TGF-β Superfamily Receptors—Targets for Antiangiogenic Therapy?

The TGF-β pathway controls a broad range of cellular behavior including cell proliferation, differentiation, and apoptosis of various cell types including tumor cells, endothelial cells, immune cells, and fibroblasts. Besides TGF-β's direct effects on tumor growth and its involvement in neoangiogenesis have received recent attention. Germline mutations in TGF-β receptors or coreceptors causing Hereditary Hemorrhagic Teleangiectasia and the Loeys-Dietz syndrome underline the involvement of TGF-β in vessel formation and maturation. Several therapeutic approaches are evaluated at present targeting the TGF-β pathway including utilization of antisense oligonucleotides against TGF-β itself or antibodies or small molecule inhibitors of TGF-β receptors. Some of these therapeutic agents have already entered the clinical arena including an antibody against the endothelium specific TGF-β class I receptor ALK-1 targeting tumor vasculature. In conclusion, therapeutic manipulation of the TGF-β pathway opens great opportunities in future cancer therapy

How does spirituality manifest in family caregivers of terminally ill cancer patients? A qualitative secondary analysis

OBJECTIVE Considering the risk of spiritual distress among terminally ill patients, experts long agree that spiritual care has to be an integral component of palliative care. Despite this consensus, the role of spirituality among family caregivers remains largely unexplored. We aimed to describe how spirituality manifests in the lived experience of family caregivers (FCs) in a palliative care context. METHOD As part of a secondary analysis, data derived from two qualitative primary studies on FCs' burdens and needs in the context of caring for a patient with a diagnosis of incurable cancer. Previously transcribed interviews were examined by means of a thematic analysis, transcending the focus of the primary studies to examine how spirituality arises and/or persists in the life of FCs from the time of diagnosis of incurable cancer up until bereavement. RESULTS Twenty-nine narratives were explored and all included spirituality as a relevant theme. Analysis revealed four aspects associated with the presence of spirituality among FCs' experiences: \textquotedblConnectedness,\textquotedbl \textquotedblReligious Faith,\textquotedbl \textquotedblTranscendence,\textquotedbl \textquotedblHope,\textquotedbl and a fifth overarching aspect which we named \textquotedblOngoing integration of spiritual experience.\textquotedbl Spirituality appeared as a multilayered phenomenon and was shaped individually among FCs' narratives. SIGNIFICANCE OF RESULTS In view of the results, exploring and discussing spirituality and underlying experiences in the situation as an FC seems likely to widen the perspective on FCs' problems and needs. Further research on spiritual needs among FCs of patients with incurable life-limiting cancer is deemed necessary

Primary NK/T cell lymphoma nasal type of the stomach with skin involvement: a case report

Since nasal NK/T cell lymphoma and NK/T cell lymphoma nasal type are rare diseases, gastric involvement has seldom been seen. We report a unique case of a patient with a primary NK/T cell lymphoma nasal type of the stomach with skin involvement. The patient had no history of malignant diseases and was diagnosed with hematemesis and intense bleeding from his gastric primary site. Shortly after this event, exanthemic skin lesions appeared with concordant histology to the primary site. Despite chemotherapy, the patient died one month after the first symptomatic appearance of disease

Cetuximab every 2 weeks versus standard weekly dosing administration schedule

Dosing schedule; Efficacy; PharmacokineticsPrograma de dosificació; Eficàcia; FarmacocinèticaPrograma de dosificación; Eficacia; FarmacocinéticaCetuximab every 2 weeks (Q2W) dosing schedule is approved by the US FDA and by the Japanese Pharmaceuticals and Medical Devices Agency in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Phase II trials have found comparable efficacy and safety for the weekly (Q1W) and Q2W schedules, and real-world studies have shown noninferiority of the Q2W compared with the Q1W schedule. Several guidelines recommend cetuximab Q2W administration as an alternative to the Q1W dosing schedule. Cetuximab Q2W can be administered with a Q2W dose of chemotherapy, making it a more convenient option to the Q1W schedule, potentially resulting in reduced costs for administration, increased flexibility for clinical staff and improved patient adherence

Symptom burden in palliative care patients: perspectives of patients, their family caregivers, and their attending physicians

Abstract Rationale The purpose of this study was to prospectively evaluate the perspectives of palliative care patients, their family caregivers, and their attending palliative care specialists on frequency, intensity, distress, and treatment requirement of the patient's physical and psychological symptoms. Patients and methods Forty advanced cancer patients and their family caregivers were recruited through a palliative care inpatient ward within 24 h after admission. Patients, caregivers, and physicians completed a modified version of the Memorial Symptom Assessment Scale (including perceived treatment requirement). Results Thirty-nine patients (98 %) suffered from at least one symptom frequently or almost constantly (median number 5; range, 0-9). Most frequent symptoms were lack of energy (95 %), tiredness (88 %), and pain (80 %), which were scored correspondingly by patients, caregivers, and physicians to be the most intensive, distressing, and treatment requiring. Treatment requirement was determined by symptom intensity or distress in patients and physicians, but by distress in caregivers. Significant differences in symptom burden between patients, caregivers, and physicians were found with regard to pain (p=.007), tiredness (p=.037), lack of energy (p<.05), anxiety (p<.05), and sadness (p<.05). Physicians underestimated 60 % of symptom dimensions, while the caregivers overestimated 77 %; however, overall median scoring differences were limited with −.10 (range, −.55 to +.25) between patients and physicians and +.33 (range, −.78 to +.61) between patients and family caregivers. Conclusions While physicians tended to underestimate, family caregivers tended to overestimate the patient's symptoms. Therefore, adequate symptom treatment can only be successful in a close dialog between patients, their caregivers, and a multidisciplinary team

Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by inhibition of FAK/src/AKT pathway

<p>Abstract</p> <p>Background</p> <p>The antiangiogenic agent cilengitide disrupts integrin binding to the extracellular matrix leading to apoptosis of activated endothelial cells. Integrins are also widely expressed in malignant glioma and integrin inhibitors may directly target tumor cells in this disease. Aim of the current study was to investigate effects of cilengitide on endothelial and glioma cells on molecular and cellular levels.</p> <p>Results</p> <p>Cilengitide caused dose-dependent detachment of endothelial cells from cell culture dishes. Proliferation of endothelial cells was significantly inhibited while the proportion of apoptotic cells was increased. Incubation of integrin-expressing glioma cells with cilengitide caused rounding and detachment after 24 hours as observed with endothelial cells. Cilengitide inhibited proliferation and induced apoptosis in glioma cells with methylated MGMT promotor when given alone or in combination with temozolomide. In endothelial as well as glioma cells cilengitide inhibited phosphorylation of FAK, Src and Akt. Assembly of cytoskeleton and tight junctions was heavily disturbed in both cell types.</p> <p>Conclusion</p> <p>Cilengitide inhibits integrin-dependent signaling, causes disassembly of cytoskeleton, cellular detachment and induction of apoptosis in endothelial and glioma cells thereby explaining the profound activity of integrin inhibitors in gliomas. The combination of cilengitide with temozolomide exerted additive effects in glioma cells as observed clinically.</p

Micro-RNA expression in cisplatin resistant germ cell tumor cell lines

<p>Abstract</p> <p>Background</p> <p>We compared microRNA expression patterns in three cisplatin resistant sublines derived from paternal cisplatin sensitive germ cell tumor cell lines in order to improve our understanding of the mechanisms of cisplatin resistance.</p> <p>Methods</p> <p>Three cisplatin resistant sublines (NTERA-2-R, NCCIT-R, 2102EP-R) showing 2.7-11.3-fold increase in drug resistance after intermittent exposure to increasing doses of cisplatin were compared to their parental counterparts, three well established relatively cisplatin sensitive germ cell tumor cell lines (NTERA-2, NCCIT, 2102EP). Cells were cultured and total RNA was isolated from all 6 cell lines in three independent experiments. RNA was converted into cDNA and quantitative RT-PCR was run using 384 well low density arrays covering almost all (738) known microRNA species of human origin.</p> <p>Results</p> <p>Altogether 72 of 738 (9.8%) microRNAs appeared differentially expressed between sensitive and resistant cell line pairs (NTERA-2R/NTERA-2 = 43, NCCIT-R/NCCIT = 53, 2102EP-R/2102EP = 15) of which 46.7-95.3% were up-regulated (NTERA-2R/NTERA-2 = 95.3%, NCCIT-R/NCCIT = 62.3%, 2102EP-R/2102EP = 46.7%). The number of genes showing differential expression in more than one of the cell line pairs was 34 between NTERA-2R/NTERA-2 (79%) and NCCIT-R/NCCIT (64%), and 3 and 4, respectively, between these two cell lines and 2102EP-R/2102EP (about 27%). Only the has-miR-10b involved in breast cancer invasion and metastasis and has-miR-512-3p appeared to be up-regulated (2-3-fold) in all three cell lines. The hsa-miR-371-373 cluster (counteracting cellular senescence and linked with differentiation potency), as well as hsa-miR-520c/-520h (inhibiting the tumor suppressor p21) were 3.9-16.3 fold up-regulated in two of the three cisplatin resistant cell lines. Several new micro-RNA species missing an annotation towards cisplatin resistance could be identified. These were hsa-miR-512-3p/-515/-517/-518/-525 (up to 8.1-fold up-regulated) and hsa-miR-99a/-100/-145 (up to 10-fold down-regulated).</p> <p>Conclusion</p> <p>Examining almost all known human micro-RNA species confirmed the miR-371-373 cluster as a promising target for explaining cisplatin resistance, potentially by counteracting wild-type P53 induced senescence or linking it with the potency to differentiate. Moreover, we describe for the first time an association of the up-regulation of micro-RNA species such as hsa-miR-512-3p/-515/-517/-518/-525 and down-regulation of hsa-miR-99a/-100/-145 with a cisplatin resistant phenotype in human germ cell tumors. Further functional analyses are warranted to gain insight into their role in drug resistance.</p