK1/2 activity during the acquisition of cancer stemness under spheroid culture conditions. High expression of this gene was also closely associated with poor prognosis in brain cancer.

Conclusion

These data suggest that MP1 contributes to cancer stemness in EGFRviii-expressing glioma cells by driving ERK activity.

http://ift.tt/2vaOG8A

Association between AKI and all-cause mortality after EVAR

http://ift.tt/2wuaiBd

Important role of calcium chloride in preventing carbon monoxide generation during desflurane degradation with alkali hydroxide-free carbon dioxide absorbents

Abstract

We investigated whether calcium chloride (CaCl₂), a supplementary additive in carbon dioxide (CO₂) absorbents, could affect carbon monoxide (CO) production caused by desflurane degradation, using a Japanese alkali-free CO₂ absorbent Yabashi Lime^®-f (YL-f), its CaCl₂-free and 1% CaCl₂-added derivatives, and other commercially available alkali-free absorbents with or without CaCl₂. The reaction between 1 L of desflurane gas (3–10%) and 20 g of desiccated specimen was performed in an artificial closed-circuit anesthesia system for 3 min at 20 or 40 °C. The CO concentration was measured using a gas chromatograph equipped with a semiconductor sensor detector. The systems were validated by detecting dose-dependent CO production with an alkali hydroxide-containing CO₂ absorbent, Sodasorb^®. Compared with YL-f, the CaCl₂-free derivative caused the production of significantly more CO, while the 1% CaCl₂-added derivative caused the production of a comparable amount of CO. These phenomena were confirmed using commercially available absorbents AMSORB^® PLUS, an alkali-free absorbent with CaCl₂, and LoFloSorb™, an alkali-free absorbent without CaCl₂. These results suggest that CaCl₂ plays an important role in preventing CO generation caused by desflurane degradation with alkali hydroxide-free CO₂ absorbents like YL-f.

http://ift.tt/2xoAYQh