LncRNA PTCSC3 affects drug resistance of anaplastic thyroid cancer through STAT3/INO80 pathway

Background: LncRNA PTCSC3 is a tumor suppressor in thyroid cancer, and its role in drug resistance of anaplastic thyroid cancer (ATC) to chemotherapy drug doxorubicin was investigated in this study.

Methods: Expression of RNA and protein was analyzed by qRT-PCR and western blot, respectively. Flow cytometry was used to analyze the expression rate of CD133⁺ cells. The endogenous expression of related genes was modulated by recombinant plasmids and cell transfection. Combination condition and interaction between PTCSC3 and STAT3 were determined by RIP and RNA pull-down assay, respectively. MTT assay was performed to detect cytotoxicity. Chromatin immunoprecipitation was conducted to identify interactions between STAT3 and DNA promoter of INO80.

Results: LncRNA PTCSC3 was low-expressed in ATC tissues and cells. Over-expressed PTCSC3 inhibited the drug resistance of ATC to doxorubicin. PTCSC3 negatively regulated STAT3, and STAT3 promoted expression of INO80. PTCSC3 regulated INO80 through STAT3. PTCSC3 suppressed stem cells properties and drug resistance of ATC to doxorubicin.

Conclusion: LncRNA PTCSC3 inhibits INO80 expression by negatively regulating STAT3, and thereby attenuating drug resistance of ATC to chemotherapy drug doxorubicin.     

Hyperthermia of magnetic nanoparticles allows passage of sodium fluorescein and Evans blue dye across the blood–retinal barrier

Purpose: The blood–retina barrier (BRB) is a biological barrier consisting of tightly interconnected endothelial cells inside the retinal vascular network that protects the neural tissue from harmful pathogens and neurotoxic molecules circulating in the bloodstream. Unfortunately, with regard to retinoblastoma, this barrier also prevents systemically administered therapeutics reaching the retinal tissue. In this study we introduce a novel technique to locally and transiently increase BRB permeability for drug delivery using hyperthermia of magnetic nanoparticles (MNPs).

Materials and methods: An alternating current (AC) magnetic field was used to induce hyperthermia of locally injected MNPs in the left ophthalmic artery of a rat model. To improve adherence on the surface of the endothelium, commercially available MNPs coated with human transferrin glycoproteins were used. After hyperthermia we assessed the extravasation of systemically injected sodium fluorescein (NaF) as well as Evans blue dye (EBD) into the retinal tissue.

Results: Spectrofluorometry and fluorescent microscopy image analysis show a significant increase of dye penetration in the retina where hyperthermia of MNPs was applied.

Conclusions: Our proposed new technique can allow both small and large dye molecules to cross the BRB. While the results are preliminary and thorough evaluation of the retinal tissue following hyperthermia is necessary, this technique has the potential to be an effective mean for the treatment of various diseases such as retinoblastoma.     

Risk factors for acute kidney injury associated with the treatment of bacterial endocarditis at a tertiary academic medical center*

Background: Acute kidney injury (AKI) is a common complication of endocarditis.

Objective: To determine risk factors for the development of AKI in patients treated for endocarditis.

Methods: This single centre, retrospective univariate and multivariate analysis to determine risk factors for the development of AKI included patients diagnosed with endocarditis between January 2009 and October 2013.

Results: Of 211 included patients, a total of 84 (39.8%) patients developed AKI. We identified multiple independent variables associated with the development of AKI, including: age ≥ 65 years, presence of hardware, chronic kidney disease, AKI on admission, infection with Staphylococcus spp, receipt of nafcillin or oxacillin or aminoglycoside and nafcillin or oxacillin or aminoglycoside and vancomycin, vancomycin trough level ≥ 20.0 mcg/ml, aminoglycoside total daily dose reduction, duration of vancomycin exceeding three days, receipt of loop diuretic or more than three concomitant nephrotoxins and duration of loop diuretic or non-steroidal anti-inflammatory drug therapy exceeding seven days.

Conclusions: In patients treated for endocarditis, multiple risk factors for AKI were identified. Prospective studies are needed to evaluate these variables for causation of AKI in patients treated for endocarditis.     

Use of specific immunoglobulins and vaccines for the management of accidental needlestick injury in the child: a practical review in the anti-vaccination movement era

Introduction: Accidental needle injury is a common but still discussed problem.

Objective: We discuss possible options to optimize the management of injured children in light of the available literature findings.

Results: The risk of viral infection is low. However, blood investigations are mandatory, as well as appropriate counselling. Anti-HBV immunoglobulins are recommended in all unvaccinated subjects exposed to a HBsAg-positive source; however, there is no agreement regarding their administration in unvaccinated children. Use of anti-tetanus immunoglobulins in unvaccinated child with minor and clean wound is well defined; however, wound type classification in the event of needlestick injury may be difficult and subjective. There is no agreement on the routine use of antiretroviral prophylaxis.

Conclusion: From a practical point of view, several unsolved issues have emerged regarding the management of the children with needlestick injury, which appear particularly relevant in the anti-vaccination movement era. International guidelines should be encouraged at this regard.     

Olaratumab for the treatment of advanced soft tissue sarcoma

Introduction: Olaratumab, a human monoclonal antibody against platelet derived growth factor receptor alpha (PDGFR- α), is the first drug that in combination with doxorubicin for the treatment of patients with advanced/metastatic soft tissue sarcoma (STS) that has showed an improved overall survival compared to doxorubicin alone. These initial results are exciting and have the potential to change the landscape of treatment for patients with STS.

Areas covered: This article reviews the development of olaratumab for oncology use by reviewing articles in PubMed for ‘platelet derived growth factor’ and ‘receptor’ and ‘soft tissue sarcoma’. We provide an overview of the published studies to date for olaratumab and specifically the use in soft tissue sarcoma.

Expert commentary: Olaratumab is a well-tolerated drug that, when combined with doxorubicin, has shown an improved overall survival compared to doxorubicin alone and the phase III confirmatory study is eagerly awaited.     

Phthalocyanine induced phototherapy coupled with Doxorubicin; a promising novel treatment for breast cancer

Introduction: Globally, breast cancer is the most common life-threatening malignant disease among women. Adjuvant chemotherapeutic treatment of anthracycline-based chemotherapy (e.g., doxorubicin) has been shown to be more advantageous over non-anthracycline-based therapies, yet possess the tenacity of developing resistance and potential side effects which have limited its use in the clinical setting. These reasons necessitate combining doxorubicin with emerging photodynamic treatment regimens.

Areas covered: In this review, the authors have concisely explained doxorubicin chemotherapy and the photobiological processes of phthalocyanine triggered photodynamic therapy (PDT). A literature search was conducted and reports demonstrating the use of doxorubicin and photodynamic therapy as a treatment modality for breast cancer were identified. More emphasis was made on studies demonstrating the efficacy and improved anticancer effect of combining chemotherapy with photodynamic therapy. However, it was concluded that for this combination therapy, still in it’s infancy, it could be relevant when integrated into standard treatment.

Expert Commentary: To these effects, comprehensive models based on experimental evaluations are needed for rational design of anthracycline-based chemotherapy and PDT to be integrated into the clinical setting.     

Results of concurrent chemotherapy and hyperthermia in patients with recurrent cervical cancer after previous chemoradiation

Background: Concomitant hyperthermia has been shown to improve response rate after cisplatin in recurrent cervical cancer in previously irradiated patients. It is unclear whether similar response rates can be obtained in patients with a recurrence after previous platinum-containing chemoradiation.

Objective: This study aimed to evaluate the outcome of cisplatin-based chemotherapy with concurrent hyperthermia in patients with recurrent cervical cancer after radiotherapy and cisplatin.

Methods: Patients with recurrent cervical cancer after cisplatin-based chemoradiation or neoadjuvant chemotherapy followed by surgery and radiotherapy who were treated with concurrent platinum-based chemotherapy and hyperthermia were eligible for this retrospective analysis. All patients received six or eight weekly platinum-based chemotherapy cycles in combination with six or eight weekly hyperthermia sessions. The time-to-event variables were estimated using Kaplan-Meier analysis. P-values less than 0.05 were considered significant.

Results: All 38 evaluable patients were selected from the hyperthermia database in the Academic Medical Centre (Amsterdam) and the Erasmus Medical Centre (Rotterdam). Mean age at relapse was 45.7 years (range 27–74). Median time to recurrence after first-line treatment was 15 months. A total of 27 patients had a local and/or regional recurrence; 11 had disease beyond the pelvis. All planned courses of cisplatin chemotherapy and hyperthermia were administered in 17/38 patients. Median follow-up was 6.5 months. One patient died during treatment; response rate was 4/37 (14%), with one complete response. Overall survival was 23% at 12 months and 4% at 24 months. The incidence of grade 3–4 haematological complications did not exceed 10%.

Conclusion: In this retrospective study, concurrent cisplatin and hyperthermia after first-line cisplatin-containing chemoradiation showed poor response and survival. We do not recommend this treatment for recurrence of locally advanced cervical cancer.     

The safety and efficacy of sonidegib for the treatment of locally advanced basal cell carcinoma

Introduction: Basal cell carcinomas (BCCs) are the commonest malignancy in the Western world. Locally advanced BCCs (laBCCs) represent tumours that have developed in difficult-to-treat facial sites, aggressively recurrent tumours, large neglected tumours and those in which current treatment options are excluded by clinical or patient-driven criteria. It is estimated laBCCs represent 1% of BCCs.

Areas covered: Sonidegib is an oral hedgehog pathway inhibitor with a novel structure. It has recently been licensed for the treatment of laBCC.

This article provides a comprehensive review of the literature regarding sonidegib, detailing the pharmacology of the compound, clinical trial data, competitor compounds and a future perspective.

Expert commentary: Sonidegib is a novel smoothened (SMO) inhibitor with comparable efficacy to vismodegib, with patient response rates of 44% (sonidegib) and 43% (vismodegib). The adverse effect profile of these two treatments is similar with the main effects being considered to be class effects of SMO inhibitors.     

The safety and efficacy of olaparib therapy in patients with relapsed ovarian cancer

Introduction: PARP inhibition is an exciting new anticancer strategy. Olaparib has recently obtained a first in class license in Europe and the USA for the treatment of relapsed BRCA-mutant ovarian cancer.

Areas covered: We review the key preclinical and clinical data surrounding its use in the maintenance setting.

Expert commentary: We also consider the market profile, regulatory issues surrounding the agent and offer a five year speculative viewpoint of its future development in ovarian cancer.     

Evaluating the addition of oxaliplatin to single agent fluoropyrimidine in the treatment of locally advanced rectal cancer: a systematic review and meta-analysis

Introduction: Multimodality treatment of patients with locally advanced rectal cancer (LARC) has significantly improved local disease control, however the unaltered overall survival (OS) implicates an inability to further control micrometastases, providing rationale for intensified systemic treatment.

A systematic review was conducted to evaluate the efficacy and toxicity of adding oxaliplatin to a fluoropyrimidine (intervention) compared with fluoropyrimidine alone (control) in the treatment of LARC.

Methods: We searched CENTRAL, Medline Ovid, PubMed and EMBASE databases. Randomised trials comparing the intervention and control delivered either pre- or post-operatively were included.

Results: Seven trials involving 4444 patients were identified; five studies evaluated the intervention vs control preoperatively; one study peri-operatively; and one, post-operatively. There was no significant difference in OS with oxaliplatin addition, HR 0.89, 95% CI, 0.75 to 1.06. There was however an improvement in disease free survival, 3-year local and distant recurrence rates (RR) favouring oxaliplatin. Preoperative oxaliplatin improved pathological complete response (pCR), but with a greater toxicity and reduced compliance with radiation.

Conclusion: There is no OS benefit with oxaliplatin, despite improved pCR, local and distant RR. Before drawing definitive conclusions, longer follow-up in included trials and availability of published data from other eligible studies, including the induction setting, are needed.     

EGFR expression in circulating tumor cells from high-grade metastatic soft tissue sarcomas

Introduction: Soft tissue Sarcomas (STS) are rare malignances, with high mortality rates. Half of patients develop metastasis. The presence of isolated Circulating Tumor Cells (CTCs) and Circulating Tumor Microemboli (CTM) in the blood may be early markers of tumor invasion. Epidermal Growth Factor (EGF) family receptors can also influence this process.

Objectives: to quantify CTCs and identify CTM as well as the EGF Receptor (EGFR) protein expression in these cells and correlate with clinical outcome in metastatic STS.

Materials and methods: Approximately 8mL of blood was prospectively collected from patients with different types of high-grade STS, before the beginning of chemotherapy. The samples were processed and filtered by ISET (Rarecells, France) for the isolation and quantification of CTCs and CTMs. EGFR expression was analyzed by immunocytochemistry (ICC) on CTCs/ CTMs.

Results: We analyzed 18 patients with median age of 49 years (18-77 y). The positivity for EGFR protein expression in CTCs was observed in 93.75% of the patients. This result shows that targeting EGFR positive CTCs from STS origen can be translated in clinical benefit for some patients. In addition, if target therapy is chosen, the EGFR expression in CTCs can be used in follow-up to measure treatment effectiveness.

Conclusions: This is the first study to demonstrate the expression of EGFR protein in CTCs from sarcoma patients. It may open an area for future investigations. The next step is to characterize CTCs in a larger cohort of patients to better understand the role of EGFR in sustaining tumor metastasis in sarcomas.     

Opportunities and challenges of long term anti-estrogenic adjuvant therapy: treatment forever or intermittently?

Introduction: Extended adjuvant (5–10 years) therapy targeted to the estrogen receptor (ER) has

significantly decreased mortality from breast cancer (BC).

Areas covered: Translational research advanced clinical testing of extended adjuvant therapy with tamoxifen or aromatase inhibitors (AIs). Short term therapy or non-compliance increase

recurrence, but surprisingly recurrence and death does not increase dramatically after 5 years of adjuvant therapy stops.

Expert commentary: Compliance ensures optimal benefit from extended antihormone adjuvant therapy.Retarding acquired resistance using CDK4/6 or mTOR inhibitors is discussed. Preventing acquired resistance from mutations of ER could be achieved with Selective ER Downregulators (SERDs), eg fulvestrant. Fulvestrant is a depot injectable so oral SERDs are sought for extended use. In reality, a ‘super SERD’ which destroys ER but improves women’s health like a Selective ER Modulator (SERM), would aid compliance to prevent recurrence and death. Estrogen-induced apoptosis occurs in 30% of BC with antihormone resistance. The ‘one in three’ rule that dictates that one in three unselected patients respond to either hormonal or antihormonal therapy in BC occurs with estrogen or antiestrogen therapy and must be improved. The goal is to maintain patients for their natural lives by blocking cancer cell survival through precision medicine using short cycles of estrogen apoptotic salvage therapy, and further extended antihormone maintenance.     

Isolated cardiac peripheral primitive neuroectodermal tumor: A case report

Background: Peripheral primitive neuroectodermal tumor isolated in the heart, presenting as a primary cardiac tumor is considered as extremely rare.

Methods: We present a 53-year-old Chinese female with a cardiac tumor which was discovered by CT.

Results: A hypo-intense tumorous mass was shown extending from the left ventricle by Cardiac CT, and fused FDG positron emission tomography demonstrated no other abnormal FDG active lesions in the body. We performed a total resection surgery of the tumor subsequently and the patient recovered well and discharged from hospital 6 d after surgery.

Conclusion: The pathological diagnosis was primary cardiac peripheral primitive neuroectodermal tumor. No tumor recurrence was shown by echocardiography during the 24 months follow-up visits.     

Radiofrequency ablation combined with percutaneous ethanol injection for hepatocellular carcinoma: a systematic review and meta-analysis

Background: Radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) are important treatments for patients with hepatocellular carcinoma (HCC) who are not eligible for resection and liver transplantation. Therefore, it is important to establish comparisons between RFA, PEI and the two therapies in combination.

Aims: To evaluate the clinical efficacy and safety of combined RFA-PEI versus monotherapy with either RFA or PEI for HCC to provide references for clinical practice and further research.

Methods: We searched all eligible studies published before September 2015 in the Cochrane Library, PubMed, Embase, Web of Science and Chinese databases, such as CBM, CNKI, VIP and WanFang and also retrieved papers from other sources. All relevant controlled trials were collected. Meta-analyses were performed using RevMan version 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

Results: Thirteen trials with 1621 patients were identified. Compared with PEI, RFA was associated with significant improvement in overall survival (OS) rate at 1, 2, 3 and 4 years, cancer-free survival (CFS) rate at 1, 2 and 3 years and complete tumour necrosis. RFA was associated with a significant reduction in the local recurrence rate at 1, 2 and 3 years. However, RFA was also associated with a higher total risk of complications. Compared with RFA alone, combined RFA-PEI was associated with a significant improvement in the OS rate at 1.5, 2 and 3 years and a significant reduction in the local recurrence rate. However, combined RFA-PEI was also associated with a higher risk of fever.

Conclusion: The combination of RFA and PEI appears to be the optimal treatment strategy when considering combined RFA-PEI or either RFA or PEI alone. Combined RFA-PEI significantly improves OS and reduces the risk of local recurrence without increasing major complications. Further large-scale studies are needed to assess economic outcomes and quality of life.     

First-line treatment of NSCLC with bevacizumab: real world data from an Italian regional based survey

Background: We aimed to explore the use of platinum plus bevacizumab in a real world NSCLC population.

Patients and methods: We retrospectively collected data from patients affected by NS-NSCLC treated with platinum plus bevacizumab across Tuscany.

Results: We evaluated 62 (median age: 63.5 [30–77] years) pts. All but one presented with adenocarcinoma and the majority had ECOG PS of 0/1. 17.7% presented with central lesion, 11.3% with brain metastasis, 38.7% with hypertension and 4.8% with mild haemoptysis. We observed a median time to progression (TTP) of 6.5 [2–37] and a median overall survival (OS) of 10.5 [2–39] months. Overall response rate (ORR) was 59.6% with a disease control rate (DCR) of 80.6%. Safety profile was acceptable. We observed five cardiovascular events and two major bleedings with no toxic deaths.

Conclusion: Safety and efficacy real world data are consistent with those from clinical trials even in a less selected population.     

Application of dynamic thermal imaging in a photocarcinogenesis mouse model

Introduction: In clinical practice and experimental settings, cutaneous premalignant and malignant lesions are commonly diagnosed by histopathological biopsy. However, this technique is invasive and results in functional or cosmetic defects. Dynamic thermal imaging is a non-invasive technique that quantifies the infra-red (IR) radiation emitted by a subject after the introduction of external thermal stimuli (such as heat or cold).

Methods: Forty hairless albino (Crl:SKH1-hr) mice were randomised to the control group or the experimental group. The experimental group was regularly irradiated with artificial ultraviolet. Clinical photographs, immunohistochemical staining and dynamic thermal imaging results of both groups were obtained.

Results: As photocarcinogenesis proceeded, faster thermal recovery to basal temperature after heat stimuli was significant on dynamic thermal imaging. With histopathological correlations, it was possible to differentiate normal, premalignant and malignant cutaneous lesions according to thermal imaging results. CD 31 staining analysis showed that increased vasculature was the key change responsible for different thermal imaging results among photocarcinogenesis steps.

Conclusions: Dynamic thermal imaging is useful to differentiate normal, premalignant and malignant cutaneous lesions. Increased vasculature is the key change responsible for different thermal imaging results.     

Female cancer patients' perceptions of the fertility preservation decision-making process: An exploratory prospective study

Purpose: To assess female cancer patients' perceptions of the fertility preservation decision-making process and to examine the effect of clinicians' support on the decision quality.

Methods: A total of 71 patients participated in this longitudinal study with two assessment time points (before cancer therapy, after cancer therapy). Self-report measures assessed the decision-making process, the decision quality and the clinicians' support.

Results: A less positive experience in the decision-making process was associated with higher decisional regret and lower decisional satisfaction. In the group that decided not to pursue FP, participants who perceived higher oncologist's support reported higher decisional satisfaction.

Conclusions: A higher quality decision is positively associated with a better experience in the decision-making process. The oncologist's support is crucial for the decisional satisfaction of patients who decide not to pursue FP.

Implications for psychosocial providers: Psychologists may be important in helping patients to adequately cope with the FP decision so that they can make a high-quality decision.     

Hyperthermia phased arrays pre-treatment evaluation

Purpose: In the hyperthermia treatment of deep-seated tumours by a phased array of radiofrequency (RF) antennas, heatability will be investigated in terms of power-to-tumour and other figures-of-merit of hyperthermia treatments to be optimised. The assumption is that each source is individually constrained to not exceed a maximal nominal power. The nominal power may differ from a source to another as a physical limit or an operative modality.

Method: Under such constraint, new procedures for the maximisation of (i) power-to-tumour, (ii) heating efficiency and, in general, (iii) power ratios as tumour-heating selectivity are proposed. (iv) The problem whether a tumour is equally heatable after turning off some antennas is addressed as array thinning.

Case study: An array of eight dipoles arranged on two lines around a head/neck is introduced to perform a numerical analysis. The achievable power-to-tumour according to the new optimizations and other performance indices adopted from the literature is tested against values of power that can be found to be sufficient for heating tumours to clinical temperatures. New solutions to data rendering in hyperthermia heating are proposed.     

External validation of a rectal cancer outcome prediction model with a cohort of patients treated with preoperative radiochemotherapy and deep regional hyperthermia

Purpose: To validate a nomogram for the prediction of treatment outcomes after preoperative radiochemotherapy and surgery for locally advanced rectal cancer with a cohort of patients treated with additional deep regional hyperthermia.

Patients and methods: A total of 86 patients were treated with preoperative radiochemotherapy and deep regional hyperthermia at our institution. For every patient, the 5-year probability for death, distant metastases and local failure based on a previously published nomogram were calculated and patients were divided into three risk groups.

Results: Low-lying and clinically lymph node positive tumours were more frequent in the validation cohort. Five-year Kaplan–Meier estimates for overall survival (OS), distant metastases-free survival (DMFS) and local control (LC) were 87.3%, 79.9%, 95.8% (observed) and 75.5%, 71%, 90% (predicted), respectively. Discrimination between low- and high-risk groups was at a significant level for all endpoints. The c-index was 0.81 (OS), 0.67 (DMFS) and 0.92 (LC), respectively.

Conclusions: The nomogram showed reasonable performance when deep regional hyperthermia is incorporated into preoperative therapy. The higher than predicted rates seen for OS and DMFS in particular in the high-risk groups warrant further prospective validation and subsequent investigation of the underlying mechanisms.     

Capture-based ultra-deep sequencing in plasma ctDNA reveals the resistance mechanism of ALK inhibitors in a patient with advanced ALK-positive NSCLC

Background: Anaplastic lymphoma kinase (ALK) is a validated molecular target in non–small-cell lung cancer (NSCLC). However, the clinical benefits of ALK inhibitors are almost universally limited by the emergence of drug resistance.

Methods: We monitored the plasma circulating tumor DNA (ctDNA) using captured-based ultra-deep sequencing analysis of one patient with metastatic ALK-positive NSCLC who had received therapies including first-, second- and third-generation ALK inhibitors. Functional in vitro studies were further undertaken to elucidate the mechanism of resistance.

Results: ALK T1151Sins mutation was detected when the patient developed resistance to ceritinib, and undetectable when she responded to lorlatinib. MET amplification was present when the tumor developed resistance to lorlatinib, and reduced when the patient received combination therapy of lorlatinib with crizotinib, which corresponded to clinical radiologic responses. In addition, further functional in vitro studies demonstrated that ALK harboring the T1151Sins mutation, while conferring resistance to ceritinib, was inhibited by lorlatinib.

Conclusions: Clinical evidence and in vitro validation revealed the clinical usefulness of captured-base ultra-deep sequencing on longitudinal plasma ctDNA in revealing the underlying resistance mechanism and guiding the precise administration of ALK inhibitors in patients with advanced ALK-positive NSCLC.