Relapses of primary cutaneous anaplastic large-cell lymphoma in a female immunocompetent patient with persistent chlamydophila pneumoniae and human herpesvirus 8 infection

Abstract

Background

We have previously reported the case of an immunocompetent female patient with a primary cutaneous CD30+ anaplastic large-cell lymphoma (PCALCL) located on her upper right eyelid characterized by the presence of a concurrent active infection by C. pneumoniae and Human herpesvirus 8 (HHV8). This finding suggested for the first time a possible association of C. pneumoniae and/or HHV8 infection, or both together, with PCALCL pathogenesis in non-immunocompromised and HIV-negative subjects. The subsequent course of the same patient's medical history is herein reported.

Findings

During the 4 years following the surgical excision of the first PCALCL, the patient developed five further skin lesions located at different anatomical sites, all histologically proven as PCALCLs. The patient underwent several cycles of doxycycline as prophylaxis against Chlamydia. Skin presence of Chlamydia spp and HHV8 was investigated in all recurrences as well as in routine control blood samples. Amplification fragments corresponding to Chlamydia were found in all skin tissues analysed except one (4/5; 80 %), whereas it was not detected in any of the peripheral blood mononuclear cell samples. Conversely, HHV8 was detected in 2/5 (40 %) of the skin biopsies, including the sample negative for Chlamydia, but in all the blood samples analysed.

Conclusions

These findings further support the hypothesis of a potential role of C. pneumoniae and HHV8 infection in the development and course of the described cutaneous lymphoma. A reciprocally promoting interaction between the two pathogens may be supposed to be relevant for PCALC occurrence and relapse.

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Nurse Faculty Beliefs and Teaching Practices for the Care of the Cancer Survivor in Undergraduate Nursing Curricula

Abstract

As the number of individuals surviving cancer continues to rise, short- and long-term effects of cancer and its treatment that result in physical, psychosocial, and spiritual needs unique to the care of the cancer survivor has not been addressed in nursing curricula. The Institute of Medicine (IOM, 2005) recommends that all health care providers are educated on the care of cancer survivors. This descriptive qualitative study explored faculty beliefs and practices regarding the inclusion of caring for the cancer survivor in undergraduate nursing curricula. Faculty knowledge of the term "cancer survivor" and their beliefs and practices regarding the placement of theory and clinical experiences on cancer survivorship were explored through face-to-face semi-structured interviews. Qualitative content analysis revealed themes and patterns related to the barriers and facilitators for disseminating information on the gap in content on care of the cancer survivor. Seven themes emerged from the content analysis of the interviews. These were as follows: (1) descriptions of cancer survivorship; (2) beliefs on inclusion of cancer survivorship care within undergraduate nursing curriculum; (3) established content on cancer survivorship care: teaching practices; (4) gaps in content on cancer survivorship care; (5) lack of supportive literature on cancer survivorship care; (6) clinical sites providing opportunities for cancer survivorship care: planned versus unplanned; and (7) barriers and facilitators to the inclusion of cancer survivorship in undergraduate nursing curricula. This study reveals the need for faculty education on the care of cancer survivors and a revision of undergraduate curriculum content.

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The impending financial healthcare burden and ethical dilemma of systemic therapy in metastatic cancer

Metastatic cancer remains a devastating disease that threatens to disrupt entire family structures creating economic and psychosocial stress. Fortunately, great strides have resulted in improved therapies over the years but at a huge social-economic cost. The economic burden has risen greatly and carries with it new ethical concerns when deciding treatment. Here, we discuss the financial and ethical challenges that oncologists and their patients face in the era of novel treatment strategies. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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MR lymphangiography in the treatment of lymphedema

Lymphedema is a common condition frequently seen in cancer patients who have had lymph node dissection +/− radiation treatment. Traditional management is mainly non-surgical and unsatisfactory. Surgical treatment has relied on excisional techniques in the past. Physiologic operations have more recently been devised to help improve this condition. Assessing patients and deciding which of the available operations to offer them can be challenging. MRI is an extremely useful tool in patient assessment and treatment planning. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Inguinal Herniation of Urinary Bladder on F-18 Sodium Fluoride (NaF) PET-CT

Abstract

Inguinal herniation of urinary bladder is uncommon and usually an incidental finding in asymptomatic patients. In some of these patients, residual urine volume and consequently, urinary tracer activity can be higher in the herniated bladder than the native bladder, in which case interpretation can be challenging on conventional planar imaging. We describe an interesting case of physiological activity in a herniated bladder simulating a "tear-drop". This case serves an important reminder that whilst F-18 NaF PET-CT has a similar spectrum of urinary activity to conventional bone scintigraphy; morphological correlation on hybrid imaging is invaluable in ensuring the physiological nature of uptake.

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Extranodal diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

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Enhanced binding of necrosis-targeting immunocytokine NHS-IL12 after local tumour irradiation in murine xenograft models

Abstract

Purpose

NHS-IL12 is an immunocytokine targeting necrotic tumour areas. IL12 shows anti-tumour activity. As local irradiation might induce additional necrosis in solid tumours, we aimed to evaluate the increase in intratumoural accumulation of NHS-IL12 after irradiation and correlate the findings with diffusion-weighted MRI studies in two xenograft models.

Methods

Human rhabdomyosarcoma (A204) and prostate cancer (PC3) cells were studied in vitro and as subcutaneous xenografts. Radiation sensitivity of the cell lines was assessed in vitro by colony formation assays. In vivo tumour necrosis was assessed based on apparent diffusion coefficients (ADC). Biodistribution of NHS-IL12 was evaluated with and without tumour irradiation using in vivo small-animal PET and ex vivo biodistribution.

Results

A204 and PC3 differed in their intrinsic radiation sensitivity. Accordingly, radiation-induced tumour necrosis was found only in A204 xenografts. In comparison with control, ADC was significantly increased after irradiation of A204 tumours with 1 × 8.0 Gy and 5 × 2.0 Gy, whereas no change in ADC was observed in PC3 xenografts in all irradiation regimes. ADC correlated with histology. An enhanced uptake of radiolabelled NHS-IL12 in A204 tumours was detected by PET and ex vivo biodistribution after tumour irradiation. In PC3 tumours, no increase in NHS-IL12 uptake was observed.

Conclusions

In dependence of the tumour model, tumour irradiation enhanced tumour necrosis measured in MRI and histology. In vivo PET and ex vivo biodistribution showed enhanced binding of NHS-IL12 in rhabdomyosarcoma xenografts. Thus, enhanced binding of necrosis-targeting immunocytokines might be a novel mechanism of additive effects in combination with irradiation.

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ATF2 predicts poor prognosis and promotes malignant phenotypes in renal cell carcinoma

Activating transcription factor 2 (ATF2) is a basic helix-loop-helix transcription factor, which has been shown to participate in the pathobiology of numerous cancers. However, the role of ATF2 in renal cell c...

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ATF2 predicts poor prognosis and promotes malignant phenotypes in renal cell carcinoma

Abstract

Background

Activating transcription factor 2 (ATF2) is a basic helix-loop-helix transcription factor, which has been shown to participate in the pathobiology of numerous cancers. However, the role of ATF2 in renal cell carcinoma (RCC) remains unclear.

Methods

ATF2 knockdown and overexpression studies were performed in RCC cells to evaluate changes in cell viability, cell cycle, apoptosis, migration and invasion. Xenograft models were used to examine the tumorigenic and metastatic capability of RCC cells upon ATF2 suppression. The expression of ATF2 in human RCC samples was determined using immunohistochemistry on a tissue microarray.

Results

ATF2 knockdown in RCC cells reduced their proliferative and metastatic potentials, whereas ATF2 overexpression enhanced these properties. Mechanistic studies revealed that the transcription of CyclinB1, CyclinD1, Snail and Vimentin was directly regulated by ATF2 in RCC cells. Moreover, ATF2 was shown to be highly expressed in RCC tissues, especially in tumors with metastases. High expression of ATF2 correlated with aggressive clinico-pathological characteristics and predicted poor prognosis of RCC patients.

Conclusions

ATF2 exerts an oncogenic role in RCC and could serve as an important prognostic biomarker.

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Leiodermatolide, a novel marine natural product, has potent cytotoxic and anti-mitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits anti-tumor activity

Abstract

Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep water sponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity towards the pancreatic cancer cell lines AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apoptosis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulin containing microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1 showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affect tubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls. The anti-tumor activities of leiodermatolide, as well as the proven utility of anti-mitotic compounds against cancer, make leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research. This article is protected by copyright. All rights reserved.

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The many unanswered questions related to the German skin cancer screening programme

Publication date: September 2016
Source:European Journal of Cancer, Volume 64
Author(s): Andreas Stang, Claus Garbe, Philippe Autier, Karl-Heinz Jöckel
In 2008, the first nationwide skin cancer screening (SCS) programme in the world was established in Germany. The main reason to implement the SCS programme in Germany was the expected reduction of costs of care due to earlier detection of skin cancer. The aim of this commentary is to raise and discuss several unanswered questions related to the German SCS programme. The evidence of a temporary mortality decline of skin melanoma after SCS in Schleswig-Holstein is lower than previously assumed and the temporary decline may have been caused by other factors than screening (e.g. awareness effects, selection bias, data artifact, and random fluctuation). The evaluation of the nationwide effect of SCS on skin cancer mortality is hampered by birth cohort effects and low quality of the routine cause-of-death statistics. The nationwide skin melanoma mortality did not decrease from 2007 through 2014. The time interval between screenings after a screening without pathological findings is unclear. Appropriate research designs are needed that monitor and evaluate the effect of SCS not only on skin cancer mortality but also on other factors that may help to judge the potential benefits and harms of SCS including aggressiveness of therapy, costs of care, quality of life, and stage-specific incidence rates of skin cancer. Furthermore, SCS may profit from a high-risk strategy instead of population-wide screening and from newer technologies for early detection of skin cancer (e.g. dermoscopy).



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Vorinostat in refractory soft tissue sarcomas – Results of a multi-centre phase II trial of the German Soft Tissue Sarcoma and Bone Tumour Working Group (AIO)

Publication date: September 2016
Source:European Journal of Cancer, Volume 64
Author(s): Thomas Schmitt, Regine Mayer-Steinacker, Frank Mayer, Viktor Grünwald, Jochen Schütte, Jörg T. Hartmann, Bernd Kasper, Johannes Hüsing, Jacek Hajda, Gregor Ottawa, Gunhild Mechtersheimer, Gerd Mikus, Jürgen Burhenne, Lorenz Lehmann, Christoph E. Heilig, Anthony D. Ho, Gerlinde Egerer
IntroductionNew treatment options for patients with metastatic Soft Tissue Sarcoma are urgently needed. Preclinical studies suggested activity of vorinostat, a histone deacetylase inhibitor.MethodsA multi-centre, open-label, non-randomised phase II trial to investigate the efficacy and safety of vorinostat in patients with locally advanced or metastatic Soft Tissue Sarcoma failing 1st-line anthracycline-based chemotherapy was initiated. Patients were treated with vorinostat 400 mg po qd for 28 d followed by a treatment-free period of 7 d, representing a treatment cycle of 5 weeks. Restaging was performed every three cycles or at clinical progression.ResultsBetween 06/10 and 09/13, 40 Soft Tissue Sarcoma patients were treated with vorinostat at seven participating centres. Patients had received 1 (n=8, 20%), 2 (n=10, 25%) or ≥3 (n=22, 55%) previous lines of chemotherapy. Best response after three cycles of treatment was stable disease (n=9, 23%). Median progression-free survival and overall survival were 3.2 and 12.3 months, respectively. Six patients showed long-lasting disease stabilisation for up to ten cycles. Statistical analyses failed to identify baseline predictive markers in this subgroup. Major toxicities (grade ≥III) included haematological toxicity (n=6, 15%) gastrointestinal disorders (n=5, 13%), fatigue (n=4, 10%), musculoskeletal pain (n=4, 10%), and pneumonia (n=2, 5%).ConclusionIn a heavily pre-treated patient population, objective response to vorinostat was low. However, a small subgroup of patients had long-lasting disease stabilisation. Further studies aiming to identify predictive markers for treatment response as well as exploration of combination regimens are warranted.Trial registration: NCT00918489 (ClinicalTrials.gov)EudraCT-number: 2008-008513-19



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Neurofeedback ineffective in paediatric brain tumour survivors: Results of a double-blind randomised placebo-controlled trial

Publication date: September 2016
Source:European Journal of Cancer, Volume 64
Author(s): Marieke Anna de Ruiter, Jaap Oosterlaan, Antoinette Yvonne Narda Schouten-van Meeteren, Heleen Maurice-Stam, Dannis Gilbert van Vuurden, Corrie Gidding, Laura Rachel Beek, Bernd Granzen, Huib N. Caron, Martha Alexandra Grootenhuis
BackgroundMany paediatric brain tumour survivors (PBTS) suffer from neurocognitive impairments. Promising effects of neurofeedback (NF) on neurocognitive functioning have been reported, however research into NF for PBTS has not been conducted. We investigated the effects of NF on neurocognitive functioning in PBTS using a double-blind randomised placebo-controlled trial with a parallel-group design (Pediatric Research on Improving Speed, Memory, and Attention; the PRISMA study).MethodsEligible for inclusion were PBTS with neurocognitive complaints, aged 8–18 years, >2 years post-treatment. They were recruited from five medical centres in the Netherlands. A randomisation table assigned participants to 30 sessions (two per week) of either NF or placebo feedback (PF) (ratio 1:1). Participants, parents, trainers, and researchers handling the data were blinded to group assignment. Participants were assessed pre-, post- and 6 months post-training to determine whether NF training would lead to improved functioning as compared with PF training. Primary outcome measures were attention, processing speed, memory, executive functioning, visuomotor integration, and intelligence. Linear mixed models analyses were used to test differences between NF and PF training over time.ResultsA total of 82 children were enrolled (mean age 13.9 years, standard deviation = 3.2, 49% males); 80 participants were randomised (NF: n = 40, PF n = 40); 71 participants completed the training (NF: n = 34, PF: n = 37); 68 participants completed training and 6 months post-training assessment (NF: n = 33, PF: n = 35). Similar improvements were found over time for the two treatment groups on the primary outcomes (all p's > 0.15).ConclusionResults indicated no specific treatment-effects of NF on neurocognitive functioning of PBTS.



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Long-term risk of renal and urinary tract diseases in childhood cancer survivors: A population-based cohort study

Publication date: September 2016
Source:European Journal of Cancer, Volume 64
Author(s): Trine Gade Bonnesen, Jeanette F. Winther, Peter H. Asdahl, Sofie de Fine Licht, Thorgerdur Gudmundsdottir, Anna Sällfors Holmqvist, Laura-Maria Madanat-Harjuoja, Laufey Tryggvadottir, Finn Wesenberg, Henrik Birn, Jørgen H. Olsen, Henrik Hasle
BackgroundChildhood cancer has been associated with long-term risk of urinary tract diseases, but risk patterns remain to be comprehensively investigated. We analysed the lifetime risk of urinary tract diseases in survivors of childhood cancer in the Nordic countries.MethodsWe identified 32,519 one-year survivors of childhood cancer diagnosed since the 1940s and 1950s in the five Nordic cancer registries and selected 211,156 population comparisons of a corresponding age, sex, and country of residence from the national population registries. To obtain information on all first-time hospitalizations for a urinary tract disease, we linked all study subjects to the national hospital registry of each country. Relative risks (RRs) and absolute excess risks (AERs) and associated 95% confidence intervals (CIs) for urinary tract diseases among cancer survivors were calculated with the appropriate morbidity rates among comparisons as reference.ResultsWe observed 1645 childhood cancer survivors ever hospitalized for urinary tract disease yielding an RR of 2.5 (95% CI 2.4–2.7) and an AER of 229 (95% CI 210–248) per 100,000 person-years. The cumulative risk at age 60 was 22% in cancer survivors and 10% in comparisons. Infections of the urinary system and chronic kidney disease showed the highest excess risks, whereas survivors of neuroblastoma, hepatic and renal tumours experienced the highest RRs.ConclusionSurvivors of childhood cancer had an excess risk of urinary tract diseases and for most diseases the risk remained elevated throughout life. The highest risks occurred following therapy of childhood abdominal tumours.



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Chemotherapy dose intensity predicted by baseline nutrition assessment in gastrointestinal malignancies: A multicentre analysis

Publication date: August 2016
Source:European Journal of Cancer, Volume 63
Author(s): Kelsey A. Klute, Julianna Brouwer, Minaxi Jhawer, Hayley Sachs, Anatasia Gangadin, Allyson Ocean, Elizabeta Popa, Tong Dai, Guojiao Wu, Paul Christos, Manish A. Shah
BackgroundMalnutrition is prevalent in cancer patients and is associated with inferior outcomes. We examined the association between malnutrition, as measured by the Subjective Global Assessment (SGA), and chemotherapy dose reduction in patients with gastrointestinal malignancies. We hypothesised that malnutrition, defined by a patient's baseline SGA, would be associated with a greater degree of chemotherapy dose-reduction, with the implication of greater chemotherapy related toxicity.DesignWe reviewed chemotherapy dosing and treatment related toxicity for patients enrolled in a prospective Gastrointestinal Cancer Registry over their first 8 weeks of treatment. We compared results between well-nourished and malnourished patients.ResultsMalnourished patients were more likely than well-nourished patients to have their starting chemotherapy dose reduced from standard published dosing (67% versus 35%, p=0.0001). Despite attenuated initial dosing, malnourished patients received a smaller fraction of planned chemotherapy (mean 80±23% versus 90±15% of cycle 1, p=0.005), primarily due to toxicity-related dose reductions. After controlling for age, gender, Eastern Cooperative Oncology Group performance status (ECOG), albumin, smoking status, body habitus, and weight loss, malnutrition remained the strongest independent predictor of the magnitude of chemotherapy dose reduction (estimate –10.3%, 95% confidence interval –19.0 to –0.1.6%, p=0.020).ConclusionsMalnutrition is an independent predictor of chemotherapy dose-reduction for toxicity. This study highlights the practical significance of malnutrition in gastrointestinal malignancies and provides a baseline for future nutrition intervention studies to improve chemotherapy tolerability in malnourished patients.



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Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – Update 2016

Publication date: August 2016
Source:European Journal of Cancer, Volume 63
Author(s): Claus Garbe, Ketty Peris, Axel Hauschild, Philippe Saiag, Mark Middleton, Lars Bastholt, Jean-Jacques Grob, Josep Malvehy, Julia Newton-Bishop, Alexander J. Stratigos, Hubert Pehamberger, Alexander M. Eggermont
Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumour and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organisation of Research and Treatment of Cancer was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. Diagnosis is made clinically using dermoscopy and staging is based upon the AJCC system. CMs are excised with 1–2 cm safety margins. Sentinel lymph node dissection is routinely offered as a staging procedure in patients with tumours >1 mm in thickness, although there is as yet no clear survival benefit for this approach. Interferon-α treatment may be offered to patients with stage II and III melanoma as an adjuvant therapy, as this treatment increases at least the disease-free survival and less clear the overall survival (OS) time. The treatment is however associated with significant toxicity. In distant metastasis, all options of surgical therapy have to be considered thoroughly. In the absence of surgical options, systemic treatment is indicated. For first-line treatment particularly in BRAF wild-type patients, immunotherapy with PD-1 antibodies alone or in combination with CTLA-4 antibodies should be considered. BRAF inhibitors like dabrafenib and vemurafenib in combination with the MEK inhibitors trametinib and cobimetinib for BRAF mutated patients should be offered as first or second line treatment. Therapeutic decisions in stage IV patients should be primarily made by an interdisciplinary oncology team ('Tumour Board').



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Nitric oxide increases the migratory activity of non-small cell lung cancer cells via AKT-mediated integrin αv and β1 upregulation

Abstract

Background

Previously, nitric oxide (NO) has been found to affect the metastatic behavior of various types of cancer. In addition, it has been found that alterations in integrin expression may have profound effects on cancer cell survival and migration. Here, we aimed at assessing the effects of non-toxic concentrations of NO on human non-small cell lung cancer (NSCLC) cells, including the expression of integrins and the migration of these cells.

Methods

The cytotoxic and proliferative effects of NO on human NSCLC-derived H460, H292 and H23 cells were tested by MTT assay. The migration capacities of these cells was evaluated by wound healing and transwell migration assays. The expression of integrins and migration-associated proteins was determined by Western blot analyses.

Results

We found that NO treatment caused a significant increase in the expression of integrin αv and β1 in all three NSCLC-derived cell lines tested. Known migration-associated proteins acting downstream of these integrins, including focal adhesion kinase (FAK), active RhoA (Rho-GTP) and active cell division control 42 (Cdc42-GTP), were found to be significantly activated in response to NO. In addition, we found that NO-treated cells showed an increased motility and that this motility was associated with a significant increase in the number of filopodia per cell. We also found that NO-treated cells exhibited increased active protein kinase G (PKG), protein kinase B (AKT) and FAK expression levels. Using a pharmacological approach, we found that the integrin-modulating effect of NO is most likely brought about by a PKG/AKT-dependent mechanism, since the observed changes in integrin expression were abolished by AKT inhibitors, but not by FAK inhibitors.

Conclusion

Our data suggest a novel role of NO in the regulation of integrin expression and, concomitantly, the migratory capacity of NSCLC cells.

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Hypoxia-inducible microRNA-488 regulates apoptosis by targeting Bim in osteosarcoma

Abstract

Background

Osteosarcoma is a malignant bone cancer of which the survival rate is still low. One reason for this low survival rate is drug resistance. In the past, it has been shown that microRNAs may play critical roles in osteosarcoma development and drug resistance. The mechanisms by which osteosarcoma cells acquire this resistance have, however, remained largely unknown. Here, we aimed at assessing the role of microRNA-488 in the acquisition of drug resistance by osteosarcoma cells.

Methods

Quantitative RT-PCR was used to measure the expression of microRNA-488 in primary osteosarcoma samples and in osteosarcoma-derived cells, whereas microRNA-488 mimics and inhibitors were used to modify its expression in these cells. Luciferase reporter, Western blotting, cell viability, apoptosis and ChIP assays were used to assess the various effects of modified microRNA-488 expression in osteosarcoma-derived cells.

Results

We found that microRNA-488 is over-expressed in primary osteosarcoma tissues and osteosarcoma-derived cells and that hypoxia can induce microRNA-488 expression via binding to the hypoxia response element (HRE) in its promoter. We also found that exogenous over-expression of microRNA-488 promotes the proliferation, reduces the apoptosis and decreases the sensitivity to chemotherapy (doxorubicin) of osteosarcoma cells via direct targeting of the tumor suppressor Bim, which is a mediator of apoptosis. In contrast, we found that transfection of a microRNA-488 inhibitor resulted in an increase in both apoptosis and drug sensitivity, and a decrease in proliferation.

Conclusions

Our data suggest that miRNA-488 may serve as a predictor of response to chemotherapy and as a therapeutic target in human osteosarcomas.

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Intestinal perforation during chemotherapeutic treatment of intra-abdominal desmoid tumor in patients with Gardner’s syndrome: report of two cases

Abstract

Background

A minority of intra-abdominal desmoid tumors is associated with Gardner's syndrome in which desmoid tumors become an important cause of morbidity and mortality if they are surgically unresectable.

Case presentation

Here, we report two cases of intestinal perforation during chemotherapy in patients with Gardner's syndrome-associated intra-abdominal desmoids. One female and one male patients who developed inoperable desmoids were given the chemotherapeutic regimen of doxorubicin plus dacarbazine, followed by meloxicam. Significant tumor regression was observed clinically. However, intestinal perforation happened in both patients. They were subjected to emergency surgery, follow-up management, and survived up to now.

Conclusions

The doxorubicin plus dacarbazine chemotherapy is an effective treatment for intra-abdominal demoid tumors in patients with Gardner's syndrome. On the other hand, given severe adverse events might occur, clinicians should pay more attention that tumor quick regression may cause intestinal perforation in which urgent surgical intervention is necessary.

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India’s Vast Potential for Clinical Outcomes Research—a Global Leader in Waiting!

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Nm23H1 mediates tumor invasion in esophageal squamous cell carcinoma by regulation of CLDN1 through the AKT signaling

Nm23H1 mediates tumor invasion in esophageal squamous cell carcinoma by regulation of CLDN1 through the AKT signaling

Oncogenesis 5, e239 (July 2016). doi:10.1038/oncsis.2016.46

Authors: K-T Kuo, C-L Chen, T-Y Chou, C-T Yeh, W-H Lee & L-S Wang

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Suppression of cell migration is promoted by miR-944 through targeting of SIAH1 and PTP4A1 in breast cancer cells

Abstract

Background

Aberrant expression of microRNAs has been associated with migration of tumor cells. In this study, we aimed to investigate the biological significance of miR-944 whose function is unknown in breast cancer.

Methods

MiR-944 expression in breast cancer cells and tumors was evaluated by Taqman qRT-PCR assays. Transcriptional profiling of MDA-MB-231 cells expressing miR-944 was performed using DNA microarrays. Cell viability, migration and invasion were assessed by MTT, scratch/wound-healing and transwell chamber assays, respectively. The luciferase reporter assay was used to evaluate targeting of SIAH1, PTP4A1 and PRKCA genes by miR-944. SIAH1 protein levels were measured by Western blot. Silencing of SIAH1 gene was performed by RNA interference using shRNAs.

Results

Our data showed that miR-944 expression was severely repressed in clinical specimens and breast cancer cell lines. Suppression of miR-944 levels was independent of hormonal status and metastatic potential of breast cancer cells. Gain-of-function analysis indicated that miR-944 altered the actin cytoskeleton dynamics and impaired cell migration and invasion. Genome-wide transcriptional profiling of MDA-MB-231 cells that ectopically express miR-944 showed that 15 genes involved in migration were significantly repressed. Notably, luciferase reporter assays confirmed the ability of miR-944 to bind the 3´UTR of SIAH1 and PTP4A1 genes, but not PRKCA gene. Congruently, an inverse correlation between miR-944 and SIAH1 protein expression was found in breast cancer cells. Moreover, SIAH1 was upregulated in 75 % of miR-944-deficient breast tumors. Finally, SIAH1 gene silencing by RNA interference significantly impaired cell migration of breast cancer cells.

Conclusions

Our results pointed out that miR-944 is a novel upstream negative regulator of SIAH1 and PTP4A1 genes and provided for the first time evidence for its functional role in migration and invasion of breast cancer cells. They also suggest that miR-944 restoration may represent a potential strategy for breast cancer therapy.

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Comparison of the miRNA profiles in HPV-positive and HPV-negative tonsillar tumors and a model system of human keratinocyte clones

Abstract

Background

Better insights into the molecular changes involved in virus-associated and -independent head and neck cancer may advance our knowledge of HNC carcinogenesis and identify critical disease biomarkers. Here we aimed to characterize the expression profiles in a matched set of well-characterized HPV-dependent and HPV-independent tonsillar tumors and equivalent immortalized keratinocyte clones to define potential and clinically relevant biomarkers of HNC of different etiology.

Methods

Fresh frozen tonsillar cancer tissues were analyzed together with non-malignant tonsillar tissues and compared with cervical tumors and normal cervical tissues. Furthermore, relative miRNAs abundance levels of primary and immortalized human keratinocyte clones were evaluated. The global quantitation of miRNA gene abundance was performed using a TaqMan Low Density Array system. The confirmation of differentially expressed miRNAs was performed on a set of formalin-fixed paraffin-embedded tumor samples enriched for the tumor cell fraction by macrodissection.

Results

We defined 46 upregulated and 31 downregulated miRNAs characteristic for the HPV-positive tonsillar tumors and 42 upregulated miRNAs and 42 downregulated miRNAs characteristic for HPV-independent tumors. In comparison with the expression profiles in cervical tumors, we defined miR-141-3p, miR-15b-5p, miR-200a-3p, miR-302c-3p, and miR-9-5p as specific for HPV induced malignancies. MiR-335-5p, miR-579-3p, and miR-126-5p were shared by the expression profiles of HPV-positive tonsillar tumors and of the HPV immortalized keratinocyte clones, whereas miR-328-3p, miR-34c-3p, and miR-885-5p were shared by the miRNA profiles of HPV-negative tonsillar tumors and the HPV-negative keratinocytes.

Conclusions

We identified the miRNAs characteristic for HPV-induced tumors and tonsillar tumors of different etiology, and the results were compared with those of the model system. Our report presents the basis for further investigations leading to the identification of clinically relevant diagnostic and/or therapeutic biomarkers for tumors of viral and non-viral etiology.

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Use and misuse of common terminology criteria for adverse events in cancer clinical trials

Abstract

Background

Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) were released in 2003 and have been used widely to report toxicity in publications or presentations describing cancer clinical trials. Here we evaluate whether guidelines for reporting toxicity are followed in publications reporting randomized clinical trials (RCTs) for cancer.

Methods

Phase III RCTs evaluating systemic cancer therapy published between 2011 and 2013, were reviewed to identify eligible studies, which stated explicitly that CTCAE v3.0 was used to report toxicity. Each AE term and its grade were located in CTCAE v3.0 to determine if they fell within the guidelines provided in the explanatory file.

Results

A total of 166 publications were included in this analysis. Criteria from CTCAE v3.0 were frequently used incorrectly. For example, CATEGORY names such as Metabolic were misreported as AEs in 19 trials, and inappropriate grades for AEs assigned frequently. For example, febrile neutropenia was graded 1 or 2 in 35 of 91 studies (38 %), but the minimum grade for this toxicity is 3. Alopecia was graded 3 or more in 19 of 77 studies (25 %), but the maximum is only grade 2.

Conclusion

The present study provides evidence of poor reporting of toxicity in clinical trials. The study provides a lower estimate for the misuse of AE terms and grades, and implies that other AE terms and grades that conform to CTCAE v3.0 guidelines may have been assigned incorrectly. Inaccurate reporting of toxicity in clinical trials can lead clinicians to make inappropriate treatment decisions.

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Expansive hematoma in delayed cerebral radiation necrosis in patients treated with T-DM1: a report of two cases

Abstract

Background

Multiple new targeted agents have been developed for patients with human epidermal growth factor receptor type 2 (HER2) – positive breast cancer. Patients with HER2– positive breast cancer will develop brain metastases with greater incidence than patients with non-HER2 cancers, and many of them will undergo stereotactic radiosurgery (SRS) or other CNS radiotherapy. The interaction between radiation effects and new targeted agents is not well understood. We report two cases suggesting a novel adverse effect of T-DM1 (trastuzumab emtansine) on symptomatic enlargement of radiation necrosis (RN) after SRS.

Case presentation

Two patients with HER2-positive breast cancer had received SRS for single brain metastasis more than 5-years ago. They had been heavily treated for HER2-positive metastatic breast cancer (trastuzumab and pacritaxel, lapatinib and capecitabine). They initiated T-DM1 therapy for progressive systematic disease 5.5 years after stereotactic irradiation, when a small RN was recognized on brain MR images of each patient. The RN lesions increased in size and became symptomatic during 13 or 14 months of T-DM1 treatment. The patients underwent surgical resection of the lesion. Pathological examination revealed necrosis, hematoma, granulation tissue and telangiectasia without neoplastic cells.

Conclusions

A potential enhancement of RN by T-DM1 in the brain may be one of important adverse events associated with the use of T-DM1 for patients after SRS. These cases highlight the need of careful follow-up when combining new systemic targeted therapies and SRS for brain metastases.

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Lifestyle in Multiple Myeloma - a longitudinal cohort study protocol

Abstract

Background

Deterioration in bone health is one of the presenting symptoms of Multiple Myeloma (MM), a cancer of plasma cells. As a consequence of this condition, patients suffer bone pain and bone damage and report cancer-related fatigue, resulting in deterioration in their quality of life. Evidence in patients with solid tumours shows promise for the positive effects of physical activity on quality of life. However, in the case of patients with MM a better understanding of the association between physical fitness and quality of life factors is still required. Therefore, this cohort study aims to objectively and longitudinally assess activity and fitness levels in patients with MM in order to explore their role in bone health, fatigue and quality of life for this patient population.

Methods/Design

The study is a prospective cohort study of MM patients in remission to assess physical activity, fatigue and bone health. Clinical markers of health, self-reported measures of psychological and physical well-being, and lifestyle behaviours are assessed at baseline, 3, 6 and 12 months. At each time point, patients complete cardiopulmonary exercise testing (CPET) along with a series of objective tests to assess physical fitness (eg accelerometry) and a number of self-report measures. A complementary qualitative study will be carried out in order to explore patients' desire for lifestyle advice and when in their cancer journey they deem such advice to be useful.

Discussion

This study will be the first to prospectively and longitudinally explore associations between physical fitness and well-being, bone health, and fatigue (along with a number of other physical and clinical outcomes) in a cohort of patients with MM with the use of objective measures. The findings will also help to identify time points within the MM pathway at which physical activity interventions may be introduced for maximum benefit.

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Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes

Abstract

Background

Expression of the androgen receptor (AR) is associated with androgen-dependent proliferation arrest and terminal differentiation of normal prostate epithelial cells. Additionally, activation of the AR is required for survival of benign luminal epithelial cells and primary cancer cells, thus androgen deprivation therapy (ADT) leads to apoptosis in both benign and cancerous tissue. Escape from ADT is known as castration-resistant prostate cancer (CRPC). In the course of CRPC development the AR typically switches from being a cell-intrinsic inhibitor of normal prostate epithelial cell proliferation to becoming an oncogene that is critical for prostate cancer cell proliferation. A clearer understanding of the context dependent activation of the AR and its target genes is therefore desirable.

Methods

Immortalized human prostate basal epithelial EP156T cells and progeny cells that underwent epithelial to mesenchymal transition (EMT), primary prostate epithelial cells (PrECs) and prostate cancer cell lines LNCaP, VCaP and 22Rv1 were used to examine context dependent restriction and activation of the AR and classical target genes, such as KLK3. Genome-wide gene expression analyses and single cell protein analyses were applied to study the effect of different contexts.

Results

A variety of growth conditions were tested and found unable to activate AR expression and transcription of classical androgen-dependent AR target genes, such as KLK3, in prostate epithelial cells with basal cell features or in mesenchymal type prostate cells. The restriction of androgen- and AR-dependent transcription of classical target genes in prostate basal epithelial cells was at the level of AR expression. Exogenous AR expression was sufficient for androgen-dependent transcription of AR target genes in prostate basal epithelial cells, but did not exert a positive feedback on endogenous AR expression. Treatment of basal prostate epithelial cells with inhibitors of epigenetic gene silencing was not efficient in inducing androgen-dependent transcription of AR target genes, suggesting the importance of missing cofactor(s).

Conclusions

Regulatory mechanisms of AR and androgen-dependent AR target gene transcription are insufficiently understood and may be critical for prostate cancer initiation, progression and escape from standard therapy. The present model is useful for the study of context dependent activation of the AR and its transcriptome.

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Cetuximab-induced aseptic meningitis: case report and review of a rare adverse event

Abstract

Background

Cetuximab is a commonly used antibody agent in the treatment of colorectal or head and neck cancer. Although it is generally well tolerated in most patients, cetuximab has been associated with some rare but serious adverse events. Aseptic meningitis is one such distinctly uncommon adverse drug reaction.

Case presentation

We present the case of a middle-aged Caucasian patient, who presented with fever and headache within a few hours of starting cetuximab therapy and was diagnosed with cetuximab-induced aseptic meningitis after a complete workup.

Conclusion

To our knowledge, this is the ninth case of cetuximab-induced aseptic meningitis reported in literature. Because of a nonspecific clinical presentation, this adverse drug reaction can be easily misdiagnosed. It is important to increase awareness of this potentially severe reaction among oncologists.

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Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer

Abstract

Background

The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains.

Methods

Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance.

Results

We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome- and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred.

Conclusion

This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns.

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The use of a multiple imputation method to investigate the trends in Histologic types of lung cancer in Songkhla province, Thailand, 1989–2013

Abstract

Background

The incidence of lung cancer in many parts of the country as shown in cancer registry statistics is not decreasing. The incidence of adenocarcinoma (ADCA) in Songkhla is now higher than that of squamous cell carcinoma (SCC) in both sexes. The percentage of the unknown histologic type of lung cancer in Songkhla is around 30 %. The objective of this study is to estimate trends in incidence of the two major histologic types of lung cancer: SCC and ADCA, in Songkhla province of Thailand from 1989 to 2013.

Methods

Age-standardized incidence rates (ASR) were used to compare and described the trends in both major types of cancers. Multinomial logistic regression models were used to impute unknown histological cancer types using a multiple imputation (MI) method to account for the high percentage of unknown histology.

Results

The multinomial predictive model for major types of lung cancer in Songkhla consisted of sex, age, year of diagnosis, and place of residence. After MI, the number of cases with both SCC and ADCA in both sexes increased by one-third of the number of cases with originally known histology. The increasing trends were observed in ADCA in both sexes while SCC in males was stable and in females was decreasing.

Conclusions

A rapid increase in the incidence of ADCA was found while the incidence of SCC in males showed no significant change and it was declining in females. These results warrant an investigation into risk factors other than cigarette smoking. The number of cases has limited use when the age structure of the population under study is changing. Year of diagnosis was one of the predictors in the MI model.

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Erratum to: Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses vasculogenic mimicry and proliferation of highly aggressive pancreatic cancer PaTu8988 cells

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CD80 down-regulation is associated to aberrant DNA methylation in non-inflammatory colon carcinogenesis

Abstract

Background

The lack of positive costimulatory molecules represents one of the mechanisms by which tumor cells evade immune surveillance. Promoter hypermethylation plays a major role in cancer development through transcriptional silencing of critical genes. The aim of this study was to examine the expression of the costimulatory molecule CD80 in relationship with genomic methylation in non-inflammatory colon carcinogenesis.

Methods

Colonic mucosal samples were collected from healthy subjects (n = 30) and from dysplastic adenoma (n = 14), and colon adenocarcinoma (n = 10). DNA methyltransferases-1, −3a, −3b and CD80 mRNA expression were quantified by real time qRT-PCR. The methylation status of CDH13, APC, MLH1, MGMT1 and RUNX3 gene promoters was assessed by methylation-specific PCR. CD80 expression was assessed in HT29, HCT-15 and LoVo cell lines after treatment with the DNA-methyltransferase inhibitor 5-Aza-2′-deoxycytidine.

Results

CD80 mRNA levels were significantly lower in the non-inflammatory dysplastic colonic mucosa of patients with one or more methylated genes and inversely correlated with patients' methylation scores (τ = −0.41, p = 0.05 and τ = −0.37, p = 0.05, respectively). Treatment with 5-Aza-2′-deoxycytidine significantly increased CD80 expression both in terms of the level of CD80 mRNA (p = 0.007) and of CD80+ cells (p = 0.003).

Conclusions

These results indicate that the failure of immune surveillance mechanisms in non-inflammatory colon carcinogenesis may be linked to genomic methylation directly or indirectly affecting CD80 expression.

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Long-term survival and BRCA status in male breast cancer: a retrospective single-center analysis

Abstract

Background

Male breast cancer (MBC) is rare. Given the paucity of randomized trials, treatment is generally extrapolated from female breast cancer guidelines.

Methods

This is a retrospective analysis of all male patients presenting with MBC at the Department of Oncology at University Federico II of Naples between January 1989 and January 2014. We recorded the following data: baseline characteristics (age, height, weight, body mass index, risk factors, family history), tumor characteristics (side affected, stage, histotype, hormonal and HER2 status, and Ki-67 expression), treatment (type of surgery, chemotherapy, endocrine therapy, and/or radiotherapy), BRCA1/2 mutation status (if available), other tumors, and long-term survival.

Results

Forty-seven patients were analyzed. Median age was 62.0 [55.0–72.0]. Among risk factors, obesity and family history of breast cancer were associated with 21 % and 30 % of MBC cases, respectively. The majority of tumors were diagnosed at an early stage: stage I (34.0 %) and stage II (44.7 %). Infiltrating ductal carcinoma was the most frequent histologic subtype (95.8 %). Hormone receptors were generally positive (88.4 % of cases were Estrogen receptor [ER] positive and 81.4 % Progesteron receptor [PgR] positive). Human epidermal growth factor receptor 2 (HER2) was positive in 26.8 % of cases; 7.0 % of MBCs were triple negative. The tumor had high proliferation index (Ki67 ≥ 20 %) in 64.7 %. Surgery was predominantly mastectomy (85.1 %), whereas quadrantectomy was performed in 14.9 % of patients. Adjuvant chemotherapy was administered to 70.7 % of patients, endocrine therapy to 90.2 %, trastuzumab to 16.7 % and radiotherapy to 32.6 %. BRCA status was available for 17 patients: 10 wild-type, 1 BRCA1 carrier, 5 BRCA2 carriers, 1 unknown variant sequence. The overall estimated long-term survival was about 90 % at 5 years, 80 % at 10 years and 70 % at 20 years. Patients carrying a BRCA mutation had a significantly lower survival than patients with wild-type BRCA (p = 0.04).

Conclusions

Long-term survival was high in MBC patients referred to our clinical unit. Survival was poorer in BRCA-mutated patients than in patients with wild-type BRCA.

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TAS-102, the first “cardio-gentle” fluoropyrimidine in the colorectal cancer landscape?

Abstract

Background

Cardiotoxicity in the form of cardiac arrhythmia, myocardial infarction, and angina-like symptoms are not rare complications of fluoropyrimidines as 5-Fluorouracil (5FU) and capecitabine.

Discussion

Tas-102, a novel oral fluoropyrimidine, was recently approved by FDA for the treatment of advanced and refractory colorectal cancer. Its unique mechanism of action doesn't seem linked with cardiotoxicity in clinical trials reported so far.

Summary

TAS 102 may represent one of the drugs of choice for patients with advanced colorectal cancer with cardiac disease. This intriguing and clinically relevant issue is briefly examined.

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Metalloproteases meprin-ɑ (MEP1A) is a prognostic biomarker and promotes proliferation and invasion of colorectal cancer

Abstract

Background

Meprin displays multiple functions in both health and disease, due in part to its broad proteolytic activity. In this report, we explored the clinical significance and functional relevance of the expression of meprin-ɑ (MEP1A) in colorectal cancer (CRC).

Methods

The mRNA and protein expression levels of MEP1A in tumor specimens obtained from CRC patients was determined by quantitative real-time PCR and Western blot assay and comparatively paired with adjacent mucosa that presented as normal tissue. ShRNA was used to knock-down MEP1A expression in CRC cell-lines and the effects of dampened expression of MEP1A on the proliferation and invasion were determined by colony formation assays, Cell Counting Kit-8 assays and matrigel invasion assays. Moreover, nude mouse xenograft models were designed to investigate the same effect in vivo. In order to determine whether MEP1A expression correlated with CRC clinicopathologic factors and survival, immunohistochemical staining of a tissue microarray containing 88 paired CRC specimens was performed.

Results

In CRC, enhanced expression of MEP1A was seen. Additionally, both in vitro and in vivo, CRC cellular proliferation and invasiveness was inhibited by dampened MEP1A expression. Several parameters were associated with enhanced MEP1A expression including tumor size (P = 0.023), staging of CRC by the American Joint Committee on Cancer (AJCC) (P = 0.024), and T (P = 0.032) and N stages (P = 0.001). Moreover, the expression of MEP1A is an independent prognostic factor for overall survival in CRC (HR 3.643; 95 % CI 0.305-5.842; P = 0.007).

Conclusion

MEP1A was not only found to be functionally important, but it might also serve as an important and unique indicator of patient prognosis and therapeutic targeting in CRC.

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Bone alkaline phosphatase as a surrogate marker of bone metastasis in gastric cancer patients

Abstract

Background

Bone metastasis is relatively uncommon in gastric cancer patients, but its incidence has been rising. Early detection of bone metastasis is important in preventing complications related to bone metastasis such as pain, fracture and the compromise of chemotherapy. In this pilot study, we investigated the feasibility of bone turnover markers as surrogate markers of bone metastasis in gastric cancer patients.

Methods

Fifty-eight patients with gastric cancer were included in this study. Serum levels of bone alkaline phosphatase (ALP), parathyroid hormone (PTH), 25(OH) D, osteocalcin (OC) and C terminal telopeptide were measured and compared between patients with bone metastasis and those without. Student's t-test and Mann-Whitney U test were used in comparing two groups, and Spearman's rank order correlation coefficient was calculated to quantify the strength of the associations.

Results

Fifty eight age- and sex-matched patients were evaluated for bone turnover markers, among whom 29 patients had bone metastasis and 29 patients with no bone metastasis. The median age was 62 and there were 20 (68.9 %) males and 9 (31.1 %) females in each group. Bone ALP was significantly higher in the patient group (57.32 ± 46.83 vs. 34.57 ± 21.57, P = 0.037) than control group. Bone ALP was positively associated with ALP, osteocalcin, CA19-9, CA 72–4 and negatively associated with 25(OH) D. According to ROC-curve analysis, at the threshold value of 29.60 μg/L, the sensitivity of bone ALP was 76.7 % and the specificity was 59.4 %.

Conclusion

Bone ALP may be a surrogate marker of bone metastasis in gastric cancer patients. More prospective studies are warranted to determine the optimal bone turnover markers in the evaluation of bone metastasis.

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Transanal total mesorectal excision (taTME) for rectal cancer: a systematic review and meta-analysis of oncological and perioperative outcomes compared with laparoscopic total mesorectal excision

Abstract

Background

Transanal total mesorectal excision (taTME) is an emerging surgical technique for rectal cancer. However, the oncological and perioperative outcomes are controversial when compared with conventional laparoscopic total mesorectal excision (laTME).

Methods

A systematic review and meta-analysis based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was conducted in PubMed, Embase and Cochrane database. All original studies published in English that compared taTME with laTME were included for critical appraisal and meta-analysis. Data synthesis and statistical analysis were carried out using RevMan 5.3 software.

Results

A total of seven studies including 573 patients (taTME group = 270; laTME group = 303) were included in our meta-analysis. Concerning the oncological outcomes, no differences were observed in harvested lymph nodes, distal resection margin (DRM) and positive DRM between the two groups. However, the taTME group showed a higher rate of achievement of complete grading of mesorectal quality (OR = 1.75, 95% CI = 1.02–3.01, P = 0.04), a longer circumferential resection margin (CRM) and less involvement of positive CRM (CRM: WMD = 0.96, 95% CI = 0.60–1.31, P <0.01; positive CRM: OR = 0.39, 95% CI = 0.17–0.86, P = 0.02). Concerning the perioperative outcomes, the results for hospital stay, intraoperative complications and readmission were comparable between the two groups. However, the taTME group showed shorter operation times (WMD = –23.45, 95% CI = –37.43 to –9.46, P <0.01), a lower rate of conversion (OR = 0.29, 95% CI = 0.11–0.81, P = 0.02) and a higher rate of mobilization of the splenic flexure (OR = 2.34, 95% CI = 0.99–5.54, P = 0.05). Although the incidence of anastomotic leakage, ileus and urinary morbidity showed no difference between the groups, a significantly lower rate of overall postoperative complications (OR = 0.65, 95% CI = 0.45–0.95, P = 0.03) was observed in the taTME group.

Conclusions

In comparison with laTME, taTME seems to achieve comparable technical success with acceptable oncologic and perioperative outcomes. However, multicenter randomized controlled trials are required to further evaluate the efficacy and safety of taTME.

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A case of lymphangioleiomyomatosis associated with endometrial cancer and severe systemic lupus erythematosus

Abstract

Background

Lymphangioleiomyomatosis (LAM) is a rare idiopathic disorder that occurs in women of childbearing age, and consists of a diffuse proliferation of abnormal smooth muscle cells along the thoracic and abdominal lymphogenous route.

Case presentation

We experienced a case of a 47-yo woman with recent history of systemic lupus erythematosus (SLE) diagnosed with endometrial cancer, initially suspected to have metastasized to pelvic and para-aortic lymph nodes based on preoperative diagnostic imaging. Subsequent pathological diagnosis revealed stage IB endometrial cancer without evidence of lymph node involvement. Instead, enlarged pelvic and para-aortic lymph nodes were found to be due to extrapulmonary LAM, from a primary lesion found inside the uterine myometrium. SLE improved after surgery.

Conclusion

This is the first reported case of comorbid endometrial cancer, SLE, and aggressive LAM metastasizing to regional lymph nodes, and strengthens the clinical evidence for a common role of mTOR pathway hyperactivity and estrogen responsiveness in the pathophysiology of metastasizing lesions of the genital tract.

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Efficacy and Treatment Costs of Monotherapy with bDMARDs in the Treatment of Rheumatoid Arthritis in Patients Intolerant to or Inappropriate to Continue Treatment with Methotrexate

Abstract

Introduction

Only limited information is available on cost efficacy of the various biological agents used to treat patients with rheumatoid arthritis with intolerance or for whom it would be inappropriate to continue treatment with conventional agents. We estimated the efficacy and treatment costs of monotherapy with biological agents in the treatment of this group of patients.

Methods

Data from two previous meta-analyses in the treatment of patients who are intolerant to methotrexate (MTX), or for whom it would be inappropriate to continue treatment with MTX was used. Pharmacoeconomic comparison between biological agents was carried out to estimate the respective cost for the number needed to treat (NNT) compared to placebo using both American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria. The analysis involved the four agents approved in Italy: adalimumab (ADA), etanercept (ETN), certolizumab pegol (CTZ), and tocilizumab (TCZ). A six-month period was considered sufficient to understand the most important differences in efficacy and treatment costs. Direct medical costs, including pharmacological therapy, administration and monitoring were considered.

Results

Using both ACR and EULAR criteria, TCZ (intravenous [iv]/subcutaneous [sc]) had a lower NNT than the other agents. The difference in NNT observed for ETN was more pronounced with EULAR criteria, whereas in the comparison with ADA, the most sensitive differences were observed with ACR criteria. ETN had the lowest treatment cost (€6402.19), followed by ADA (€6698.84), TCZ sc (€6887.61), and TCZ iv (€7130.83). TCZ sc had the lowest cost for NNT with both ACR and EULAR criteria. The differences compared to ETN and ADA were significant and related with the level of efficacy. Sensitivity analysis confirmed these results.

Conclusion

TCZ is a cost-effective therapeutic option compared to other tumor necrosis factor-α inhibitors (ADA, ETA, CTZ) as first-line monotherapy for patients who are intolerant to MTX, or for whom it is inappropriate to continue treatment with MTX.

Funding

Roche SpA.

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Expression of Selenoprotein Genes Is Affected by Heat Stress in IPEC-J2 Cells

Abstract

The aim of this study was to explore the impacts of heat stress (HS) on expressions of selenoprotein genes in IPEC-J2 cells. Cells were cultured with 5 % CO₂-humidified chamber at 37 °C until the cells grew to complete confluence and then exposed to a mild hyperthermia at 41.5 °C (HS) or 37 °C (control) for another 24 h, finally harvested for total RNA or protein extraction. Real-time quantitative PCRs (qPCRs) were performed to compare gene expression of 25 selenoprotein genes, 3 tight junction-related genes, and 10 inflammation-related genes. Protein expressions of heat shock protein 70 (Hsp70) and selenoprotein X and P (SelX and SelP) were also investigated by Western blot. The results showed that HS up-regulated (P < 0.05) Hsp70 and one tight junction-related gene [zonula occludens-1 (Zo-1)] in IPEC-J2 cells. At the same time, HS up-regulated (P < 0.05) 4 selenoprotein genes (Gpx3, Dio2, Selk, Sels) and three inflammation-related genes (Il-6, Icam-1, Tgf-β) and down-regulated (P < 0.05 or as indicated) six selenoprotein genes (Gpx2, Gpx6, Txnrd1, Selh, Selm, Selx) and three inflammation-related genes (Ifn-β, Mcp-1, Tnf-α) in the cells. HS also exhibited impacts on protein expressions, which up-regulated Hsp70, down-regulated SelX, and showed no effect on SelP in IPEC-J2 cells. Our results showed that HS affected the expression of inflammation-related genes and up-regulated gene and protein expressions of Hsp70. The changes of so many selenoprotein genes expression implied a potential link between selenoprotein genes and HS. Moreover, the results provided by this IPEC-J2 model may be used to further study the interactive mechanisms between selenoprotein function and potential intestinal damage induced by HS.

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Acute Copper and Ascorbic Acid Supplementation Inhibits Non-heme Iron Absorption in Humans

Abstract

The objective of the study is to determine the effect of copper (Cu) plus the reducing agent ascorbic acid (AA) on the absorption of non-heme iron (Fe). Experimental study with block design in which each subject was his own control. After signing an informed consent, 14 adult women using an effective method of contraception and negative pregnancy test received 0.5 mg Fe, as ferrous sulfate, alone or with Cu, as copper sulfate, plus ascorbic acid (AA/Cu 2/1 molar ratio) at 4/1; 6/1 and 8/1 Cu/Fe molar ratios as an aqueous solution on days 1, 2, 14, and 15 of the study. Fe absorption was assessed by erythrocyte incorporation of iron radioisotopes ⁵⁵Fe and ⁵⁹Fe. Geometric mean (range ± SD) absorption of Fe at 4/1 and 6/1 Cu/Fe molar ratios (and AA/Cu 2/1 molar ratio) and Fe alone was 57.4 % (35.7–92.1 %), 64.2 % (45.8–89.9 %), and 38.8 % (20.4–73.8 %), respectively (ANOVA for repeated measures p < 0.001; post hoc test Scheffé, p < 0.05). This is attributable to the enhancing effect of AA on non-heme Fe absorption; however, Fe absorption at Cu/Fe 8/1 molar ratio was 47.3 % (27.7–80.8) (p = NS compared with Fe alone). It was expected that Fe absorption would have been equal or greater than at 4/1 and 6/1 molar ratios. Copper in the presence of ascorbic acid inhibits non-heme Fe absorption at Cu/Fe 8/1 molar ratio.

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Effects of Physical Activity on Trace Elements and Depression Related Biomarkers in Children and Adolescents

Abstract

Not much is known about the role of physical activity (PA), obesity related variables, and trace elements as potential risk factors affecting neurotransmitters in schoolchildren with depression. Our objective was to investigate the effect of physical activity (PA) on depressive symptoms in children and adolescents. Also, we aimed to study the association of demographic variables, serum levels of Copper (Cu), Zinc (Zn), serotonin, and salivary cortisol with depression in this population. One hundred and fifty school children (90 boys and 60 girls) aged 7–18 years were recruited for this study. All participants were evaluated for depression using CDI-score analysis. Their physical activity levels were checked using pre-validated questionnaires. The serum levels of Copper (Cu), Zinc (Zn), cortisol, and serotonin were estimated using atomic absorption, and immunoassay techniques. About 48.7 % of the study population had depressive symptoms (CDI-score; ≥13), and were classified into mild, moderate, and severe categories. Older children, especially girls, had higher levels of depression. Participants with moderate and severe depression had significantly lower physical activity, serotonin, and zinc levels, Zn/Cu ratios, and significantly higher copper and cortisol levels. Physically active boys showed significantly lower depressive CDI-scores and improvement in cortisol, serotonin, Cu, and Zn concentrations compared to girls of sedentary life style. CDI- scores correlated positively with BMI, cortisol and Cu, and negatively with PA, serotonin and Zn concentrations. BMI, cortisol, serotonin, Cu and Zn, could explain about 59.3–79 % of the depressive symptoms among schoolchildren, according to stepwise regression analysis. This was especially true in especially older girls. PA and an adequate balance in Zn and Cu levels, plays a positive role in improving CDI-depressive score, BMI, serotonin and cortisol levels among schoolchildren.

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Association of Serum Magnesium Level with Odds of Prediabetes and Diabetes in a Southern Chinese Population: a Prospective Nested Case-Control Study

Abstract

Although emerging clinical evidence supports that magnesium deficiency is a risk factor for the development of type 2 diabetes, there are sparse studies concerning the dynamic change of serum magnesium with the risk of diabetes and its early stages. In this nested case-control study, we performed a 75-g oral glucose tolerance test or a standardized steamed bread meal test in 178 subjects with incident glucose metabolism impairment (33 with type 2 diabetes and 145 with prediabetes) and 178 matched controls at baseline and at 3-year follow-up and determined the associations between baseline serum magnesium levels as well as changes in serum magnesium levels at follow-up and odds of prediabetes and diabetes. After adjusting for potential confounders, the odds ratios of risk for prediabetes and type 2 diabetes in the highest quartile of serum magnesium levels were 0.22 (95 % confidence intervals [CI] 0.10–0.49; p for trend <0.001) and 0.02 (95 % CI 0.00–0.29; p for trend = 0.009), respectively, as compared with the lowest quartile. In addition, a significant decline in the serum magnesium level was detected in type 2 diabetes cases (p = 0.015) at 3 years as compared with at baseline. These results suggest that a low magnesium level is an independent risk factor for prediabetes and type 2 diabetes, and that the reduction of serum magnesium is associated with type 2 diabetes in a southern Chinese population.

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Storage of Heparinised Canine Whole Blood for the Measurement of Glutathione Peroxidase Activity

Abstract

Glutathione peroxidase activity is used as a biomarker of selenium status in dogs. Freshly collected blood samples are usually measured, due to the lack of knowledge on the effect of storing the samples. This study investigated if the analysis of glutathione peroxidase activity in whole blood collected from dogs was affected by storage of between 5 and 164 days. Results indicated that glutathione peroxidase activity was more variable in the freshly analysed samples compared to the stored samples. Although the mean differences between fresh and stored samples were not always equal to zero, this is thought to be caused by the variability of reagent preparation rather than by storage, as no consistent increase or decrease in glutathione peroxidase activity was found. Therefore, it can be concluded that heparinised dog blood samples can be successfully stored up to 164 days before analysis of glutathione peroxidase activity.

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The Effect of Magnesium on Visual Evoked Potentials in L-NAME-Induced Hypertensive Rats

Abstract

In the literature, although there are many studies regarding complications of hypertension, information concerning its influence on visual evoked potentials (VEPs) is limited. This study aims to clarify the possible therapeutic effects of the preferential magnesium (Mg) treatment on VEPs in an experimental hypertension model. Rats were divided into four groups as follows: control, Mg treated (Mg), N(omega)-nitro-l-arginine methyl ester (L-NAME) hypertension, and L-NAME hypertension + Mg treated (L-NAME + Mg). Hypertension was induced by L-NAME which was given to rats orally over 6 weeks (25 mg/kg/day in drinking water). A magnesium-enriched diet (0.8 g/kg) was given to treatment groups for 6 weeks. Systolic blood pressure (SBP) was determined by using the tail-cuff method. Flash VEPs were recorded. Our results revealed that the SBP was significantly increased in the L-NAME group compared to control. Magnesium treatment significantly attenuated SBP in the hypertensive rats compared to the L-NAME group. The mean latencies of P1, N1, P2, N2, and P3 components were significantly prolonged in hypertensive rats compared to control. Treatment with Mg provided a significant decrease in the latencies of P1, N1, P2, N2, and P3 potentials in the L-NAME + Mg group compared to the L-NAME group. Plasma Mg levels were increased in the L-NAME + Mg group compared to the L-NAME group. No change was detected in the Mg levels of the brains in all experimental groups. Magnesium treatment had no effect on the brain nitrate/nitrite and thiobarbituric acid-reactive substances (TBARS) levels in hypertensive rats compared to non-treated rats. There was a positive correlation between the brain TBARS levels and SBP of the rats. The present study suggests that Mg supplementation has the potential to prevent VEP changes in the L-NAME-induced hypertension model.

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Allergic-like reactions to asparaginase: Atypical allergies without asparaginase inactivation

Abstract

Background

Asparaginase is an important component of pediatric acute lymphoblastic leukemia (ALL) therapy. Unfortunately, this treatment is hampered by hypersensitivity reactions. In general, allergies – regardless of severity – cause complete inactivation of the drug. However, we report atypical allergic reactions without inactivation of asparaginase, here called allergic-like reactions.

Procedure

Patients with an allergic-like reaction, who were treated according to the Dutch Childhood Oncology Group ALL-11 or the CoALL 08–09 protocol, were described. The reactions were identified by continual measurement of asparaginase activity levels. Characteristics, including timing of occurrence, symptoms, grade, and the presence of antiasparaginase antibodies, were compared to those of real allergies.

Results

Fourteen allergic-like reactions occurred in nine patients. Five reactions were to PEGasparaginase and nine to Erwinia asparaginase. Allergic-like reactions occurred relatively late after the start of infusion compared to real allergies. Antibodies were absent in all but one patient with an allergic-like reaction, while they were detected in all patients with a real allergy. Symptoms and grade did not differ between the groups. Asparaginase was continued with the same formulation in six patients of whom four finished treatment with adequate activity levels.

Conclusions

In conclusion, allergic-like reactions occur relatively late after the start of infusion and without antibodies. Despite these clinical differences, allergic-like reactions can only be distinguished from real allergies by continually measuring asparaginase activity levels. If clinically tolerated, formulations should not be switched in case of allergic-like reactions. Moreover, failure to recognize these reactions may lead to a less favorable prognosis if asparaginase therapy is terminated unnecessarily.

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Issue Information

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The Cancer Communication Assessment Tool for Patients and Families (CCAT-PF): a new measure

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[Standard of care of carcinomas on cancer of unknown primary site in 2016].

[Standard of care of carcinomas on cancer of unknown primary site in 2016].

Bull Cancer. 2016 Jun 29;

Authors: Benderra MA, Ilié M, Hofman P, Massard C

Abstract
Patients with Cancer of unknown primary (cup) represent 2-10%, and have disseminated cancers for which we cannot find the primary site despite the clinical, pathological and radiological exams at our disposal. Diagnosis is based on a thorough clinical and histopathologic examination as well as new imaging techniques. Several clinicopathologic entities requiring specific treatment can be identified. Genome sequencing and liquid biopsy (circulating tumor cells and tumor free DNA) could allow further advances in the diagnosis. Therapeutically, in addition to surgery, radiotherapy and chemotherapy, precision medicine provides new therapeutic approaches.

PMID: 27372228 [PubMed - as supplied by publisher]

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Enhanced binding of necrosis-targeting immunocytokine NHS-IL12 after local tumour irradiation in murine xenograft models

Abstract

Purpose

NHS-IL12 is an immunocytokine targeting necrotic tumour areas. IL12 shows anti-tumour activity. As local irradiation might induce additional necrosis in solid tumours, we aimed to evaluate the increase in intratumoural accumulation of NHS-IL12 after irradiation and correlate the findings with diffusion-weighted MRI studies in two xenograft models.

Methods

Human rhabdomyosarcoma (A204) and prostate cancer (PC3) cells were studied in vitro and as subcutaneous xenografts. Radiation sensitivity of the cell lines was assessed in vitro by colony formation assays. In vivo tumour necrosis was assessed based on apparent diffusion coefficients (ADC). Biodistribution of NHS-IL12 was evaluated with and without tumour irradiation using in vivo small-animal PET and ex vivo biodistribution.

Results

A204 and PC3 differed in their intrinsic radiation sensitivity. Accordingly, radiation-induced tumour necrosis was found only in A204 xenografts. In comparison with control, ADC was significantly increased after irradiation of A204 tumours with 1 × 8.0 Gy and 5 × 2.0 Gy, whereas no change in ADC was observed in PC3 xenografts in all irradiation regimes. ADC correlated with histology. An enhanced uptake of radiolabelled NHS-IL12 in A204 tumours was detected by PET and ex vivo biodistribution after tumour irradiation. In PC3 tumours, no increase in NHS-IL12 uptake was observed.

Conclusions

In dependence of the tumour model, tumour irradiation enhanced tumour necrosis measured in MRI and histology. In vivo PET and ex vivo biodistribution showed enhanced binding of NHS-IL12 in rhabdomyosarcoma xenografts. Thus, enhanced binding of necrosis-targeting immunocytokines might be a novel mechanism of additive effects in combination with irradiation.

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Fast exchange fluxes around the pyruvate node: a leaky cell model to explain the gain and loss of unlabelled and labelled metabolites in a tracer experiment

Abstract

Background

Glucose and glutamine are the two dominant metabolic substrates in cancer cells. In ¹³C tracer experiments, however, it is necessary to account for all significant input substrates, as some natural (unlabelled) substrate in the medium, often derived from serum, can be metabolised by cells despite not showing signs of net consumption.

Results

Using [U-¹³C₆]-glucose tracers and measuring extracellular metabolite enrichments by GC-MS, we found that pancreatic cells HPDE and PANC-1 secrete lactate, pyruvate, TCA cycle metabolites and non-essential amino acids synthesised from glucose. Focusing our investigations on pyruvate exchange in HEK293 cells, we observed that the four metabolites pools, intracellular and extracellular lactate and pyruvate, had similar ¹³C enrichment trajectories. This indicated that these metabolites can mix rapidly. Using a hybrid ¹³C-MFA, we followed to show that the lactate exchange flux had increased when extracellular lactate concentration was increased by 10-fold. By allowing rapid exchange fluxes around the pyruvate node, ¹³C-MFA revealed that PANC-1 cells cultured in [U-¹³C₆]-glucose doubled the conversion of unlabelled substrates to pyruvate when treated with TNF-α.

Conclusions

The current work established the possibility that a cell's range of significant input substrates may be broader than anticipated. Metabolite exchange can affect intracellular enrichments. In particular, we showed that pyruvate was more strongly connected to lactate than to upstream glycolytic intermediates and that a fast lactate exchange may alter the outcome of flux analyses. Nevertheless, the leaky cell model may be an opportunity in disguise—the ability to continuously monitor metabolism using only the enrichments of extracellular metabolites.

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Major and Minor Duodenal Papilla Neuroendocrine Tumors in Type 1 Neurofibromatosis: Case Report

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Histone demethylase LSD1 controls the phenotypic plasticity of cancer cells

Abstract

Epigenetic mechanisms underlie the phenotypic plasticity of cells, while aberrant epigenetic regulation through genetic mutations and/or misregulated expression of epigenetic factors leads to aberrant cell fate determination, which provides a foundation for oncogenic transformation. Lysine-specific demethylase-1 (LSD1, KDM1A) removes methyl groups from methylated proteins, including histone H3, and is frequently overexpressed in various types of solid tumor and hematopoietic neoplasm. While LSD1 is involved in a wide variety of normal physiological processes, including stem cell maintenance and differentiation, it is also a key player in oncogenic processes, including compromised differentiation, enhanced cell motility and metabolic reprogramming. Here, we present an overview of how LSD1 epigenetically regulates cellular plasticity through distinct molecular mechanisms in different biological contexts. Targeted inhibition of the context-dependent activities of LSD1 may provide a highly selective means to eliminate cancer cells.

This article is protected by copyright. All rights reserved.

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Co-design of mHealth Delivered Interventions: A Systematic Review to Assess Key Methods and Processes

Abstract

Most mobile health (mHealth) programmes are designed with minimal input from target end users and are not truly personalised or adaptive to their specific and evolving needs. This review describes the methods and processes used in the co-design of mHealth interventions. Nine relevant studies of varying design were identified following searches of six academic databases. All employed co-design or participatory methods for the development of a health intervention delivered via a mobile device, with three focusing on health behaviour change (one on nutrition) and six on management of a health condition. Overall, six key phases of design and 17 different methods were used. Sufficiency of reporting was poor, and no study undertook a robust assessment of efficacy; these factors should be a focus for future studies. An opportunity exists to use co-design methods to develop acceptable and feasible mHealth interventions, especially to support improved nutrition and for minority and indigenous groups.

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